EP4561624A1 - Méthodes de traitement de patients atteints d'un cancer urothélial localement avancé ou métastatique avec des conjugués anticorps-médicament (cam) qui se lient à des protéines 191p4d12 en combinaison avec du pembrolizumab - Google Patents

Méthodes de traitement de patients atteints d'un cancer urothélial localement avancé ou métastatique avec des conjugués anticorps-médicament (cam) qui se lient à des protéines 191p4d12 en combinaison avec du pembrolizumab

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Publication number
EP4561624A1
EP4561624A1 EP23847474.6A EP23847474A EP4561624A1 EP 4561624 A1 EP4561624 A1 EP 4561624A1 EP 23847474 A EP23847474 A EP 23847474A EP 4561624 A1 EP4561624 A1 EP 4561624A1
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EP
European Patent Office
Prior art keywords
population
subject
treated
subjects
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP23847474.6A
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German (de)
English (en)
Inventor
Anne-Sophie Carret
Oyewale O. ABIDOYE
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Merck Sharp and Dohme LLC
Agensys Inc
Seagen Inc
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Merck Sharp and Dohme LLC
Agensys Inc
Seagen Inc
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Application filed by Merck Sharp and Dohme LLC, Agensys Inc, Seagen Inc filed Critical Merck Sharp and Dohme LLC
Publication of EP4561624A1 publication Critical patent/EP4561624A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6861—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from kidney or bladder cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • ADC antibody drug conjugates
  • 191P4D12 (which is also known as Nectin-4) is a 66 kDa type I transmembrane protein that belongs to the nectin family of adhesion molecules. It is composed of an extracellular domain (ECD) containing 3 immunoglobulin (Ig)-like subdomains, a transmembrane helix, and an intracellular region (Takai et al., Annu Rev Cell Dev Biol (2008); 24: 309-42).
  • ECD extracellular domain
  • Ig immunoglobulin
  • Nectins are thought to mediate Ca 2+ -independent cell-cell adhesion via both homophilic and heterophilic trans-interactions at adherens junctions where they can recruit cadherins and modulate cytoskeletal rearrangements (Rikitake et al., Cell Mol Life Sci (2008); 65(2): 253-63.). Sequence identity of Nectin-4 to other Nectin family members is low and ranges between 25%–30% in the ECD (Reymond et al., Biol Chem (2001); 276(46): 43205-15). [0007] The 3 Ig-like subdomains in the ECD of Nectin-4 are designated V, C1 and C2.
  • Nectin-4 was originally identified by bioinformatics and cloned from human trachea (Reymond et al., J Biol Chem (2001) 276(46): 43205-15.).
  • Nectin-4 was identified as markedly upregulated in urothelial cancer using suppression subtractive hybridization on a pool of urothelial cancer specimens. Characterization of expression in multiple tumor specimens, both at the ribonucleic acid (RNA) level and by immunohistochemistry (IHC), also demonstrated high levels of Nectin-4 in breast, pancreatic, lung, and other cancers (Challita-Eid et al., Cancer Res (2016); 76(10): 3003-13.). [0009] Nectin-4 has been found to be expressed in multiple cancers, particularly urothelial, breast, lung, pancreatic, and ovarian cancers.
  • PD-1 is recognized as an important molecule in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe, Arlene H. et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology (2007); 8:239-245).
  • B7-H1 Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues.
  • B7-DC Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC)
  • B7-DC Two known ligands for PD-1, PD-L1 (B7-DC), are expressed in human cancers arising in various tissues.
  • PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment (Dong, Haidong et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
  • Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.
  • IgG4 immunoglobulin G4
  • pembrolizumab is indicated for the treatment of patients across a number of indications and is indicated for the first-line treatment of patients with unresectable or metastatic CRC that is microsatellite instability-high or mismatch repair deficient (MSI-H/dMMR).
  • Pembrolizumab is the current standard of care for first line MSI- H/dMMR mCRC.
  • IARC International Agency for Research on Cancer
  • urothelial cancer kills more than 165000 patients annually and is the ninth most common cancer overall worldwide. Approximately 151000 new cases of urothelial cancer are diagnosed annually in Europe, with 52000 deaths per year.
  • Urothelial cancer is the most common type of bladder cancer (90 percent of cases), and can also be found in the urothelial cells that line the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.
  • First-line therapy for metastatic urothelial cancer in patients with sufficient renal function consists of cis-diamminedichloroplatinum (II) (cisplatin)-based combinations, like methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine plus cisplatin, which demonstrate an objective response rate (ORR) up to 55%, including approximately 12% complete responses (CRs) (von der Maase 2000).
  • ORR objective response rate
  • CRs complete responses
  • Pembrolizumab (Keytruda®) received accelerated approval from the FDA in May 2017 as first line treatment for patients with la/mUC ineligible for cisplatin. The study on which approval was based resulted in an ORR of 29% and median response duration not reached at the time of the analysis (median follow-up time of 7.8 months) (Pembrolizumab Prescribing Information, Merck Sharp and Dohme Corp., 2017).
  • first line cisplatin-ineligible patients typically include carboplatin-based regimens or single-agent taxane or gemcitabine (Cathomas et al., Hematol Oncol Clin North Am (2015); 29(2): 329-40.).
  • gemcitabine Cathomas et al., Hematol Oncol Clin North Am (2015); 29(2): 329-40.
  • Few options are available for second-line treatment of metastatic disease.
  • the small-molecule tubulin inhibitor vinflunine (Javlor®) was authorized in 2009 based on modest activity (overall response rate 9%), moderate survival benefit of 2 months (6.9 months for vinflunine + best supportive care (BSC) vs 4.6 months for BSC alone, hazard ratio 0.88), and a favorable safety profile (Bellmunt et al.
  • PD-1 and PD-L1 inhibitors are currently being evaluated in clinical trials for urothelial cancer, as first and second-line therapy (Mullane et al., Curr Opin Urol (2016);26(6): 556-63).
  • CPIs offer a new approach to treatment of metastatic urothelial cancer, tumor responses have occurred in a minority of patients and the improvement in long-term survival is only a few months.
  • bladder cancer represents approximately 5 percent in men (fifth most common neoplasm) and 3 percent in women (eighth most common neoplasm). The incidence is increasing slowly, concurrent with an increasing older population.
  • American Cancer Society cancer.org estimates that there are 81,400 new cases annually, including 62,100 in men and 19,300 in women, which accounts for 4.5% of all cancer cases. The age-adjusted incidence in the United States is 20 per 100,000 for men and women.
  • bladder cancer There are an estimated 17,980 deaths from bladder cancer in annually (13,050 in men and 4,930 in women), which accounts for 3% of cancer related deaths. Bladder cancer incidence and mortality strongly increase with age and will be an increasing problem as the population becomes more elderly. Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020, and bladder cancer will be attributed to approximately 210,000 deaths worldwide. [0027] Most bladder cancers recur in the bladder. Bladder cancer is managed with a combination of transurethral resection of the bladder (TUR) and intravesical chemotherapy or immunotherapy. The multifocal and recurrent nature of bladder cancer points out the limitations of TUR. Most muscle-invasive cancers are not cured by TUR alone.
  • Radical cystectomy and urinary diversion is the most effective means to eliminate the cancer but carry an undeniable impact on urinary and sexual function.
  • treatment modalities that are beneficial for bladder cancer patients.
  • additional therapeutic methods for urothelial and bladder cancers include the use of antibodies and antibody drug conjugates, including in combination with other agents, as treatment modalities. 3. Summary [0029] Provided herein are methods for the treatment of various cancers in human subjects, including methods for treating patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy with antibody drug conjugates (ADC) that bind to 191P4D12 proteins in combination with pembrolizumab.
  • ADC antibody drug conjugates
  • the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment and has not received previous treatment with an immune checkpoint inhibitor (CPI) (e.g., a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab)).
  • CPI immune checkpoint inhibitor
  • a method of treating cancer in a human subject comprising administering to the subject: (a) an effective amount of an antibody drug conjugate (ADC) comprising an anti- 191P4D12 antibody or antigen binding fragment thereof and (b) an effective amount of an anti-PD-1 antibody; wherein the anti-191P4D12 antibody or antigen binding fragment thereof binds to 191P4D12 and is conjugated to one or more units of monomethyl auristatin E (MMAE); wherein the anti-PD-1 antibody comprises: (i) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 24, 25 and 26, respectively and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 29, 30 and 31, respectively; wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region
  • Embodiment 2 The method of embodiment 1, wherein the subject has visceral metastases.
  • Embodiment 3. The method of embodiment 1, wherein the subject has lymph nodes only disease.
  • Embodiment 4. The method of any one of embodiments 1 to 3, wherein the disease site of origin is in the upper tract.
  • Embodiment 5. The method of any one of embodiments 1 to 3, wherein the disease site of origin is in the lower tract.
  • Embodiment 6. The method of any one of embodiments 1 to 5, wherein the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10.
  • CPS PD-L1 expression combined positive score
  • Embodiment 8 The method of any one of embodiments 1 to 6, wherein the subject has a Nectin-4 H-score between 0 and 300.
  • Embodiment 9. The method of any one of embodiments 1 to 7, wherein the subject has a Nectin-4 H-score between 0 and 200.
  • Embodiment 10. The method of any one of embodiments 1 to 9, wherein the subject has an ECOG performance status score of 1 to 2. [0041] Embodiment 11.
  • Embodiment 12 The method of any one of embodiments 1 to 9, wherein the subject has one or more of the conditions selected from the group consisting of: ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss.
  • Embodiment 12 The method of any one of embodiments 1 to 9, wherein the subject has NYHA Class III heart failure.
  • Embodiment 13 The method of embodiment 11, wherein the subject has an ECOG performance status score of 2, and wherein the subject (i) has hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • Embodiment 14 The method of embodiment 14, wherein the subject (i) has hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • Embodiment 15 The method of embodiment 11, wherein the impaired renal function is determined by CrCl less than 60 but no less than 30 mL/min.
  • Embodiment 16 The method of embodiment 11, wherein the impaired renal function is determined by CrCl less than 30 but no less than 15 mL/min.
  • Embodiment 19 The method of any one of embodiments 14 to 18, wherein the CrCl is measured by 24 hour urine collection or estimated by the Cockcroft-Gault criteria.
  • Embodiment 20 The method of any one of embodiments 1 to 19, wherein the subject has no more than Grade 2 sensory or motor neuropathy.
  • Embodiment 21 The method of any one of embodiments 1 to 20, wherein the subject has no active central nervous system metastases.
  • Embodiment 22 The method of any one of embodiments 1 to 21, wherein the subject has no uncontrolled diabetes. [0053] Embodiment 23.
  • Embodiment 24 The method of embodiment 23, wherein the associated diabetes symptoms comprise or consist of polyuria, polydipsia, or both polyuria and polydipsia.
  • Embodiment 25 The method of any one of embodiments 1 to 24, wherein the subject has locally advanced or metastatic urothelial cancer.
  • Embodiment 26 The method of any one of embodiments 1 to 25, wherein the subject has locally advanced or metastatic bladder cancer.
  • Embodiment 27 Embodiment 27.
  • the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, CDR-H2 comprising the amino acid sequence of SEQ ID NO:10, CDR-H3 comprising the amino acid sequence of SEQ ID NO:11; CDR-L1 comprising the amino acid sequence of SEQ ID NO:12, CDR-L2 comprising the amino acid sequence of SEQ ID NO:13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:14, or wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:16, CDR-H2 comprising the amino acid sequence of SEQ ID NO:17, CDR-H3 comprising the amino acid sequence of SEQ ID NO:18; CDR-L1 comprising the amino acid sequence of SEQ ID NO:19, CDR-L2 comprising the amino acid sequence of SEQ ID NO:
  • Embodiment 28 The method of any one of embodiments 1 to 26, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR-H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR-H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR- L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR-L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO:14, or wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR-L1 consisting of the amino acid sequence of SEQ ID NO:9,
  • Embodiment 29 The method of any one of embodiments 1 to 28, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.
  • Embodiment 30 The method of any one of embodiments 1 to 28, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.
  • the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
  • Embodiment 31 The method of any one of embodiments 1 to 30, wherein the anti-191P4D12 antigen binding fragment is an Fab, F(ab′)2, Fv or scFv.
  • Embodiment 32 Embodiment 32.
  • Embodiment 33 The method of any one of embodiments 1 to 30 and 32, wherein the anti-191P4D12 antibody is an IgG1 and light chain is a kappa light chain
  • Embodiment 34 The method of any one of embodiments 1 to 33, wherein the anti-191P4D12 antibody or antigen binding fragment thereof is recombinantly produced.
  • Embodiment 35 The method of any one of embodiments 1 to 34, wherein the anti-191P4D12 antibody or antigen binding fragment is conjugated to each unit of MMAE via a linker.
  • Embodiment 36 The method of embodiment 35, wherein the linker is an enzyme-cleavable linker, and wherein the linker forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof.
  • Embodiment 37 The method of embodiment 35 or 36, wherein the linker has a formula of: –Aa–Ww–Yy–; wherein –A– is a stretcher unit, a is 0 or 1; –W– is an amino acid unit, w is an integer ranging from 0 to 12; and –Y– is a spacer unit, y is 0, 1, or 2.
  • Embodiment 38 Embodiment 38.
  • Embodiment 39 The method of embodiment 37 or 38, wherein the stretcher unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof; and wherein the spacer unit is linked to MMAE via a carbamate group.
  • Embodiment 40 The method of any one of embodiments 1 to 39, wherein the ADC comprises from 1 to 20 units of MMAE per antibody or antigen binding fragment thereof.
  • Embodiment 41 Embodiment 41.
  • Embodiment 42 The method of any one of embodiments 1 to 41, wherein the ADC comprises from 2 to 8 units of MMAE per antibody or antigen binding fragment thereof.
  • Embodiment 43 The method of any one of embodiments 1 to 42, wherein the ADC comprises from 3 to 5 units of MMAE per antibody or antigen binding fragment thereof.
  • Embodiment 44 The method of any one of embodiments 1 to 43, wherein the ADC has the following structure: wherein L- represents the anti-191P4D12 antibody or antigen binding fragment thereof and p is from 1 to 10.
  • Embodiment 45 The method of embodiment 44, wherein p is from 2 to 8.
  • Embodiment 46 The method of embodiment 44 or 45, wherein p is from 3 to 5.
  • Embodiment 47 The method of any one of embodiments 44 to 46, wherein p is from 3 to 4.
  • Embodiment 48 The method of any one of embodiments 44 to 47, wherein p is about 4.
  • Embodiment 49 The method of any one of embodiments 44 to 47, wherein the average p value of the effective amount of the antibody drug conjugates is about 3.8.
  • Embodiment 50 Embodiment 50.
  • Embodiment 52 The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1 mg/kg of the subject’s body weight.
  • Embodiment 53 The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1 mg/kg of the subject’s body weight.
  • Embodiment 54 The method of any one of embodiments 1 to 53, wherein the ADC is administered to the subject by an intravenous (IV) injection or infusion.
  • Embodiment 55 The method of any one of embodiments 1 to 54, wherein the ADC is administered to the subject by an IV injection or infusion up to 2 days of a 21-day treatment cycle.
  • Embodiment 56 The method of any one of embodiments 1 to 55, wherein the ADC is administered to the subject by an IV injection or infusion on days 1 and 8 of a 21-day treatment cycle.
  • Embodiment 57 The method of any one of embodiments 1 to 56, wherein the ADC is administered to the subject by an IV injection or infusion over about 30 minutes up to 2 days of a 21-day treatment cycle.
  • Embodiment 58 The method of any one of embodiments 1 to 57, wherein the ADC is administered by an IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.
  • Embodiment 59 The method of any one of embodiments 1 to 58, wherein the ADC is formulated in a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20), and trehalose dehydrate.
  • Embodiment 60 Embodiment 60.
  • the ADC has the following structure: wherein L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4, the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg/kg of the subject’s body weight, and wherein the dose is administered by an IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.
  • L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4
  • the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino
  • Embodiment 63 The method of any one of embodiments 1 to 60, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 100 mg to about 400 mg.
  • Embodiment 64 The method of any one of embodiments 1 to 61, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg.
  • Embodiment 65 The method of embodiment 62, wherein: (a) the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.
  • Embodiment 66 Embodiment 66.
  • Embodiment 67 The method of any one of embodiments 1 to 66, wherein the anti-PD-1 antibody is administered to the subject by an IV infusion on day 1 in each treatment cycle of 21 days.
  • Embodiment 68 The method of any one of embodiments 1 to 67, wherein the anti-PD-1 antibody is administered to the subject by an IV infusion over about 30 minutes on 1 day of the 21-day treatment cycle.
  • Embodiment 69 Embodiment 69.
  • Embodiment 70 The method of any one of embodiments 1 to 69, whereby the subject has a complete response following the treatment.
  • Embodiment 71 The method of any one of embodiments 1 to 69, wherein the subject has a partial response following the treatment.
  • Embodiment 72 The method of any one of embodiments 1 to 69, wherein the subject has a complete response or a partial response following the treatment.
  • Embodiment 73 The method of any one of embodiments 1 to 69, wherein the subject has a complete response or a partial response following the treatment.
  • Embodiment 74 The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 6 months following the treatment.
  • Embodiment 75 The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 12 months following the treatment.
  • Embodiment 76 The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 24 months following the treatment.
  • Embodiment 77 The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 24 months following the treatment.
  • Embodiment 81 The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 27 months following the treatment.
  • Embodiment 78 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 6 months following the treatment.
  • Embodiment 79 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 8 months following the treatment.
  • Embodiment 80 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 12 months following the treatment.
  • Embodiment 81 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 12 months following the treatment.
  • Embodiment 85 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 20 months following the treatment.
  • Embodiment 82 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 29 months following the treatment.
  • Embodiment 83 The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least or about 22 months following the treatment.
  • Embodiment 84 The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least or about 27 months following the treatment.
  • Embodiment 85 The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least or about 20 months following the treatment.
  • Embodiment 82 The method of any one of embodiments 1 to 69, wherein the subject has a progression free survival of at least or about 29 months following the treatment.
  • Embodiment 83 The method of any
  • Embodiment 86 The method of any one of embodiments 1 to 69, wherein the subject has a overall survival of at least or about 30 months following the treatment.
  • Embodiment 86 The method of any one of embodiments 1 to 69, wherein the subject has an overall survival ranging from 19 to 25 months following the treatment.
  • Embodiment 87 The method of any one of embodiments 1 to 69, wherein the subject has an overall survival ranging from 28 to 32 months following the treatment.
  • Embodiment 88 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein percentage of the subjects having complete response in the treated population is at least or about 10%.
  • Embodiment 89 Embodiment 89.
  • Embodiment 90 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein objective response rate in the treated population is at least or about 65%.
  • Embodiment 91 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein objective response rate in the treated population ranges from 53% to 75%.
  • Embodiment 92 Embodiment 92.
  • Embodiment 95 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein percentage of the subjects having stable disease in the treated population is at least or about 22%.
  • Embodiment 93 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein duration of response in the treated population is at least or about 6 months.
  • Embodiment 94 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein duration of response in the treated population is at least or about 12 months.
  • Embodiment 95 Embodiment 95.
  • Embodiment 96 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein duration of response in the treated population is at least or about 24 months.
  • Embodiment 96 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein duration of response in the treated population is at least or about 27 months.
  • Embodiment 97 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein progression free survival in the treated population is at least or about 6 months.
  • Embodiment 98 Embodiment 98.
  • Embodiment 101 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein progression free survival in the treated population is at least or about 12 months.
  • Embodiment 99 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein progression free survival in the treated population is at least or about 20 months.
  • Embodiment 100 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein progression free survival in the treated population is at least or about 29 months.
  • Embodiment 101 Embodiment 101.
  • Embodiment 104 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 22 months.
  • Embodiment 102 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 27 months.
  • Embodiment 103 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 30 months.
  • Embodiment 104 Embodiment 104.
  • Embodiment 105 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein overall survival in the treated population ranges from 19 to 25 months.
  • Embodiment 105 The method of any one of embodiments 1 to 69, wherein a population of the subjects is treated by the methods, and wherein overall survival in the treated population ranges from 30 to 32 months.
  • Embodiment 106 The method of any one of embodiments 1 to 70 and 72, wherein the complete response rate is at least or about 10% for a population of subjects treated with the method.
  • Embodiment 107 Embodiment 107.
  • Embodiment 108 The method of any one of embodiments 1 to 72, wherein objective response rate is at least or about 65% for a population of subjects treated with the method.
  • Embodiment 109 The method of any one of embodiments 1 to 72, wherein objective response rate is from 53% to 75% for a population of subjects treated with the method.
  • Embodiment 110 The method of any one of embodiments 1 to 69 and 73, wherein the stable disease rate is at least or about 22% for a population of subjects treated with the method.
  • Embodiment 111 The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least or about 6 months for a population of subjects treated with the method.
  • Embodiment 112. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least or about 12 months for a population of subjects treated with the method.
  • Embodiment 113. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least or about 24 months for a population of subjects treated with the method.
  • Embodiment 114 Embodiment 114.
  • Embodiment 115 The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression free survival is at least or about 6 months for a population of subjects treated with the method.
  • Embodiment 116 The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression free survival is at least or about 12 months for a population of subjects treated with the method.
  • Embodiment 117 The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression free survival is at least or about 12 months for a population of subjects treated with the method.
  • Embodiment 120 The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression free survival is at least or about 20 months for a population of subjects treated with the method.
  • Embodiment 118 The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression free survival is at least or about 29 months for a population of subjects treated with the method.
  • Embodiment 119 The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 22 months for a population of subjects treated with the method.
  • Embodiment 120 The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 22 months for a population of subjects treated with the method.
  • Embodiment 121 The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 27 months for a population of subjects treated with the method.
  • Embodiment 121 The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 30 months for a population of subjects treated with the method.
  • Embodiment 122 The method of any one of embodiments 1 to 69, 79, and 80, wherein the overall survival is from 19 to 25 months for a population of subjects treated with the method.
  • Embodiment 123 Embodiment 123.
  • FIGS.1A-1E depict the nucleotide and amino acid sequences of nectin-4 protein (FIG.1A), the nucleotide and amino acid sequences of the heavy chain (FIG.1B) and light chain (FIG.1C) of Ha22-2(2.4)6.1, and the amino acid sequences of the heavy chain (FIG. 1D) and light chain of Ha22-2(2.4)6.1 (FIG.1E).
  • FIG.2 depicts the overall study design of the clinical study described in Section 6.1.
  • FIG.3 depicts the study stages of the clinical study, which is a phase 1b/2 study of enfortumab vedotin combined with pembrolizumab as first-line treatment in patients with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are unable to receive cisplatin-based chemotherapy, as described in Section 6.1.
  • FIG.4 depicts the European Organization for the Research and Treatment (EORTC) Core Quality of Life (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, Version 3), as described in Section 6.1.
  • FIG.5 depicts the EuroQol-5 Dimensions (EQ-5D-5L) described in Section 6.1.
  • FIG.6 depicts tumor reduction (i.e., tumor size (% change from baseline)) for individual patients in the clinical study, as described in Section 6.1.
  • FIG.7 depicts the percent change from baseline in sum of diameters of target lesions over time (in months) per blinded independent central review in the clinical study, as described in Section 6.1.
  • FIG.8 depicts ORR subgroup analysis of patients administered a combination of enfortumab vedotin and pembrolizumab (i.e., the EV+pembro arm) in the clinical study described in Section 6.1.
  • FIG.9 depicts ORR subgroup analysis of patients administered enfortumab vedotin monotherapy (i.e., the EV Mono arm) in the clinical study described in Section 6.1.
  • FIG.10 depicts the H-score of Nectin-4 expression at baseline and best response per blinded independent central review in the clinical study, as described in Section 6.1.
  • FIG.11 depicts the H-score of Nectin-4 expression at baseline and best overall response per blinded independent central review in the clinical study, as described in Section 6.1.
  • FIG.12 depicts duration of response (DOR) per blinded independent central review in the clinical study described in Section 6.1.
  • FIG.13 depicts progression-free survival per blinded independent central review in the clinical study described in Section 6.1.
  • FIG.14 depicts overall survival in the clinical study described in Section 6.1.
  • FIG.15 depicts duration of response (DOR) per blinded independent central review in the clinical study described in Section 6.2.
  • FIG.16 depicts progression-free survival per blinded independent central review in the clinical study described in Section 6.2.
  • FIG.17 depicts overall survival in the clinical study described in Section 6.2. 5.
  • antibody immunoglobulin
  • Ig immunoglobulin
  • monoclonal antibodies including agonist, antagonist, neutralizing antibodies, full length or intact monoclonal antibodies
  • antibody compositions with polyepitopic or monoepitopic specificity polyclonal or monovalent antibodies
  • multivalent antibodies multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity)
  • An antibody can be human, humanized, chimeric and/or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc.
  • antibody is intended to include a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed.1995); and Kuby, Immunology (3d ed.1997).
  • the specific molecular antigen can be bound by an antibody provided herein, including a polypeptide or an epitope.
  • Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived.
  • Non-limiting examples of functional fragments include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab) 2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody.
  • antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen- binding site that binds to an antigen (e.g., one or more CDRs of an antibody).
  • an antigen e.g., one or more CDRs of an antibody.
  • antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Plückthun and Skerra, 1989, Meth. Enzymol.178:497-515; and Day, Advanced Immunochemistry (2d ed.1990).
  • the antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule.
  • Antibodies may be agonistic antibodies or antagonistic antibodies.
  • the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • An “antigen” is a structure to which an antibody can selectively bind.
  • a target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound.
  • the target antigen is a polypeptide.
  • an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.
  • an “intact” antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CH1, CH2 and CH3.
  • the constant regions may include human constant regions or amino acid sequence variants thereof.
  • an intact antibody has one or more effector functions.
  • the terms “antigen binding fragment,” “antigen binding domain,” “antigen binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDRs).
  • Antigen-binding fragment as used herein include “antibody fragment,” which comprise a portion of an intact antibody, such as the antigen-binding or variable region of the intact antibody.
  • antibody fragments include, without limitation, Fab, Fab’, F(ab’)2, and Fv fragments; diabodies and di-diabodies (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci.90:6444-48; Lu et al., 2005, J. Biol. Chem.280:19665-72; Hudson et al., 2003, Nat. Med.9:129-34; WO 93/11161; and U.S. Pat.
  • binding refers to an interaction between molecules including, for example, to form a complex. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and/or van der Waals interactions. A complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as an antigen, is the affinity of the antibody or functional fragment for that epitope.
  • the ratio of dissociation rate (k off ) to association rate (k on ) of a binding molecule (e.g., an antibody) to a monovalent antigen (koff/kon) is the dissociation constant KD, which is inversely related to affinity.
  • KD dissociation constant
  • the value of K D varies for different complexes of antibody and antigen and depends on both k on and k off .
  • the dissociation constant K D for an antibody provided herein can be determined using any method provided herein or any other method well-known to those skilled in the art.
  • the affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen.
  • a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity.
  • the extent of binding of an antibody or antigen binding fragment to a “non-target” protein is less than about 10% of the binding of the binding molecule or antigen binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIA.
  • FACS fluorescence activated cell sorting
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target.
  • An antibody or antigen binding fragment that binds to an antigen includes one that is capable of binding the antigen with sufficient affinity such that the binding molecule is useful, for example, as a diagnostic agent in targeting the antigen.
  • an antibody or antigen binding fragment that binds to an antigen has a dissociation constant (KD) of less than or equal to 1000 nM, 800 nM, 500 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM.
  • KD dissociation constant
  • an antibody or antigen binding fragment binds to an epitope of an antigen that is conserved among the antigen from different species (e.g., between human and cyno species).
  • Binding affinity generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (K D ).
  • K D dissociation constant
  • Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer.
  • a variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. Specific illustrative embodiments include the following.
  • the “KD” or “KD value” may be measured by assays known in the art, for example by a binding assay.
  • the K D may be measured in a RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81).
  • the KD or KD value may also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by Octet®, using, for example, a Octet®QK384 system, or by Biacore®, using, for example, a Biacore®TM- 2000 or a Biacore®TM-3000.
  • an “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the Octet®QK384, the Biacore®TM-2000, or the Biacore®TM-3000 system.
  • BLI biolayer interferometry
  • SPR surface plasmon resonance
  • the antibodies or antigen binding fragments can comprise “chimeric” sequences in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55).
  • the antibodies or antigen binding fragments can comprise portions of “humanized” forms of nonhuman (e.g., murine) antibodies that are chimeric antibodies that include human immunoglobulins (e.g., recipient antibody) in which the native CDR residues are replaced by residues from the corresponding CDR of a nonhuman species (e.g., donor antibody) such as mouse, rat, rabbit, or nonhuman primate comprising the desired specificity, affinity, and capacity.
  • a nonhuman species e.g., donor antibody
  • humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • a humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the antibodies or antigen binding fragments can comprise portions of a “fully human antibody” or “human antibody,” wherein the terms are used interchangeably herein and refer to an antibody that comprises a human variable region and, for example, a human constant region. In specific embodiments, the terms refer to an antibody that comprises a variable region and constant region of human origin.
  • Fully human antibodies in certain embodiments, can also encompass antibodies which bind polypeptides and are encoded by nucleic acid sequences which are naturally occurring somatic variants of human germline immunoglobulin nucleic acid sequence.
  • the term “fully human antibody” includes antibodies comprising variable and constant regions corresponding to human germline immunoglobulin sequences as described by Kabat et al. (See Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242).
  • a “human antibody” is one that possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies.
  • Human antibodies can be produced using various techniques known in the art, including phage-display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol.227:381; Marks et al., 1991, J. Mol. Biol.222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1: 755-68). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al., 1991, J.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., mice (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol.6(5):561-66; Brüggemann and Taussing, 1997, Curr. Opin. Biotechnol.8(4):455-58; and U.S. Pat. Nos.6,075,181 and 6,150,584 regarding XENOMOUSE TM technology).
  • the antibodies or antigen binding fragments can comprise portions of a “recombinant human antibody,” wherein the phrase includes human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse or cow) that is transgenic and/or transchromosomal for human immunoglobulin genes (see e.g., Taylor, L.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • the antibodies or antigen binding fragments can comprise a portion of a “monoclonal antibody,” wherein the term as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts, and each monoclonal antibody will typically recognize a single epitope on the antigen.
  • a “monoclonal antibody,” as used herein is an antibody produced by a single hybridoma or other cell. The term “monoclonal” is not limited to any particular method for making the antibody.
  • the monoclonal antibodies useful in the present disclosure may be prepared by the hybridoma methodology first described by Kohler et al., 1975, Nature 256:495, or may be made using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No.4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol.222:581-97, for example.
  • Other methods for the preparation of clonal cell lines and of monoclonal antibodies expressed thereby are well-known in the art.
  • a typical 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgGs, the 4- chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges.
  • Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the ⁇ and ⁇ chains and four CH domains for ⁇ and ⁇ isotypes.
  • Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (CL) at its other end.
  • the VL is aligned with the VH
  • the CL is aligned with the first constant domain of the heavy chain (CH1).
  • Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.
  • the pairing of a VH and VL together forms a single antigen-binding site.
  • Fab refers to an antibody region that binds to antigens.
  • a conventional IgG usually comprises two Fab regions, each residing on one of the two arms of the Y-shaped IgG structure. Each Fab region is typically composed of one variable region and one constant region of each of the heavy and the light chain.
  • variable region and the constant region of the heavy chain in a Fab region are VH and CH1 regions
  • variable region and the constant region of the light chain in a Fab region are VL and CL regions.
  • the VH, CH1, VL, and CL in a Fab region can be arranged in various ways to confer an antigen binding capability according to the present disclosure.
  • VH and CH1 regions can be on one polypeptide
  • VL and CL regions can be on a separate polypeptide, similarly to a Fab region of a conventional IgG.
  • VH, CH1, VL and CL regions can all be on the same polypeptide and oriented in different orders as described in more detail in the sections below.
  • variable region refers to a portion of the light or heavy chains of an antibody that is generally located at the amino- terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen.
  • the variable region of the heavy chain may be referred to as “VH.”
  • the variable region of the light chain may be referred to as “VL.”
  • variable refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen.
  • variable regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” that are each about 9-12 amino acids long.
  • FRs framework regions
  • hypervariable regions that are each about 9-12 amino acids long.
  • the variable regions of heavy and light chains each comprise four FRs, largely adopting a ⁇ sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases form part of, the ⁇ sheet structure.
  • the hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed.1991)).
  • the constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
  • the variable regions differ extensively in sequence between different antibodies.
  • the variable region is a human variable region.
  • variable region residue numbering refers to the numbering system used for heavy chain variable regions or light chain variable regions of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, an FR or CDR of the variable domain.
  • a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 and three inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.
  • the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra).
  • the “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra).
  • the “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.
  • the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy-terminal portion includes a constant region.
  • the constant region can be one of five distinct types, (e.g., isotypes) referred to as alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ), and mu ( ⁇ ), based on the amino acid sequence of the heavy chain constant region.
  • the distinct heavy chains differ in size: ⁇ , ⁇ , and ⁇ contain approximately 450 amino acids, while ⁇ and ⁇ contain approximately 550 amino acids.
  • these distinct types of heavy chains give rise to five well-known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4.
  • the term “light chain” when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy-terminal portion includes a constant region.
  • the approximate length of a light chain is 211 to 217 amino acids.
  • ⁇ kappa
  • ⁇ lambda
  • the terms “hypervariable region,” “HVR,” “Complementarity Determining Region,” and “CDR” are used interchangeably.
  • CDR refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH ⁇ -sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL ⁇ -sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. [00194] CDR regions are well-known to those skilled in the art and have been defined by well-known numbering systems. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., supra).
  • Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol.196:901-17).
  • the end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol.2 (Kontermann and Dübel eds., 2d ed.2010)).
  • the “contact” hypervariable regions are based on an analysis of the available complex crystal structures.
  • Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information System ® (Lafranc et al., 2003, Dev. Comp. Immunol.27(1):55-77).
  • IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates.
  • CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain.
  • location of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody.
  • CDR complementary determining region
  • individual CDRs e.g., “CDR-H1, CDR-H2” of the antibody or region thereof
  • CDR-H1, CDR-H2 individual CDRs
  • the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, or Contact method. In other cases, the particular amino acid sequence of a CDR is given.
  • Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH.
  • the term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor.
  • the term refers to the portion of an immunoglobulin molecule comprising a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site.
  • the constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.
  • the term “framework” or “FR” refers to those variable region residues flanking the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
  • the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
  • a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations comprising a mixture of antibodies with and without the K447 residue.
  • a “functional Fc region” possesses an “effector function” of a native sequence Fc region.
  • exemplary “effector functions” include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor), etc.
  • effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or domain) and can be assessed using various assays known to those skilled in the art.
  • a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g., substituting, addition, or deletion).
  • the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, or from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of a parent polypeptide.
  • the variant Fc region herein can possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, or at least about 90% homology therewith, for example, at least about 95% homology therewith.
  • an “epitope” is a term in the art and refers to a localized region of an antigen to which a binding molecule (e.g., an antibody) can specifically bind.
  • An epitope can be a linear epitope or a conformational, non-linear, or discontinuous epitope.
  • an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope).
  • a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure.
  • a binding molecule binds to a group of amino acids regardless of whether they are folded in a natural three dimensional protein structure.
  • a binding molecule requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.
  • polypeptide and peptide and protein are used interchangeably herein and refer to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.
  • polypeptides containing one or more analogs of an amino acid including but not limited to, unnatural amino acids, as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure may be based upon antibodies or other members of the immunoglobulin superfamily, in certain embodiments, a “polypeptide” can occur as a single chain or as two or more associated chains.
  • pharmaceutically acceptable means being approved by a regulatory agency of the Federal or a state government, or listed in United States Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
  • Excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
  • a pharmaceutically acceptable excipient is an aqueous pH buffered solution.
  • MMAE monomethyl auristatin E.
  • a hyphen (-) designates the point of attachment to the pendant molecule.
  • Cyhemotherapeutic Agent refers to all chemical compounds that are effective in inhibiting tumor growth.
  • Non-limiting examples of chemotherapeutic agents include alkylating agents; for example, nitrogen mustards, ethyleneimine compounds and alkyl sulphonates; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, anti-tubulin agents such as vinca alkaloids, auristatins and derivatives of podophyllotoxin; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, for example, DNA minor groove binders; and growth factor receptor antagonists.
  • chemotherapeutic agents include cytotoxic agents (as defined herein), antibodies, biological molecules and small molecules.
  • substitutions of amino acids are known to those of skill in this art and may be made generally without altering the biological activity of the resulting molecule.
  • Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson, et al., MOLECULAR BIOLOGY OF THE GENE, The Benjamin/Cummings Pub. Co., p.224 (4th Edition 1987)).
  • Such exemplary substitutions are preferably made in accordance with those set forth in Table 2 and Table 3.
  • such changes include substituting any of isoleucine (I), valine (V), and leucine (L) for any other of these hydrophobic amino acids; aspartic acid (D) for glutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) and vice versa; and serine (S) for threonine (T) and vice versa.
  • substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine (G) and alanine (A) can frequently be interchangeable, as can alanine (A) and valine (V).
  • Methionine (M) which is relatively hydrophobic, can frequently be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are frequently interchangeable in locations in which the significant feature of the amino acid residue is its charge and the differing pK’s of these two amino acid residues are not significant. Still other changes can be considered “conservative” in particular environments (see, e.g. Table 3 herein; pages 13-15 “Biochemistry” 2nd ED. Lubert Stryer ed (Stanford University); Henikoff et al., PNAS 1992 Vol 8910915-10919; Lei et al., J Biol Chem 1995 May 19; 270(20):11882-11886).
  • a given position of two polypeptide sequences is not identical, the similarity or conservativeness of that position can be determined by assessing the similarity of the amino acid of the position, for example, according to Table 3.
  • a degree of similarity between sequences is a function of the number of matching or homologous positions shared by the sequences.
  • the alignment of two sequences to determine their percent sequence similarity can be done using software programs known in the art, such as, for example, those described in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999).
  • default parameters are used for the alignment, examples of which are set forth below.
  • One alignment program well known in the art that can be used is BLAST set to default parameters.
  • the determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • a preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:22642268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:58735877.
  • Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol.215:403.
  • Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res.25:33893402.
  • PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.).
  • BLAST Gapped BLAST
  • PSI Blast programs the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov).
  • NCBI National Center for Biotechnology Information
  • Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:1117. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package.
  • ALIGN program version 2.0
  • cytotoxic agent refers to a substance that inhibits or prevents the expression activity of cells, function of cells and/or causes destruction of cells.
  • the term is intended to include radioactive isotopes, chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • cytotoxic agents include, but are not limited to auristatins (e.g., auristatin E, auristatin F, MMAE and MMAF), auromycins, maytansinoids, ricin, ricin A-chain, combrestatin, duocarmycins, dolastatins, doxorubicin, daunorubicin, taxols, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, cro
  • Antibodies may also be conjugated to an anti- cancer pro-drug activating enzyme capable of converting the pro-drug to its active form.
  • the term “effective amount” or “therapeutically effective amount” as used herein refers to the amount of binding molecule (e.g., an antibody) or pharmaceutical composition provided herein which is sufficient to result in the desired outcome.
  • the terms “subject” and “patient” may be used interchangeably.
  • a subject is a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey and human). In specific embodiments, the subject is a human.
  • the subject is a mammal, e.g., a human, diagnosed with a condition or disorder. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a condition or disorder.
  • administer or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and/or any other method of physical delivery described herein or known in the art.
  • the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of a disease or condition resulting from the administration of one or more therapies. Treating may be determined by assessing whether there has been a decrease, alleviation and/or mitigation of one or more symptoms associated with the underlying disorder such that an improvement is observed with the patient, despite that the patient may still be afflicted with the underlying disorder.
  • Treating includes both managing and ameliorating the disease.
  • the terms “manage,” “managing,” and “management” refer to the beneficial effects that a subject derives from a therapy which does not necessarily result in a cure of the disease.
  • the terms “prevent,” “preventing,” and “prevention” refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptom(s) (e.g., a cancer).
  • cancer or “cancer cell” is used herein to denote a tissue or cell found in a neoplasm which possesses characteristics which differentiate it from normal tissue or tissue cells.
  • a “locally advanced” cancer refers to a cancer that has spread from where it started to nearby tissue or lymph nodes.
  • a “metastatic” cancer refers to a cancer that has spread from where it started to different part of the body.
  • the terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range.
  • the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.
  • variant refers to a molecule that exhibits a variation from a described type or norm, such as a protein that has one or more different amino acid residues in the corresponding position(s) of a specifically described protein (e.g. the 191P4D12 protein shown in FIG.1A.) An analog is an example of a variant protein.
  • Splice isoforms and single nucleotides polymorphisms are further examples of variants.
  • the “191P4D12 proteins” and/or “191P4D12 related proteins” of the disclosure include those specifically identified herein (see, FIG.1A), as well as allelic variants, conservative substitution variants, analogs and homologs that can be isolated/generated and characterized without undue experimentation following the methods outlined herein or readily available in the art. Fusion proteins that combine parts of different 191P4D12 proteins or fragments thereof, as well as fusion proteins of a 191P4D12 protein and a heterologous polypeptide are also included.
  • 191P4D12-related protein refers to a polypeptide fragment or a 191P4D12 protein sequence of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25 amino acids; or, at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 330, 335, 339 or more amino acids.
  • Urothelial cancer and bladder cancer including locally advanced urothelial cancer, metastatic urothelial cancer, locally advanced bladder cancer and metastatic bladder cancer
  • Urothelial cancer and bladder cancer in patients who are ineligible for cisplatin are particularly difficult diseases to treat.
  • these patients are frail, suffer from multiple comorbidities beyond their urothelial cancer/bladder cancer and are not able to tolerate additional treatment, leading many to discontinue therapy altogether. As such, these patients have a poor prognosis and few treatment options.
  • This disclosure is based in part upon the results of the first clinical trial to demonstrate objective responses, in which a combination of enfortumab vedotin and pembrolizumab was administered as first-line treatment to patients with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are unable to receive cisplatin-based chemotherapy.
  • the disclosure thus provides demonstrated efficacious methods to treat patients with urothelial cancer and/or bladder cancer (including locally advanced urothelial cancer, metastatic urothelial cancer, locally advanced bladder cancer and metastatic bladder cancer) who are unable to receive cisplatin-based chemotherapy in this setting due to inadequate kidney function or other conditions as provided herein.
  • kits for the treatment of cancer in a subject using an ADC that binds 191P4D12 and an anti-PD-1 antibody e.g., pembrolizumab.
  • the human subject treated with the methods provided herein has not received previous cancer treatment other than the ADC that binds 191P4D12.
  • the human subject treated with the methods provided herein has not received previous treatment that includes or consists of an immune checkpoint inhibitor (CPI).
  • the CPI is an anti-PD-1 antibody (e.g., pembrolizumab).
  • the CPI is a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
  • the CPI is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.
  • the human subject treated with the methods provided herein has not received an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists).
  • the agent directed to another stimulatory or co inhibitory T-cell receptor is a CD137 agonist, a CTLA 4 inhibitor, or an OX-40 agonist.
  • the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment. In other embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment and has not received previous treatment including or consisting of a CPI.
  • the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, and has not received adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, has not received adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization, and has not received prior systemic treatment for locally advanced or metastatic disease.
  • the cancer is urothelial cancer. In certain embodiments, the cancer is bladder cancer.
  • the cancer is cancer of the renal pelvis. In certain embodiments, the cancer is cancer of the ureter. In certain embodiments, the cancer is cancer of the urethra. In one embodiment, the cancer is locally advanced cancer. In another embodiment, the cancer is metastatic cancer. In a further embodiment, the cancer is locally advanced urothelial cancer. In a further embodiment, the cancer is unresectable locally advanced urothelial cancer. In yet another embodiment, the cancer is metastatic urothelial cancer. In one embodiment, the cancer is locally advanced bladder cancer. In another embodiment, the cancer is metastatic bladder cancer.
  • the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2.
  • the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function (e.g., glomerular filtration rate (GFR) or creatinine clearance ⁇ 60 mL/min but ⁇ 30 mL/min (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD] or 24 hour urine)).
  • impaired renal function e.g., glomerular filtration rate (GFR) or creatinine clearance ⁇ 60 mL/min but ⁇ 30 mL/min (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD] or 24 hour urine
  • the conditions for determining the cisplatin ineligibility comprise or consist of no less than Grade 2 hearing loss (e.g., CI CTCAE Version 4.03 Grade ⁇ 2 hearing loss). In certain embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and impaired renal function. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and no less than Grade 2 hearing loss.
  • Grade 2 hearing loss e.g., CI CTCAE Version 4.03 Grade ⁇ 2 hearing loss
  • the conditions for determining the cisplatin ineligibility comprise or consist of NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and impaired renal function. In some embodiments, the conditions for
  • the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease.
  • the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject (i) has Hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • Impaired renal function can be determined as various means known and available in the art. Various embodiments are provided herein to determine the impaired renal function for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraph.
  • the impaired renal function is determined by glomerular filtration rate (GFR) less than 60 mL/min. In some embodiments, the impaired renal function is determined by GFR less than 60 but no less than 30 mL/min. In certain embodiments, the impaired renal function is determined by GFR less than 30 but no less than 15 mL/min. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD].
  • MDRD modification of diet in renal disease
  • the impaired renal function is determined by creatinine clearance (CrCl) less than 60 mL/min. In some embodiments, the impaired renal function is determined by CrCl less than 60 but no less than 30 mL/min. In certain embodiments, the impaired renal function is determined by CrCl less than 30 but no less than 15 mL/min. In some embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL/min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 mL/min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL/min and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL/min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 60 mL/min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 60 mL/min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 60 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR l less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 60 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD]. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject did not receive adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject has Hemoglobin ⁇ 10 g/dL
  • (ii) has GFR ⁇ 50 mL/min
  • (iii) does not have NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL/min.
  • the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 mL/min.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL/min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL/min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 60 mL/min, and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 60 mL/min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 60 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 60 mL/min, and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of all three of CrCl less than 60 mL/min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the CrCl is measured by 24 hour urine collection.
  • the CrCl is estimated by the Cockcroft-Gault criteria.
  • the subject did not receive prior systemic treatment for locally advanced or metastatic disease.
  • the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject (i) has Hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • other specific conditions based on GFR or creatinine clearance can be used to determine the cisplatin ineligibility for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL/min.
  • the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and GFR less than 60 but no less than 30 mL/min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL/min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL/min and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD]. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject (i) has Hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL/min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 but no less than 30 mL/min.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL/min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL/min and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of CrCl less than 60 but no less than 30 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria.
  • the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL/min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and GFR less than 30 but no less than 15 mL/min.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL/min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL/min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria.
  • the GFR is measured by modification of diet in renal disease [MDRD].
  • the subject did not receive prior systemic treatment for locally advanced or metastatic disease.
  • the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject has Hemoglobin ⁇ 10 g/dL;
  • ii) has GFR ⁇ 50 mL/min; and
  • (iii) does not have NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL/min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 30 but no less than 15 mL/min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL/min and no less than Grade 2 hearing loss.
  • the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL/min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss, in any combination or permutation.
  • the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL/min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of CrCl less than 30 but no less than 15 mL/min, no less than Grade 2 hearing loss, and NYHA Class III heart failure.
  • the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject did not receiveadjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • the subject has ECOG performance status score of 2
  • the subject (i) has Hemoglobin ⁇ 10 g/dL; (ii) has GFR ⁇ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
  • 5.2.1.2 Additional Patient Demographics the human subjects for whom the methods provided herein can be used are human subjects having various other conditions.
  • the human subjects for whom the methods provided herein may have histologically documented locally advanced or metastatic urothelial (previously known as transitional cell) cancer (e.g., cancer of the bladder, renal pelvis, ureter, or urethra).
  • the human subjects for whom the methods provided herein may be eligible for CPI therapy.
  • the human subjects for whom the methods provided herein may measurable disease according to RECIST Version 1.1.
  • the human subjects for whom the methods provided herein may have lesions in a prior irradiated field that have progressed to be considered measurable.
  • the human subjects for whom the methods provided herein can have ECOG performance status score of 0.
  • the human subjects for whom the methods provided herein can have ECOG performance status score of 1.
  • the human subjects for whom the methods provided herein can have ECOG performance status score of 2.
  • the human subjects for whom the methods provided herein can have ECOG performance status score of 1 to 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 1 or 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 to 1. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 or 1. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 to 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 or 2.
  • the human subjects for whom the methods provided herein can have ECOG performance status score of 0, 1, or 2.
  • the human subjects for whom the methods provided herein may have an anticipated life expectancy of ⁇ 3 months. Some embodiments of the methods provided in this paragraph may have any of the preceding embodiments in any combination or permutation.
  • the human subjects for whom the methods provided herein can be used are human subjects having various other conditions. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count (ANC) no less than 1500/ ⁇ L.
  • ANC absolute neutrophil count
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL, wherein the subject does not have erythropoietin dependency and wherein the subject has not been administered a packed red blood cell (pRBC) transfusion within 2 weeks prior to treatment. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 5.6 mmol/L.
  • pRBC packed red blood cell
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 5.6 mmol/L, wherein the subject does not have erythropoietin dependency and wherein the subject has not been administered a packed red blood cell (pRBC) transfusion within 2 weeks prior to treatment.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L.
  • the human subjects for whom the methods provided herein can be used also have the conditions of serum bilirubin no more than either of 1.5 times of upper limit of normal (ULN), direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of CrCl no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of CrCl or GFR no less than 30 mL/min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of CrCl no less than 30 mL/min, wherein the subjects have creatinine levels >1.5 ⁇ institutional ULN and/or ⁇ 1.5 ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of GFR no less than 30 mL/min, wherein the subjects have creatinine levels >1.5 ⁇ institutional ULN and/or ⁇ 1.5 ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L and platelet count no less than 100,000/ ⁇ L.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L and hemoglobin no less than 9 g/dL or 5.6 mmol/L.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L and CrCl no less than 30 mL/min, wherein the subjects have creatinine levels >1.5 ⁇ institutional ULN and/or ⁇ 1.5 ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L and hemoglobin no less than 9 g/dL or 5.6 mmol/L.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease and CrCl no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of CrCl or GFR no less than 30 mL/min and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, and hemoglobin no less than 9 g/dL or 5.6 mmol/L.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L and serum bilirubin no more than either of 1.5 times of ULN or 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL/min.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of any one of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • the human subjects for whom the methods provided herein can be used also have the conditions of any two of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN, in any combination or permutation.
  • the human subjects for whom the methods provided herein can be used also have the conditions of any three of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN, in any combination or permutation.
  • the human subjects for whom the methods provided herein can be used also have the conditions of any four of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN, in any combination or permutation.
  • the human subjects for whom the methods provided herein can be used also have the conditions of any five of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN, in any combination or permutation.
  • the human subjects for whom the methods provided herein can be used also have the conditions of all six of absolute neutrophil count no less than 1500/ ⁇ L, platelet count no less than 100,000/ ⁇ L, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than either of 1.5 times of ULN, direct bilirubin ⁇ ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 ⁇ ULN, or serum bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 fold of ULN.
  • Phoenix criteria for biochemical recurrence e.g., ⁇ 2.0 ng/mL above nadir.
  • the human subjects for whom the methods provided herein may have untreated low-risk prostate cancer, wherein the subject has a Gleason score ⁇ 6, on active surveillance with PSA doubling time >1 year (based on at least 3 values determined >1 month apart).
  • the human subjects for whom the methods provided herein can be used are human subjects free from certain conditions.
  • the human subjects for whom the methods provided herein have not received any prior treatment with a CPI.
  • a CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
  • the human subjects for whom the methods provided herein have not received atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.
  • the human subjects for whom the methods provided herein have not received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor including, but not limited to, CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists.
  • the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy.
  • the human subjects for whom the methods provided herein can have no active central nervous system metastases.
  • the human subjects for whom the methods provided herein can have no uncontrolled diabetes.
  • the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy and no active central nervous system metastases. In some embodiments, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy and no uncontrolled diabetes. In yet other embodiments, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy no active central nervous system metastases, and no uncontrolled diabetes. In some embodiments, the human subjects for whom the methods provided herein can have any one of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes.
  • the human subjects for whom the methods provided herein can have any two of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can have all three of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes. In one embodiment of the methods provided in this paragraph, the uncontrolled diabetes is determined by hemoglobin A1c (HbA1c) no less than 8%. In some embodiments of the methods provided in this paragraph, the uncontrolled diabetes is determined by HbA1c between 7 and 8% with associated diabetes symptoms that are not otherwise explained.
  • HbA1c hemoglobin A1c
  • the associated diabetes symptoms comprise or consist of polyuria. In some other embodiments of the methods provided in this paragraph, the associated diabetes symptoms comprise or consist of polydipsia. In yet other embodiments of the methods provided in this paragraph, the associated diabetes symptoms comprise or consist of both polyuria and polydipsia. [00244] In certain embodiments, the human subjects for whom the methods provided herein may have no ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment. In certain embodiments, the human subjects for whom the methods provided herein may have no ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment, wherein the prior treatment is radiotherapy or surgery.
  • the human subjects for whom the methods provided herein may have no conditions requiring high doses of steroids (e.g., >10 mg/day of prednisone or equivalent) or other immunosuppressive medications. In one embodiment, the human subjects for whom the methods provided herein may have no conditions requiring high doses of steroids or other immunosuppressive medications, wherein the steroids or other immunosuppressive medications are not inhaled or topical steroids. In certain embodiments, the human subjects for whom the methods provided herein may have no prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
  • steroids e.g., >10 mg/day of prednisone or equivalent
  • the human subjects for whom the methods provided herein may have no conditions requiring high doses of steroids or other immunosuppressive medications, wherein the steroids or other immunosuppressive medications are not inhaled or topical steroids.
  • the human subjects for whom the methods provided herein may have no prior treatment with enfortumab
  • the human subjects for whom the methods provided herein may have no history of another invasive malignancy within 3 years before treatment with the methods provided herein. In certain embodiments, the human subjects for whom the methods provided herein may have no evidence of residual disease from a previously diagnosed malignancy. In certain embodiments, the human subjects for whom the methods provided herein may not receive systemic antimicrobial treatment for active infection, wherein the infection is a viral, bacterial, or fungal infection, at the time of first dose of enfortumab vedotin. systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin.
  • the human subjects for whom the methods provided herein may have no positive hepatitis B surface antigen and/or antihepatitis B core antibody. In certain embodiments, the human subjects for whom the methods provided herein may have no active hepatitis C infection or known human immunodeficiency virus (HIV) infection. In certain embodiments, the human subjects for whom the methods provided herein may have no active tuberculosis.
  • HIV human immunodeficiency virus
  • the human subjects for whom the methods provided herein may have no documented history of a cerebral vascular event (e.g., a stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with NYHA Class IV within 6 months prior to the first dose of enfortumab vedotin.
  • a cerebral vascular event e.g., a stroke or transient ischemic attack
  • unstable angina e.g., myocardial infarction
  • cardiac symptoms including congestive heart failure
  • the human subjects for whom the methods provided herein may have no radiotherapy or major surgery within 2 weeks prior to treatment with the methods provided herein.
  • the human subjects for whom the methods provided herein may have no treatment with chemotherapy, biologics, or investigational agents not completed 4 weeks prior to treatment with the methods provided herein.
  • the human subjects for whom the methods provided herein may have no known severe ( ⁇ Grade 3) hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
  • the human subjects for whom the methods provided herein may have no known severe ( ⁇ Grade 3) hypersensitivity to pembrolizumab or to any excipient contained in the drug formulations of pembrolizumab.
  • the human subjects for whom the methods provided herein may have no active keratitis or corneal ulcerations.
  • the human subjects for whom the methods provided herein may have no active autoimmune disease that has required systemic treatment in past 2 years (e.g., use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
  • the human subjects for whom the methods provided herein may have no active autoimmune disease that has required systemic treatment in past 2 years, wherein the systemic treatment comprises disease modifying agents, corticosteroids, or immunosuppressive drugs.
  • the systemic treatment is not replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency).
  • the systemic treatment is not thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency.
  • the human subjects for whom the methods provided herein may have no history of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
  • the human subjects for whom the methods provided herein may have no prior allogeneic stem cell or solid organ transplant.
  • the human subjects for whom the methods provided herein may not have received a live, attenuated vaccine within 30 days prior to treatment with the methods provided herein.
  • the live vaccine is a measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, or typhoid vaccine.
  • the live, attenuated vaccine is an intranasal influenza vaccine.
  • the human subjects for whom the methods provided herein may have no underlying medical condition that impairs the ability of the subject to receive or tolerate the methods provided herein.
  • the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided herein, the CrCl is estimated by the Cockcroft-Gault criteria.
  • the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided herein, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD]. [00247] In some embodiments of the methods provided herein, the subject has been treated with one or more other cancer treatments. In certain embodiments of the methods provided herein, the urothelial cancer, including locally advanced or metastatic urothelial cancer, has been treated with one or more other cancer treatments. [00248] In some embodiments, the CPI described herein can comprise or consist of any CPI as described in this Section (Section 5.2.1).
  • the ADCs that can be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5, and 6, selection of patients for treatment is described herein and exemplified in this Section (Section 5.2) and Sections 3 and 6, dosing regimens and pharmaceutical composition for administering the therapeutic agent are described in this Section (Section 5.2), Sections5.4, 5.6, 5.7 and 6 below, the biomarkers that can be used for identifying the therapeutic agents, selecting the patients, determining the outcome of these methods, and/or serving as criteria in any way for these methods are described herein and exemplified in this Section (Section 5.2, including 5.2.1 and 5.2.2) and Section 6, the biomarkers can be determined as described in Section 5.8 or as known in the art, therapeutic outcomes for the methods provided herein are described in this Section (Section 5.2 including Section 5.2.1.4) and Sections 3 and 6, additional therapeutic outcomes for the methods provided herein can be improvement of
  • the methods provided herein include all permutations and combinations of the patients, therapeutic agents, dosing regiments, biomarkers, and therapeutic outcomes as described above and below.
  • the methods provided herein are used for treating subjects having urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein.
  • the methods provided herein are used for treating subjects who have urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein.
  • the methods provided herein are used for treating subjects having locally advanced urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used for treating subjects who have locally advanced urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein and who have been previously treated with a CPI.
  • the methods provided herein are used for treating subjects having metastatic cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used for treating subjects who have metastatic urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein. [00253] In some embodiments, the 191P4D12 RNA expression in the cancers is determined by polynucleotide hybridization, sequencing (assessing the relative abundance of the sequences), and/or PCR (including RT-PCR).
  • the 191P4D12 protein expression in the cancers is determined by IHC, analysis in fluorescence-activated cell sorting (FACS), and/or western blotting. In some embodiments, the 191P4D12 protein expression in the cancers is determined by more than one method. In some embodiments, the 191P4D12 protein expression in the cancers is determined by two methods of IHC. [00254] In some embodiments, the locally advanced or metastatic urothelial cancers are confirmed histologically, cytologically, or both histologically and cytologically. In some embodiments, the locally advanced or metastatic bladder cancers are confirmed histologically, cytologically, or both histologically and cytologically.
  • the subject has visceral metastases. In some embodiments, the subject has lymph nodes only disease. In some embodiments, the disease site of origin is in the upper tract. In some embodiments, the disease site of origin is in the lower tract. [00256] In some embodiments, the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10. PD-L1 protein expression is determined by using the Combined Positive Score (CPS), which is the number of PD-L1 positive cells (i.e., tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, and then multiplied by 100. In some embodiments, the subject has a PD-L1 expression CPS less than 10.
  • CPS Combined Positive Score
  • Urothelial cancer generally has a median H-score from 260- 270.
  • the subject has a Nectin-4 H-score between 0 and 300.
  • the subject has a Nectin-4 H-score between 0 and 250, between 0 and 200, between 0 and 150, between 0 and 100, or between 0 and 50.
  • the subject has a Nectin-4 H-score between 0 and 200. 5.2.1.3 Checkpoint Inhibitors and Combination Therapy with Pembrolizumab Checkpoint Inhibitors
  • the subjects that can be treated in the methods provided herein have certain phenotypic or genotypic characteristics.
  • the subjects have any permutation and combination of the phenotypic or genotypic characteristics described herein.
  • the phenotypic or genotypic characteristics are determined histologically, cytologically, or both histologically and cytologically.
  • the histological and/or the cytological determination of the phenotypic and/or genotypic characteristics are performed as described in American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines based on the most recently analyzed tissue, which is incorporated herein in their entirety by reference.
  • the phenotypic or genotypic characteristics are determined by sequencing including the next generation sequencing (e.g. NGS from Illumina, Inc), DNA hybridization, and/or RNA hybridization.
  • a CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
  • the human subjects for whom the methods provided herein have not received prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor.
  • the human subjects for whom the methods provided herein have not received prior treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
  • checkpoint inhibitor or “checkpoint inhibitor” (CPI) refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
  • Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-Ll and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252- 264).
  • checkpoint proteins include LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. These proteins appear responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies. [00260] In certain embodiments, the checkpoint inhibitor for the methods provided herein can be an inhibitors or activators against a checkpoint protein that upregulated in cancer.
  • the checkpoint inhibitor for the methods provided herein can be an inhibitors or activators against a checkpoint protein including LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA.
  • a checkpoint protein including LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA.
  • the checkpoint inhibitor for the methods provided herein can be an inhibitors or activators selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a B7 inhibitor, a TIM3 (HAVCR2) inhibitor, an OX40 (CD134) inhibitor, a GITR agonist, a CD137 agonist, or a CD40 agonist, a VTCN1 inhibitor, an IDO1 inhibitor, a CD276 inhibitor, a PVRIG inhibitor, a TIGIT inhibitor, a CD25 (IL2RA) inhibitor, an IFNAR2 inhibitor, an IFNAR1 inhibitor, a CSF1R inhibitor, a VSIR (VISTA) inhibitor, or a therapeutic agent targeting HLA.
  • a PD-1 inhibitor a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a B7 inhibitor, a TIM3
  • the checkpoint inhibitor is a CTLA-4 inhibitor.
  • the CTLA-4 inhibitor is an anti-CTLA-4 antibody.
  • anti-CTLA-4 antibodies include, but are not limited to, those described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein in their entireties.
  • the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206).
  • the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX- 101).
  • Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name YervoyTM.
  • the checkpoint inhibitor is a PD-1/PD-L1 inhibitor. Examples of PD-l/PD-L1 inhibitors include, but are not limited to, those described in US Patent Nos.7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Patent Application Publication Nos.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or Natural Killer T cell) and in specific embodiments also blocks binding of PD- L2 expressed on a cancer cell to the immune-cell expressed PD-1.
  • PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and in specific embodiments blocks binding of both human PD-L1 and PD-L2 to human PD-1.
  • the checkpoint inhibitor is a PD-1 inhibitor or antagonist.
  • the PD-1 inhibitor or antagonist is an anti-PD-1 antibody.
  • the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106) or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab).
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name OpdivoTM.
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name KeytrudaTM.
  • the anti-PD-1 antibody is CT-011, a humanized antibody. CT-011 administered alone has failed to show response in treating acute myeloid leukemia (AML) at relapse.
  • the anti-PD-1 antibody is AMP-224, a fusion protein.
  • the PD-1 antibody is BGB-A317.
  • BGB- A317 is a monoclonal antibody in which the ability to bind Fc gamma receptor I is specifically engineered out, and which has a unique binding signature to PD-1 with high affinity and superior target specificity.
  • the PD-1 antibody is cemiplimab.
  • the PD-1 antibody is camrelizumab.
  • the PD-1 antibody is sintilimab.
  • the PD-1 antibody is tislelizumab.
  • the PD-1 antibody is TSR-042.
  • the PD-1 antibody is PDR001.
  • the PD-1 antibody is toripalimab.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is an anti-PD-L1 antibody.
  • the anti- PD-L1 antibody is MEDI4736 (durvalumab).
  • the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01).
  • the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A, and Tecentriq®).
  • the PD-L1 inhibitor is avelumab.
  • the checkpoint inhibitor is a PD-L2 inhibitor.
  • the PD-L2 inhibitor is an anti-PD-L2 antibody.
  • the anti- PD-L2 antibody is rHIgM12B7A.
  • the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor.
  • the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al., J. Immunol., 2007, 179, 4202-4211).
  • the LAG-3 inhibitor is BMS-986016.
  • the checkpoint inhibitors is a B7 inhibitor.
  • the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor.
  • the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).
  • the checkpoint inhibitors is a TIM3 (T-cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).
  • the checkpoint inhibitor is an OX40 (CD134) agonist.
  • the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti- OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469. [00271] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti- GITR antibody is TRX518. [00272] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF- 05082566.
  • the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti- CD40 antibody is CF-870,893. [00274] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15). [00275] In one embodiment, the checkpoint inhibitor is a VTCN inhibitor. In one embodiment, the VTCN inhibitor is FPA150. [00276] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod. In one embodiment, the IDO inhibitor is epacadostat.
  • the IDO inhibitor is BMS986205. In yet another embodiment, the IDO inhibitor is Navoximod. In one embodiment, the IDO inhibitor is PF-06840003. In another embodiment, the IDO inhibitor is KHK2455. In yet another embodiment, the IDO inhibitor is RG70099. In one embodiment, the IDO inhibitor is IOM-E. In another embodiment, the IDO inhibitor is or IOM-D. [00277] In some embodiments, the checkpoint inhibitor is a TIGIT inhibitor. In certain embodiments, the TIGIT inhibitor is an anti-TIGIT antibody. In one embodiment, the TIGIT inhibitor is MTIG7192A. In another embodiment, the TIGIT inhibitor is BMS-986207.
  • the TIGIT inhibitor is OMP-313M32. In one embodiment, the TIGIT inhibitor is MK-7684. In another embodiment, the TIGIT inhibitor is AB154. In yet another embodiment, the TIGIT inhibitor is CGEN-15137. In one embodiment, the TIGIT inhibitor is SEA-TIGIT. In another embodiment, the TIGIT inhibitor is ASP8374. In yet another embodiment, the TIGIT inhibitor is AJUD008. [00278] In some embodiments, the checkpoint inhibitor is a VSIR inhibitor. In certain embodiments, the VSIR inhibitor is an anti-VSIR antibody. In one embodiment, the VSIR inhibitor is MTIG7192A. In another embodiment, the VSIR inhibitor is CA-170.
  • the VSIR inhibitor is JNJ 61610588. In one embodiment, the VSIR inhibitor is HMBD-002. [00279] In some embodiments, the checkpoint inhibitor is a TIM3 inhibitor. In certain embodiments, the TIM3 inhibitor is an anti-TIM3 antibody. In one embodiment, the TIM3 inhibitor is AJUD009. [00280] In some embodiments, the checkpoint inhibitor is a CD25 (IL2RA) inhibitor. In certain embodiments, the CD25 (IL2RA) inhibitor is an anti-CD25 (IL2RA) antibody. In one embodiment, the CD25 (IL2RA) inhibitor is daclizumab. In another embodiment, the CD25 (IL2RA) inhibitor is basiliximab.
  • the checkpoint inhibitor is an IFNAR1 inhibitor. In certain embodiments, the IFNAR1 inhibitor is an anti-IFNAR1 antibody. In one embodiment, the IFNAR1 inhibitor is anifrolumab. In another embodiment, the IFNAR1 inhibitor is sifalimumab. [00282] In some embodiments, the checkpoint inhibitor is a CSF1R inhibitor. In certain embodiments, the CSF1R inhibitor is an anti-CSF1R antibody. In one embodiment, the CSF1R inhibitor is pexidartinib. In another embodiment, the CSF1R inhibitor is emactuzumab. In yet another embodiment, the CSF1R inhibitor is cabiralizumab.
  • the CSF1R inhibitor is ARRY-382. In another embodiment, the CSF1R inhibitor is BLZ945. In yet another embodiment, the CSF1R inhibitor is AJUD010. In one embodiment, the CSF1R inhibitor is AMG820. In another embodiment, the CSF1R inhibitor is IMC-CS4. In yet another embodiment, the CSF1R inhibitor is JNJ-40346527. In one embodiment, the CSF1R inhibitor is PLX5622. In another embodiment, the CSF1R inhibitor is FPA008. [00283] In some embodiments, the checkpoint inhibitor is a therapeutic agent targeting HLA. In certain embodiments, the therapeutic agent targeting HLA is an anti-HLA antibody. In one embodiment, the therapeutic agent targeting HLA is GSK01.
  • the therapeutic agent targeting HLA is IMC-C103C. In yet another embodiment, the therapeutic agent targeting HLA is IMC-F106C. In one embodiment, the therapeutic agent targeting HLA is IMC-G107C. In another embodiment, the therapeutic agent targeting HLA is ABBV-184. [00284] The methods described herein can be used in combination with one or more second active agents as described herein where appropriate for treating diseases described herein and understood in the art.
  • PD-1 Antagonists and Pembrolizumab Provided herein are methods for the treatment of various cancers in subjects, including subjects with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are unable to receive cisplatin-based chemotherapy, using an antibody drug conjugate (ADC) that binds 191P4D12 in combination with pembrolizumab.
  • ADC antibody drug conjugate
  • the treatment is a first-line treatment. In other embodiments, the treatment is a second-line treatment.
  • Pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab) alternatively referred to herein as “pembro,” is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol.27, No.2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs described in Table 4. Pembrolizumab has been approved by the U.S. FDA as described in the Prescribing Information for KEYTRUDATM (Merck & Co., Inc., Rahway, NJ, USA; initial U.S. approval 2014, updated March 2021).
  • a “pembrolizumab variant” or “a variant thereof” pertaining to a pembrolizumab sequence means a monoclonal antibody that comprises heavy chain and light chain sequences that are substantially identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g., the variant positions are located in the FR regions or the constant region, and optionally has a deletion of the C- terminal lysine residue of the heavy chain.
  • pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.
  • a pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.
  • the PD-1 antagonist useful in the treatment, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 or IgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • mAbs that bind to human PD-1 are described in U.S. patent nos. US7488802, US7521051, US8008449, US8354509, and US8168757, and International application publn. nos. WO2004/004771, WO2004/072286, WO2004/056875, US2011/0271358, and WO 2008/156712.
  • Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include: pembrolizumab (also known as MK-3475), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol.27, No.2, pages 161-162 (2013) and that comprises the heavy and light chain amino acid sequences shown in Table 2; nivolumab (BMS-936558), a human IgG4 mAb with the structure described in WHO Drug Information, Vol.27, No.1, pages 68-69 (2013) and that comprises the heavy and light chain amino acid sequences shown in Table 2; the humanized antibodies h409A11, h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is being developed by MedImmune; cemiplimab; camrelizumab; sintilimab; tislelizumab; and toripalimab.
  • Additional anti-PD-1 antibodies contemplated for use herein include MEDI0680 (U.S. Patent no.8609089), BGB-A317 (U.S. Patent publ. no.2015/0079109), INCSHR1210 (SHR-1210) (PCT International application publ. no. WO2015/085847), REGN-2810 (PCT International application publ. no. WO2015/112800), PDR001 (PCT International application publ. no. WO2015/112900), TSR-042 (ANB011) (PCT International application publ. no. WO2014/179664) and STI- 1110 (PCT International application publ. no. WO2014/194302).
  • mAbs that bind to human PD-L1 are described in US8383796.
  • Specific anti- human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include BMS-936559, MEDI4736, and MSB0010718C.
  • the PD-1 antagonist is pembrolizumab (KEYTRUDATM, Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVOTM, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (TECENTRIQTM, Genentech, San Francisco, CA, USA), durvalumab (IMFINZITM, AstraZeneca Pharmaceuticals LP, Wilmington, DE), cemiplimab (LIBTAYOTM, Regeneron Pharmaceuticals, Tarrytown, NY, USA) avelumab (BAVENCIOTM, Merck KGaA, Darmstadt, Germany) or dostarlimab (JEMPERLITM, GlaxoSmithKline LLC, Philadelphia, PA).
  • pembrolizumab KYTRUDATM, Merck & Co., Inc., Rahway, NJ, USA
  • OPDIVOTM Bristol-Myers Squibb Company, Princeton, NJ, USA
  • the PD-1 antagonist is pidilizumab (U.S. Pat. No.7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD, USA), PDR001 (U.S. Pat. No.9,683,048), BGB-A317 (U.S. Pat. No.8,735,553), or MGA012 (MacroGenics, Rockville, MD).
  • the PD-1 antagonist useful in the methods of the invention is an anti-PD-1 antibody that blocks the binding of PD-1 to PD-L1 and PD-L2.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 24, 25 and 26, respectively and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 29, 30 and 31, respectively.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO:32 or a variant thereof, and (b) a light chain variable region comprising SEQ ID NO:37 or a variant thereof.
  • a variant of a heavy chain variable region sequence is identical to the reference sequence except having up to six conservative amino acid substitutions in the framework region (i.e., outside of the CDRs).
  • a variant of a light chain variable region sequence is identical to the reference sequence except having up to three conservative amino acid substitutions in the framework region (i.e., outside of the CDRs).
  • the PD-1 antagonist is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO: 33 and (b) a light chain comprising SEQ ID NO:28.
  • the PD-1 antagonist is an anti-PD-1 antibody that comprises two heavy chains and two light chains, and wherein the heavy and light chains comprise the amino acid sequences in SEQ ID NO:33 and SEQ ID NO:28, respectively.
  • the PD-1 antagonist inhibits the binding of PD-L1 to PD-1, and in specific embodiments also inhibits the binding of PD-L2 to PD-1.
  • the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, that specifically binds to PD-1 or to PD-L1 and blocks the binding of PD- L1 to PD-1.
  • Table 4 below provides a list of the amino acid sequences of exemplary anti-PD-1 mAbs for use in the treatment method, medicaments and uses of the present invention. Table 4 Exemplary PD-1 Antibody Sequences Table 5 Additional PD-1 Antibodies and Antigen Binding Fragments Useful in the Formulations, Methods and Uses Provided Herein
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region, e.g. a human constant region, such as g1, g2, g3, or g4 human heavy chain constant region or a variant thereof.
  • the anti- PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region, e.g. a human light chain constant region, such as lambda or kappa human light chain region or a variant thereof.
  • the human heavy chain constant region can be g4 and the human light chain constant region can be kappa.
  • the Fc region of the antibody is g4 with a Ser228Pro mutation (Schuurman, J et.al., Mol. Immunol.38: 1-8, 2001).
  • different constant domains may be appended to humanized VL and VH regions derived from the CDRs provided herein.
  • a heavy chain constant domain other than human IgG1 may be used, or hybrid IgG1/IgG4 may be utilized.
  • human IgG1 antibodies provide for long half-life and for effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody.
  • a human IgG4 constant domain for example, may be used.
  • the present invention includes the use of anti-PD-1 antibodies or antigen-binding fragments thereof which comprise an IgG4 constant domain.
  • the IgG4 constant domain can differ from the native human IgG4 constant domain (Swiss-Prot Accession No.
  • the PD-1 antagonist is an antibody or antigen binding protein that has a variable light domain and/or a variable heavy domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence identity to one of the variable light domains or variable heavy domains described above, and exhibits specific binding to PD-1.
  • the PD-1 antagonist is an antibody or antigen binding protein comprising variable light and variable heavy domains having up to 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.
  • the checkpoint inhibitor is administered after the administration of the ADCs provided herein.
  • the checkpoint inhibitor is administered simultaneously (e.g., in the same dosing period) with the ADCs provided herein. In yet other embodiments, the checkpoint inhibitor is administered after the administration of the ADCs provided herein.
  • the amount of the checkpoint inhibitor for the various methods provided herein can be determined by standard clinical techniques. In certain embodiments, the amount of the PD-1 antagonist, e.g., pembrolizumab, for the various methods are provided in Section 5.6.
  • the subjects that can be treated in the methods provided herein is a mammal. In some embodiments, the subjects that can be treated in the methods provided herein is a human.
  • the methods provided herein can provide beneficial therapeutic outcomes for these cisplatin ineligible human subjects.
  • the human subject has a complete response following the treatment by a method provided herein.
  • the human subject has a partial response following the treatment by a method provided herein.
  • the human subject has complete response or a partial response following the treatment by a method provided herein.
  • the response is determined by evaluating the tumor or cancer site (lesions).
  • the criteria for determining complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) are described in Table 10.
  • the human subjects and patients are used interchangeably. Therefore, a person skilled in the art would understand that the human subjects can be interchangeable with patients in any of the methods provided herein.
  • the therapeutic outcome of the methods provided herein thus can be evaluated based on any one or more of the response criteria described above.
  • the human subject has a partial response following the treatment by a method provided herein.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 35% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 40% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 45% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 50% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 55% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 60% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 65% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 70% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 75% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 80% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 85% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 90% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 95% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • the diameter is determined according to the longest diameter of a lesion. In certain embodiments, the diameter is determined according to the longest diameter of a lesion in the plane of measurement.
  • the diameter is determined according to the longest diameter of a lesion in the plane of measurement with a minimal size of 10mm by CT scan. In certain embodiments, the diameter is determined according to the longest diameter of a lesion in the plane of measurement with a minimal size of 10mm by CT scan and CT slice thickness no greater than 5 mm.
  • the therapeutic outcomes of the methods provided herein can also be evaluated based on whether the disease is stable following the treatment. In one embodiment, the human subject has a stable disease following the treatment by a method provided herein. In another embodiment, the human subject does not have a progressive disease following the treatment by a method provided herein.
  • therapeutic outcomes based on the complete response, partial response, or stable disease can be evaluated with respect to a population of human subjects treated by a method provided herein by evaluating the percentage of the subjects having complete response, partial response, or stable disease in the treated population.
  • the therapeutic outcome or efficacy measure applies to outcomes achieved by actually treating a population of subjects.
  • the therapeutic outcome or efficacy measure refers to the outcome or efficacy that is capable of being achieved if a population of human subjects was treated with a method as disclosed herein. While the following sections discuss the treatment of an actual population of human subjects, is should be understood that corresponding methods in which the outcome or efficacy measure is capable of being achieved in a patient population are also encompassed herein.
  • the ADC is enfortumab vedotin.
  • the ADC is a biosimilar of enfortumab vedotin.
  • the PD-1 antagonist or anti-PD-1 antibody is pembrolizumab.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 2%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 5%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 10%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 10.5%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 15%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 20%.
  • the complete response rate is at least or about 10% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 2% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 5% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 10% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 10.5% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 15% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 20% for a population of subjects treated with the method.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 25%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 30%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 35%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 40%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 45%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 50%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 53.9%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 54%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 55%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 60%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 65%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 70%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 75%.
  • the partial response rate is at least or about 25% for a population of subjects treated with the method.
  • the partial response rate is at least or about 30% for a population of subjects treated with the method.
  • the partial response rate is at least or about 35% for a population of subjects treated with the method.
  • the partial response rate is at least or about 40% for a population of subjects treated with the method.
  • the partial response rate is at least or about 45% for a population of subjects treated with the method.
  • the partial response rate is at least or about 50% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 53.9% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 54% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 55% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 60% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 65% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 70% for a population of subjects treated with the method.
  • the partial response rate is at least or about 75% for a population of subjects treated with the method.
  • percentage of the subjects having stable disease can be used as the evaluation criteria for the therapeutic outcome in the human subjects treated by a method provided herein.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 10%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 15%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 20%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 22%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 22.4%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 25%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 30%.
  • a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 35%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 40%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 45%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having stable disease in the treated population is at least or about 50%.
  • the stable disease rate is at least or about 10% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 15% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 20% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 22% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 22.4% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 25% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 30% for a population of subjects treated with the method.
  • the stable disease rate is at least or about 35% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 40% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 45% for a population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 50% for a population of subjects treated with the method.
  • objective response rate which is the sum of percentage of subjects having completed response and those having partial response, can be used as the evaluation criteria for the therapeutic outcome in the human subjects treated by a method provided herein. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 30%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 35%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 40%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 45%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 50%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 52.7%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 53%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 55%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 60%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 64.5%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 65%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 70%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 75%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 75.1%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 80%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 85%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population is at least or about 90%. [00317] In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 40% to 80%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 40% to75%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 40% to 70%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 45% to 80%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 45% to 75%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 45% to 70%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 50% to 80%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 50% to 75%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 52.7% to 75.1%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 55% to 80%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 55% to 75%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 55% to 70%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 55% to 65%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 60% to 80%.
  • a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 60% to 75%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 60% to 70%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein objective response rate in the treated population ranges from 60% to 65%. [00318] In one embodiment, the objective response rate is at least or about 30% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 30% for a population of subjects treated with the method.
  • the objective response rate is at least or about 35% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 40% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 45% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 50% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 55% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 60% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 64.5% for a population of subjects treated with the method.
  • the objective response rate is at least or about 65% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 70% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 80% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 85% for a population of subjects treated with the method. In another embodiment, the objective response rate is at least or about 90% for a population of subjects treated with the method. [00319] In one embodiment, the objective response rate is from 40% to 80% for a population of subjects treated with the method.
  • the objective response rate is from 40% to 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 40% to 70% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 45% to 80% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 45% to 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 45% to 70% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 50% to 80% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 50% to 75% for a population of subjects treated with the method.
  • the objective response rate is from 52.7% to 75.1% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 53% to 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 55% to 80% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 55% to 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 55% to 70% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 55% to 65% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 60% to 80% for a population of subjects treated with the method.
  • the objective response rate is from 60% to 75% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 60% to 70% for a population of subjects treated with the method. In another embodiment, the objective response rate is from 60% to 65% for a population of subjects treated with the method.
  • the therapeutic outcome of the methods provided herein can be evaluated based on the duration of response as set forth in Section 6.1.8.2(ii). In one embodiment, the human subject has a duration of response of at least or about 5 months following the treatment. In another embodiment, the human subject has a duration of response of at least or about 6 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 7 months following the treatment.
  • the human subject has a duration of response of at least or about 8 months following the treatment. In one embodiment, the human subject has a duration of response of at least or about 9 months following the treatment. In another embodiment, the human subject has a duration of response of at least or about 10 months following the treatment. In yet another embodiment, the human subject has a duration of response of at least or about 11 months following the treatment. In one embodiment, the human subject has a duration of response of at least or about 12 months following the treatment. In another embodiment, the human subject has a duration of response of at least or about 13 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 14 months following the treatment.
  • the human subject has a duration of response of at least or about 15 months following the treatment. In one embodiment, the human subject has a duration of response of at least or about 16 months following the treatment. In another embodiment, the human subject has a duration of response of at least or about 17 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 18 months following the treatment. In yet another embodiment, the human subject has a duration of response of at least or about 19 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 20 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 21 months following the treatment.
  • the human subject has a duration of response of at least or about 22 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 23 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 24 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 25 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 26 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 27 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 28 months following the treatment.
  • the human subject has a duration of response of at least or about 29 months following the treatment. In a further embodiment, the human subject has a duration of response of at least or about 30 months following the treatment. [00321] In another embodiment, the human subject has a duration of response ranging from 5 to 30 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 29 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 28 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 27 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 26 months following the treatment.
  • the human subject has a duration of response ranging from 5 to 25 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 24 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 23 months following the treatment. In some embodiments, the human subject has a duration of response ranging from 5 to 22 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 21 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 20 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 5 to 19 months following the treatment.
  • the human subject has a duration of response ranging from 5 to 18 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 17 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 16 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 5 to 15 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 5 to 14 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 13 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 12 months following the treatment.
  • the human subject has a duration of response ranging from 6 to 30 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 29 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 28 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 27 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 26 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 25 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 24 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 23 months following the treatment.
  • the human subject has a duration of response ranging from 6 to 22 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 21 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 20 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 6 to 19 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 6 to 18 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 17 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 16 months following the treatment.
  • the human subject has a duration of response ranging from 6 to 15 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 6 to 14 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 13 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 12 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 22 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 21 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 7 to 20 months following the treatment.
  • the human subject has a duration of response ranging from 7 to 19 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 18 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 17 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 7 to 16 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 7 to 15 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 14 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 13 months following the treatment.
  • the human subject has a duration of response ranging from 7 to 12 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 30 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 30 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 10 to 30 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 30 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 30 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 13 to 30 months following the treatment.
  • the human subject has a duration of response ranging from 14 to 30 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 30 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 30 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 17 to 30 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 30 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 27 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 27 months following the treatment.
  • the human subject has a duration of response ranging from 10 to 27 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 27 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 27 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 13 to 27 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 14 to 27 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 27 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 27 months following the treatment.
  • the human subject has a duration of response ranging from 17 to 27 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 27 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 22 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 22 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 10 to 22 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 22 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 22 months following the treatment.
  • the human subject has a duration of response ranging from 13 to 22 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 14 to 22 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 22 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 22 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 17 to 22 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 22 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 21 months following the treatment.
  • the human subject has a duration of response ranging from 7 to 20 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 8 to 19 months following the treatment. In one embodiment, the human subject has a duration of response ranging from 9 to 18 months following the treatment. In another embodiment, the human subject has a duration of response ranging from 10 to 17 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 16 months following the treatment. In yet another embodiment, the human subject has a duration of response ranging from 12 to 15 months following the treatment. In a further embodiment, the human subject has a duration of response ranging from 13 to 14 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 5 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 6 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 7 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 8 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 9 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 10 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 11 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 12 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 13 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 14 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 15 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 16 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 17 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 18 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 19 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 20 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 21 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 22 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 23 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 24 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 25 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 26 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 27 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 28 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 29 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response in the treated population is at least or about 30 months following the treatment. [00323] In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 30 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 28 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 27 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 25 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 24 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 23 months. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 21 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 20 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 19 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 17 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 16 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 15 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 14 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 5 to 13 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 27 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 25 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 24 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 23 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 20 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 19 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 16 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 15 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 14 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 13 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 12 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 30 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 29 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 28 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 25 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 24 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 23 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 20 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 19 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 16 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 15 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 14 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 13 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 12 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6.41 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 8 to 22 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 9 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 10 to 22 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 11 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 12 to 12 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 13 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 14 to 22 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 15 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 16 to 22 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 17 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 18 to 22 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 8 to 27 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 9 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 10 to 27 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 11 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 12 to 27 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 13 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 14 to 27 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 15 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 16 to 27 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 17 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 18 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 19 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 20 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 21 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 22 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 23 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 24 to 27 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 30 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 8 to 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 9 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 10 to 30 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 11 to 30 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 12 to 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 13 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 14 to 30 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 15 to 30 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 16 to 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 17 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 18 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 19 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 20 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 21 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 22 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 23 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 24 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 25 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 26 to 30 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 27 to 30 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 6 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 7 to 20 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 8 to 19 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 9 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 10 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 11 to 16 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 12 to 15 months.
  • a population of the human subjects is treated by a method provided herein, wherein the duration of response of in the treated population ranges from 13 to 24 months.
  • the duration of response is at least or about 5 months for a population of subjects treated with the method.
  • the duration of response is at least or about 6 months for a population of subjects treated with the method.
  • the duration of response is at least or about 7 months for a population of subjects treated with the method.
  • the duration of response is at least or about 8 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 9 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 10 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 11 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 12 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 13 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 14 months for a population of subjects treated with the method.
  • the duration of response is at least or about 15 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 16 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 17 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 18 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 19 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 20 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 21 months for a population of subjects treated with the method.
  • the duration of response is at least or about 22 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 23 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 24 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 25 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 26 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 27 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 28 months for a population of subjects treated with the method.
  • the duration of response is at least or about 29 months for a population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 30 months for a population of subjects treated with the method.
  • the therapeutic outcome of the methods provided herein can be evaluated based on the progression free survival as set forth in Section 6.1.8.2(iv).
  • the human subject has a progression free survival of at least or about 5 months following the treatment. In another embodiment, the human subject has a progression free survival of at least or about 6 months following the treatment. In a further embodiment, the human subject has a progression free survival of at least or about 7 months following the treatment.
  • the human subject has a progression free survival of at least or about 8 months following the treatment. In one embodiment, the human subject has a progression free survival of at least or about 9 months following the treatment. In another embodiment, the human subject has a progression free survival of at least or about 10 months following the treatment. In a further embodiment, the human subject has a progression free survival of at least or about 11 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 12 months following the treatment. In one embodiment, the human subject has a progression free survival of at least or about 13 months following the treatment. In another embodiment, the human subject has a progression free survival of at least or about 14 months following the treatment.
  • the human subject has a progression free survival of at least or about 22 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 23 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 24 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 25 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 26 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 27 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 28 months following the treatment.
  • the human subject has a progression free survival of at least or about 29 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 30 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 31 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 32 months following the treatment. In yet another embodiment, the human subject has a progression free survival of at least or about 33 months following the treatment. [00326] In another embodiment, the human subject has a progression free survival ranging from 5 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 32 months following the treatment.
  • the human subject has a progression free survival ranging from 5 to 31 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 30 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 28 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 27 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 26 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 25 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 24 months following the treatment.
  • the human subject has a progression free survival ranging from 5 to 23 months following the treatment. In some embodiments, the human subject has a progression free survival ranging from 5 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 21 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 5 to 20 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 5 to 19 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 5 to 18 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 17 months following the treatment.
  • the human subject has a progression free survival ranging from 5 to 16 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 5 to 15 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 5 to 14 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 5 to 13 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 5 to 12 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 33 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 32 months following the treatment.
  • the human subject has a progression free survival ranging from 6 to 31 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 30 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 29 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 28 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 27 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 26 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 25 months following the treatment.
  • the human subject has a progression free survival ranging from 6 to 22 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 24 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 23 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 6 to 21 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 6 to 20 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 19 months following the treatment.
  • the human subject has a progression free survival ranging from 6 to 18 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 6 to 17 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 6 to 16 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 6 to 15 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 6 to 14 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 6 to 13 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 6 to 12 months following the treatment.
  • the human subject has a progression free survival ranging from 7 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 32 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 31 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 30 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 28 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 27 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 26 months following the treatment.
  • the human subject has a progression free survival ranging from 7 to 25 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 24 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 23 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 7 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 21 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 7 to 20 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 7 to 19 months following the treatment.
  • the human subject has a progression free survival ranging from 7 to 18 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 17 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 7 to 16 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 7 to 15 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 7 to 14 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 7 to 13 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 7 to 12 months following the treatment.
  • the human subject has a progression free survival ranging from 8 to 22 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 9 to 22 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 10 to 22 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 11 to 22 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 12 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 13 to 22 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 14 to 22 months following the treatment.
  • the human subject has a progression free survival progression free survival ranging from 15 to 22 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 16 to 22 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 17 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 18 to 22 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 8 to 33 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 9 to 33 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 10 to 33 months following the treatment.
  • the human subject has a progression free survival ranging from 11 to 33 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 12 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 13 to 33 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 14 to 33 months following the treatment. In yet another embodiment, the human subject has a progression free survival progression free survival ranging from 15 to 33 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 16 to 33 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 17 to 33 months following the treatment.
  • the human subject has a progression free survival ranging from 18 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 19 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 20 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 21 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 22 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 23 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 24 to 33 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 25 to 33 months following the treatment.
  • the human subject has a progression free survival ranging from 8 to 29 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 9 to 29 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 10 to 29 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 11 to 29 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 12 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 13 to 29 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 14 to 29 months following the treatment.
  • the human subject has a progression free survival progression free survival ranging from 15 to 29 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 16 to 29 months following the treatment. In one embodiment, the human subject has a progression free survival ranging from 17 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 18 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 19 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 20 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 21 to 29 months following the treatment.
  • the human subject has a progression free survival ranging from 22 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 23 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 24 to 29 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 25 to 29 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 6 to 21 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 7 to 20 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 8 to 19 months following the treatment.
  • the human subject has a progression free survival ranging from 9 to 18 months following the treatment. In another embodiment, the human subject has a progression free survival ranging from 10 to 17 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 11 to 16 months following the treatment. In yet another embodiment, the human subject has a progression free survival ranging from 12 to 15 months following the treatment. In a further embodiment, the human subject has a progression free survival ranging from 13 to 14 months following the treatment. [00327] In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 5 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 6 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 7 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 8 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 9 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 10 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 11 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 5 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 12 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 13 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 14 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 15 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 16 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 17 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 18 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 19 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 20 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 21 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 22 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 23 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 24 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 25 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 26 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 27 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 28 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 29 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 30 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 31 months following the treatment. In certain embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 32 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival in the treated population is at least or about 33 months following the treatment.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 32 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 31 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 30 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 29 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 28 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 25 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 24 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 23 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 20 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 19 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 16 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 15 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 14 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 13 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 5 to 12 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 32 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 31 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 30 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 28 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 27 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 25 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 24 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 23 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 21 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 20 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 19 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 17 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 16 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 15 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 14 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 13 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 12 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 33 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 32 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 31 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 30 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 29 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 28 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 26 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 25 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 24 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 23 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 22 months. In some embodiments, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 20 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 19 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 16 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 15 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 14 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 13 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 12 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6.41 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 8 to 33 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 9 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 10 to 33 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 11 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 12 to 33 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 13 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 14 to 33 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 15 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 16 to 33 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 17 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 18 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 19 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 20 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 21 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 22 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 23 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 24 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 25 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 26 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 27 to 33 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 28 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 29 to 33 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 8 to 29 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 9 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 10 to 29 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 11 to 29 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 12 to 29 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 13 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 14 to 29 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 15 to 29 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 16 to 29 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 17 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 18 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 19 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 20 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 21 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 22 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 23 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 24 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 25 to 29 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 26 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 27 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 28 to 29 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 8 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 9 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 10 to 22 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 11 to 22 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 12 to 12 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 13 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 14 to 22 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 15 to 22 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 16 to 22 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 17 to 22 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 18 to 22 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 6 to 21 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 7 to 20 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 8 to 19 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 9 to 18 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 10 to 17 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 11 to 16 months.
  • a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 12 to 15 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the progression free survival of in the treated population ranges from 13 to 24 months. [00329] In some embodiments, the progression free survival is at least or about 6 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 5 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 6 months for a population of subjects treated with the method.
  • the progression free survival is at least or about 7 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 8 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 9 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 10 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 11 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 12 months for a population of subjects treated with the method.
  • the progression free survival is at least or about 13 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 14 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 15 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 16 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 17 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 18 months for a population of subjects treated with the method.
  • the progression free survival is at least or about 19 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 20 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 21 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 22 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 23 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 24 months for a population of subjects treated with the method.
  • the progression free survival is at least or about 25 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 26 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 27 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 28 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 29 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 30 months for a population of subjects treated with the method.
  • the progression free survival is at least or about 31 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 32 months for a population of subjects treated with the method. In some embodiments, some embodiments, the progression free survival is at least or about 33 months for a population of subjects treated with the method. [00330]
  • the therapeutic outcome of the methods provided herein can be evaluated based on the overall survival as set forth in Section 6.1.8.2(v). In one embodiment, the human subject has an overall survival of at least or about 5 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 6 months following the treatment.
  • the human subject has an overall survival of at least or about 7 months following the treatment. In yet another embodiment, the human subject has an overall survival of at least or about 8 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 9 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 10 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 11 months following the treatment. In yet another embodiment, the human subject has an overall survival of at least or about 12 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 13 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 14 months following the treatment.
  • the human subject has an overall survival of at least or about 14.7 months following the treatment. In yet another embodiment, the human subject has an overall survival of at least or about 15 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 16 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 16.1 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 17 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 18 months following the treatment. In yet another embodiment, the human subject has an overall survival of at least or about 19 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 20 months following the treatment.
  • the human subject has an overall survival of at least or about 21 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 22 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 22.3 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 23 months following the treatment. In yet another embodiment, the human subject has an overall survival of at least or about 24 months following the treatment. In one embodiment, the human subject has an overall survival of at least or about 25 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 26 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 27 months following the treatment.
  • the human subject has an overall survival of at least or about 28 months following the treatment. In another embodiment, the human subject has an overall survival of at least or about 29 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 30 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 31 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 32 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 33 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 34 months following the treatment. In a further embodiment, the human subject has an overall survival of at least or about 35 months following the treatment.
  • the human subject has an overall survival ranging from 10 to 35 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 10 to 34 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 10 to 33 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 10 to 32 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 10 to 31 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 10 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 10 to 29 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 10 to 28 months following the treatment.
  • the human subject has an overall survival ranging from 10 to 27 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 10 to 26 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 10 to 25 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 11 to 35 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 12 to 35 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 13 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 14 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 14 to 35 months following the treatment.
  • the human subject has an overall survival ranging from 15 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 16 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 17 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 18 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 19 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 20 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 21 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 22 to 35 months following the treatment.
  • the human subject has an overall survival ranging from 23 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 24 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 25 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 26 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 27 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 28 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 29 to 35 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 30 to 35 months following the treatment.
  • the human subject has an overall survival ranging from 31 to 35 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 15 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 16 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 17 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 18 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 19 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 20 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 21 to 32 months following the treatment.
  • the human subject has an overall survival ranging from 22 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 23 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 24 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 25 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 26 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 27 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 28 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 29 to 32 months following the treatment.
  • the human subject has an overall survival ranging from 30 to 32 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 31 to 32 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 15 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 16 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 17 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 18 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 19 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 20 to 30 months following the treatment.
  • the human subject has an overall survival ranging from 21 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 22 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 23 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 24 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 25 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 26 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 27 to 30 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 28 to 30 months following the treatment.
  • the human subject has an overall survival ranging from 29 to 30 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 16 to 29 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 17 to 29 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 17 to 28 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 18 to 28 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 18 to 27 months following the treatment. In a further embodiment, the human subject has an overall survival ranging from 17 to 27 months following the treatment. In yet another embodiment, the human subject has an overall survival ranging from 17 to 26 months following the treatment.
  • the human subject has an overall survival ranging from 18 to 26 months following the treatment. In another embodiment, the human subject has an overall survival ranging from 18 to 25 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 19 to 25 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 19 to 24 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 20 to 24 months following the treatment. In one embodiment, the human subject has an overall survival ranging from 20 to 23 months following the treatment. [00332] Additionally, in some embodiments, the overall survival is evaluated for a population of human subjects treated by a method provided herein by evaluating the median or mean overall survival in the treated population.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 5 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 6 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 7 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 8 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 9 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 10 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 10.51 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 11 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 12 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 13 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 14 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 14.7 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 15 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 16 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 16.1 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 17 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 18 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 19 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 20 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 21 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 22 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 22.3 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 23 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 24 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 25 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 26 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 27 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 28 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 29 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 31 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 32 months.
  • a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 33 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 34 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the median or mean overall survival in the treated population is at least or about 35 months. [00333] In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 35 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 34 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 33 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 32 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 31 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 28 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 27 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 26 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 10 to 25 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 11 to 35 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 12 to 35 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 13 to 35 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 14 to 35 months. In one embodiment, 14 to 35 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 15 to 35 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 16 to 35 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 17 to 35 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 18 to 35 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 19 to 35 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 15 to 30 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 16 to 30 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 16 to 29 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 17 to 29 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 17 to 28 months. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 18 to 28 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 18 to 27 months. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 17 to 27 months. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 17 to 26 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 18 to 26 months.
  • a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 18 to 25 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 19 to 25 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 19 to 24 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 20 to 24 months. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the overall survival in the treated population ranges from 20 to 23 months.
  • the median overall survival is at least or about 5 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 6 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 7 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 8 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 9 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 10 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 11 months for a population of subjects treated with the method.
  • the median overall survival is at least or about 12 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 13 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 14 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 15 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 16 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 17 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 18 months for a population of subjects treated with the method.
  • the median overall survival is at least or about 19 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 20 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 21 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 22 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 22.3 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 23 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 24 months for a population of subjects treated with the method.
  • the median overall survival is at least or about 25 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 26 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 27 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 28 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 29 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 30 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 31 months for a population of subjects treated with the method.
  • the median overall survival is at least or about 32 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 33 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 34 months for a population of subjects treated with the method. In one embodiment, the median overall survival is at least or about 35 months for a population of subjects treated with the method. [00335] In one embodiment, the overall survival is from 10 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 34 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 33 months for a population of subjects treated with the method.
  • the overall survival is from 10 to 32 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 31 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 29 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 28 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 27 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 26 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 10 to 25 months for a population of subjects treated with the method.
  • the overall survival is from 11 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 12 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 13 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 14 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 15 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 16 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 17 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 18 to 35 months for a population of subjects treated with the method.
  • the overall survival is from 19 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 15 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 16 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 16 to 29 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 17 to 29 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 17 to 28 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 18 to 28 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 18 to 27 months for a population of subjects treated with the method.
  • the overall survival is from 17 to 27 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 17 to 26 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 18 to 26 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 18 to 25 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 19 to 25 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 19 to 24 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 20 to 24 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 20 to 23 months for a population of subjects treated with the method.
  • the overall survival is from 25 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 26 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 27 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 28 to 30 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 26 to 31 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 27 to 31 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 28 to 31 months for a population of subjects treated with the method.
  • the overall survival is from 29 to 31 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 27 to 32 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 28 to 32 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 29 to 32 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 30 to 32 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 28 to 33 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 29 to 33 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 30 to 33 months for a population of subjects treated with the method.
  • the overall survival is from 31 to 33 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 29 to 34 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 30 to 34 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 31 to 34 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 32 to 34 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 30 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 31 to 35 months for a population of subjects treated with the method. In one embodiment, the overall survival is from 32 to 35 months for a population of subjects treated with the method.
  • the overall survival is from 33 to 35 months for a population of subjects treated with the method. 5.2.2 Methods of Treating Cancer in Patient Populations Based on Additional Selection Criteria [00337] Provided herein are methods for the treatment of various cancers in subjects, wherein the cancers have any of the suitable markers and/or characteristics as provided in Section 6. Also provided herein are methods for the treatment of various cancers in subjects, wherein the subjects have any of the suitable characteristics as provided in Section 6.
  • a method of preventing or treating cancer in a subject comprising administering to the subject an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; and wherein the subject has any of the suitable characteristics as provided in Section 6.
  • CDRs complementarity determining regions
  • a method of preventing or treating cancer in a subject comprising administering to the subject an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; and wherein the cancer has any of the suitable markers and/or characteristics as provided in Section 6.
  • CDRs complementarity determining regions
  • a method of preventing or treating cancer in a subject comprising administering to the subject an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), and wherein the subject has any of the suitable characteristics as provided in Section 6.
  • MMAE monomethyl auristatin E
  • a method of preventing or treating cancer in a subject comprising administering to the subject an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), and wherein the cancer has any of the suitable markers and/or characteristics as provided in Section 6.
  • the subject is a human subject.
  • the therapeutic agents including ADCs that can be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5, and 6, selection of patients for treatment is described herein and exemplified in Section 5.2 including Sections 5.2.1 and 5.2.2 and Sections 3 and 6, dosing regimens and pharmaceutical composition for administering the therapeutic agent are described in Section 5.4, 5.6, 5.7, and Section 6 below, the biomarkers that can be used for identifying the therapeutic agents, selecting the patients, determining the outcome of these methods, and/or serving as criteria in any way for these methods are described herein and exemplified in Section 5.2 including Sections 5.2.1 and 5.2.2 and Sections 3 and 6, the biomarkers can be determined as described in Section 5.8 or as known in the art, therapeutic outcomes for the methods provided herein are described in this Section (Section 5.2 including Section 5.2.1.4) and Sections 3 and 6, additional therapeutic outcomes for the methods provided herein can be improvement of the
  • the methods provided herein include all permutations and combinations of the patients, therapeutic agents, dosing regiments, biomarkers, and therapeutic outcomes as described above and below.
  • 5.3 Antibody Drug Conjugates for the Methods [00343]
  • the ADC used in the methods comprises or is an anti-191P4D12 ADC described herein and/or in US Patent No.8,637,642, which is herein incorporated in its entirety by reference.
  • the anti-191P4D12 antibody drug conjugate provided for the methods herein comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 as provided herein, including in Sections 3, 5.3.1, and 6, conjugated to one or more units of cytotoxic agents (drug units, or D) as provided herein, including in Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Sections 5.3.2 and 5.3.4.
  • the cytotoxic agents (drug units, or D) can be covalently linked directly or via a linker unit (LU) as provided herein, including in Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Section 5.3.3.
  • the antibody drug conjugate compound has the following formula: or a pharmaceutically acceptable salt or solvate thereof; wherein: L is the antibody unit, e.g., the anti-nectin-4 antibody or an antigen binding fragment thereof for example as provided in Sections 3, 5.3.1, and 6, and (LU-D) is a linker unit-drug unit moiety, wherein: LU- is a linker unit for example as provided in Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Section 5.3.3, and D is a drug unit having cytostatic or cytotoxic activity against a target cell for example as provided Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Sections 5.3.2 and 5.3.4; and p is an integer from 1 to 20 with further examples provided in Sections 3 and 6 and this Section (Section 5.3).
  • p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3.
  • p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4.
  • p is about 1.
  • p is about 2.
  • p is about 3.
  • p is about 4.
  • p is about 3.8.
  • p is about 5.
  • p is about 6.
  • p is about 7.
  • p is about 8.
  • p is about 9.
  • p is about 10.
  • p is about 11.
  • p is about 12. In some embodiments, p is about 13. In some embodiments, p is about 14. In some embodiments, p is about 15. In some embodiments, p is about 16. In some embodiments, p is about 17. In some embodiments, p is about 18. In some embodiments, p is about 19. In some embodiments, p is about 20.
  • the antibody drug conjugate compound has the following formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: L is the Antibody unit, e.g., the anti-nectin-4 antibody or an antigen binding fragment thereof for example as provided in Sections 3, 5.3.1, and 6; and -A a -W w -Y y - is a linker unit (LU), wherein: -A- is a stretcher unit, a is 0 or 1, each -W- is independently an amino acid unit, w is an integer ranging from 0 to 12, -Y- is a self-immolative spacer unit, y is 0, 1 or 2, each for example as provided in Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Section 5.3.3; D is a drug units having cytostatic or cytotoxic activity against the target cell for example as provided Sections 3 and 6 and this Section (Section 5.3) with further disclosures in Sections 5.3.2 and 5.3.4; and
  • a is 0 or 1, w is 0 or 1, and y is 0, 1 or 2. In some embodiments, a is 0 or 1, w is 0 or 1, and y is 0 or 1. In some embodiments, p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3.
  • p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4.
  • p is about 1.
  • p is about 2.
  • p is about 3.
  • p is about 4.
  • p is about 3.8.
  • p is about 5.
  • p is about 6.
  • p is about 7.
  • p is about 8.
  • p is about 9.
  • p is about 10.
  • p is about 11.
  • p is about 12. In some embodiments, p is about 13. In some embodiments, p is about 14. In some embodiments, p is about 15. In some embodiments, p is about 16. In some embodiments, p is about 17. In some embodiments, p is about 18. In some embodiments, p is about 19. In some embodiments, p is about 20. In some embodiments, when w is not zero, y is 1 or 2. In some embodiments, when w is 1 to 12, y is 1 or 2. In some embodiments, w is 2 to 12 and y is 1 or 2. In some embodiments, a is 1 and w and y are 0.
  • the cytotoxic agent as part of any of the ADCs provided herein for the methods comprises, consists of, or is MMAE.
  • the drug loading is represented by p, the average number of drug molecules per antibody unit. Drug loading can range from 1 to 20 drugs (D) per antibody. The average number of drugs per antibody in preparation of conjugation reactions can be characterized by conventional means such as mass spectroscopy, ELISA assay, and HPLC. The quantitative distribution of antibody drug conjugates in terms of p can also be determined.
  • separation, purification, and characterization of homogeneous antibody drug conjugates where p is a certain value from antibody drug conjugates with other drug loadings can be achieved by means such as reverse phase HPLC or electrophoresis.
  • p is from 2 to 8.
  • the ADC is enfortumab vedotin. In certain embodiments of the methods provided herein, including in Sections 3, 5.2, and 6 and this Section (Section 5.3), the ADC is a biosimilar of enfortumab vedotin.
  • the antibody or antigen binding fragment thereof that binds to nectin-4-related proteins is an antibody or antigen binding fragment that specifically binds to nectin-4 protein comprising amino acid sequence of SEQ ID NO:2 (see FIG.1A).
  • the corresponding cDNA encoding the 191P4D12 protein has a sequence of SEQ ID NO:1 (see FIG.1A).
  • the antibody that specifically binds to nectin-4 protein comprising amino acid sequence of SEQ ID NO:2 includes antibodies that can bind to other nectin-4-related proteins.
  • antibodies that bind nectin-4 protein comprising amino acid sequence of SEQ ID NO:2 can bind nectin-4-related proteins such as nectin-4 variants and the homologs or analogs thereof.
  • the anti-nectin-4 antibody provided herein is a monoclonal antibody.
  • the antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:4 (cDNA sequence of SEQ ID NO:3), and/or a light chain comprising an amino acid sequence of SEQ ID NO:6 (cDNA sequence of SEQ ID NO:5), as shown in FIGS.1B and 1C.
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 (which is the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 136th amino acid (serine) of SEQ ID NO:7) and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 (which is the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8).
  • CDRs complementarity determining regions
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining region 1 (CDR-H1), CDR-H2, and CDR-H3 comprising the amino acid sequences of the corresponding CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region sequence set forth in SEQ ID NO:22 (which is the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 136th amino acid (serine) of SEQ ID NO:7) and a light chain variable region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of the corresponding CDR-L1, CDR-L2, and CDR-L3 in the light chain variable region sequence set forth in SEQ ID NO:23 (which is the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8).
  • CDR-H1 complementarity determining region 1
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 (which is the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 136th amino acid (serine) of SEQ ID NO:7) and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 (which is the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8).
  • CDRs complementarity determining regions
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining region 1 (CDR-H1), CDR-H2, and CDR-H3 consisting of the amino acid sequences of the corresponding CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable region sequence set forth in SEQ ID NO:22 (which is the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 136th amino acid (serine) of SEQ ID NO:7) and a light chain variable region comprising CDR-L1, CDR-L2, and CDR-L3 consisting of the amino acid sequences of the corresponding CDR-L1, CDR-L2, and CDR-L3 in the light chain variable region sequence set forth in SEQ ID NO:23 (which is the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8).
  • CDR-H1 complementarity determining
  • SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:7 and SEQ ID NO:8 are as shown in FIGS.1D and 1E and listed below: SEQ ID NO:22 SEQ ID NO:23 SEQ ID NO:7 SEQ ID NO:8 DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC [00357] CDR sequences can be determined according to well-known numbering systems. As described above, CDR regions are well-known to those skilled in the art and have been defined by well-known numbering systems.
  • CDRs Kabat Complementarity Determining Regions
  • Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol.196:901-17).
  • the end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol.2 (Kontermann and Dübel eds., 2d ed.2010)).
  • IMGT ImMunoGeneTics
  • IG immunoglobulins
  • TCR T-cell receptors
  • MHC major histocompatibility complex
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Kabat numbering and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Kabat numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to AbM numbering and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to AbM numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Chothia numbering and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Chothia numbering.
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Chothia numbering
  • a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Chothia numbering.
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Contact numbering and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Contact numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to IMGT numbering and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to IMGT numbering.
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to IMGT numbering
  • a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to IMGT numbering.
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Kabat numbering and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Kabat numbering.
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Kabat numbering
  • a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Kabat numbering.
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to AbM numbering and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to AbM numbering.
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to AbM numbering
  • a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to AbM numbering.
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Chothia numbering and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Chothia numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to Contact numbering and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to Contact numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the anti-nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 according to IMGT numbering and a light chain variable region comprising CDRs consisting of the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23 according to IMGT numbering.
  • CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
  • the CDR sequences according to different numbering systems can be readily determined, e.g., using online tools such as the one provided by Antigen receptor Numbering And Receptor ClassificatIon (ANARCI).
  • ANARCI Antigen receptor Numbering And Receptor ClassificatIon
  • the heavy chain CDR sequences within SEQ ID NO:22, and the light chain CDR sequences within SEQ ID NO:23 according to Kabat numbering as determined by ANARCI are listed in Table 6 below.
  • Table 6 [00369]
  • the heavy chain CDR sequences within SEQ ID NO:22, and the light chain CDR sequences within SEQ ID NO:23 according to IMGT numbering as determined by ANARCI are listed in Table 7 below.
  • the antibody or antigen binding fragment thereof comprises CDR-H1 comprising an amino acid sequence of SEQ ID NO:9, CDR-H2 comprising an amino acid sequence of SEQ ID NO:10, CDR-H3 comprising an amino acid sequence of SEQ ID NO:11, CDR-L1 comprising an amino acid sequence of SEQ ID NO:12, CDR-L2 comprising an amino acid sequence of SEQ ID NO:13, and CDR-L3 comprising an amino acid sequence of SEQ ID NO:14.
  • the antibody or antigen binding fragment thereof comprises CDR-H1 comprising an amino acid sequence of SEQ ID NO:16, CDR-H2 comprising an amino acid sequence of SEQ ID NO:17, CDR-H3 comprising an amino acid sequence of SEQ ID NO:18, CDR-L1 comprising an amino acid sequence of SEQ ID NO:19, CDR-L2 comprising an amino acid sequence of SEQ ID NO:20, and CDR-L3 comprising an amino acid sequence of SEQ ID NO:21.
  • the antibody or antigen binding fragment thereof comprises CDR-H1 consisting of an amino acid sequence of SEQ ID NO:9, CDR-H2 consisting of an amino acid sequence of SEQ ID NO:10, CDR-H3 consisting of an amino acid sequence of SEQ ID NO:11, CDR-L1 consisting of an amino acid sequence of SEQ ID NO:12, CDR-L2 consisting of an amino acid sequence of SEQ ID NO:13, and CDR-L3 consisting of an amino acid sequence of SEQ ID NO:14.
  • the antibody or antigen binding fragment thereof comprises CDR-H1 consisting of an amino acid sequence of SEQ ID NO:16, CDR-H2 consisting of an amino acid sequence of SEQ ID NO:17, CDR-H3 consisting of an amino acid sequence of SEQ ID NO:18, CDR-L1 consisting of an amino acid sequence of SEQ ID NO:19, CDR-L2 consisting of an amino acid sequence of SEQ ID NO:20, and CDR-L3 consisting of an amino acid sequence of SEQ ID NO:21.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23. [00375] In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO:22 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO:23.
  • the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
  • the antibody comprises a heavy chain consisting of the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain consisting of the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
  • amino acid sequence modification(s) of antibodies described herein are contemplated. For example, it may be desirable to optimize the binding affinity and/or other biological properties of the antibody, including but not limited to specificity, thermostability, expression level, effector functions, glycosylation, reduced immunogenicity, or solubility.
  • antibody variants can be prepared.
  • antibody variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide.
  • amino acid changes can alter post-translational processes of the antibody, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
  • the antibodies provided herein are chemically modified, for example, by the covalent attachment of any type of molecule to the antibody.
  • the antibody derivatives can include antibodies that have been chemically modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. Additionally, the antibody can contain one or more non- classical amino acids.
  • Variations can be a substitution, deletion, or insertion of one or more codons encoding the single domain antibody or polypeptide that results in a change in the amino acid sequence as compared with the original antibody or polypeptide.
  • Amino acid substitutions can be the result of replacing one amino acid with another amino acid comprising similar structural and/or chemical properties, such as the replacement of a leucine with a serine, e.g., conservative amino acid replacements.
  • Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which results in amino acid substitutions.
  • Insertions or deletions can optionally be in the range of about 1 to 5 amino acids.
  • the substitution, deletion, or insertion includes fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, or fewer than 2 amino acid substitutions relative to the original molecule.
  • the substitution is a conservative amino acid substitution made at one or more predicted non-essential amino acid residues. The variation allowed can be determined by systematically making insertions, deletions, or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the parental antibodies.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing multiple residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Antibodies generated by conservative amino acid substitutions are included in the present disclosure. In a conservative amino acid substitution, an amino acid residue is replaced with an amino acid residue comprising a side chain with a similar charge. As described above, families of amino acid residues comprising side chains with similar charges have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity.
  • the encoded protein can be expressed and the activity of the protein can be determined conservative (e.g., within an amino acid group with similar properties and/or side chains) substitutions can be made, so as to maintain or not significantly change the properties.
  • Amino acids can be grouped according to similarities in the properties of their side chains (see, e.g., Lehninger, Biochemistry 73-75 (2d ed.1975)): (1) non-polar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); and (4) basic: Lys (K), Arg (R), His(H).
  • Naturally occurring residues can be divided into groups based on common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.
  • any cysteine residue not involved in maintaining the proper conformation of the antibody also can be substituted, for example, with another amino acid, such as alanine or serine, to improve the oxidative stability of the molecule and to prevent aberrant crosslinking.
  • the variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis.
  • Site-directed mutagenesis see, e.g., Carter, 1986, Biochem J.237:1-7; and Zoller et al., 1982, Nucl. Acids Res.10:6487-500
  • cassette mutagenesis see, e.g., Wells et al., 1985, Gene 34:315-23
  • Covalent modifications of antibodies are included within the scope of the present disclosure.
  • Covalent modifications include reacting targeted amino acid residues of an antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the antibody.
  • Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the ⁇ -amino groups of lysine, arginine, and histidine side chains (see, e.g., Creighton, Proteins: Structure and Molecular Properties 79-86 (1983)), acetylation of the N-terminal amine, and amidation of any C- terminal carboxyl group.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain having certain homology or identity to the heavy chain as set forth in SEQ ID NO:7 and a light chain having certain homology or identity to the light chain as set forth in SEQ ID NO:8.
  • Such embodiments of heavy/light chains with homology or identity are further provided as follows.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 70% homology or identity to the heavy chain as set forth in SEQ ID NO:7.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 75% homology or identity to the heavy chain as set forth in SEQ ID NO:7. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 80% homology or identity to the heavy chain as set forth in SEQ ID NO:7. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 85% homology or identity to the heavy chain as set forth in SEQ ID NO:7. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 90% homology or identity to the heavy chain as set forth in SEQ ID NO:7.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain having more than 95% homology or identity to the heavy chain as set forth in SEQ ID NO:7. In certain embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain having any of the provided homology or identity to the heavy chain as set forth in SEQ ID NO:7, wherein the CDRs (CDR-H1, CDR-H2, and CDR-H3) are identical to the CDRs in the heavy chain as set forth in SEQ ID NO:7. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain having more than 70% homology or identity to the light chain as set forth in SEQ ID NO:8.
  • the antibody or antigen binding fragment provided herein comprises a light chain having more than 75% homology or identity to the light chain as set forth in SEQ ID NO:8. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain having more than 80% homology or identity to the light chain as set forth in SEQ ID NO:8. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain having more than 85% homology or identity to the light chain as set forth in SEQ ID NO:8. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain having more than 90% homology or identity to the light chain as set forth in SEQ ID NO:8.
  • the antibody or antigen binding fragment provided herein comprises a light chain having more than 95% homology or identity to the light chain as set forth in SEQ ID NO:8. In certain embodiments, the antibody or antigen binding fragment provided herein comprises a light chain having any of the provided homology or identity to the light chain as set forth in SEQ ID NO:8, wherein the CDRs (CDR-L1, CDR-L2, and CDR-L3) are identical to the CDRs in the light chain as set forth in SEQ ID NO:8. In certain embodiments, the antibody or antigen binding fragment provided herein comprises any homologous light chain and any homologous heavy chain as provided in this paragraph in any combination or permutation.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having certain homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22 and a light chain variable region having certain homology or identity to the light chain variable region as set forth in SEQ ID NO:23.
  • heavy chain variable regions and light chain variable regions with homology or identity are further provided as follows.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 70% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 75% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 80% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 85% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22. In some embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 90% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having more than 95% homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22. In certain embodiments, the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having any of the provided homology or identity to the heavy chain variable region as set forth in SEQ ID NO:22, wherein the CDRs (CDR-H1, CDR-H2, and CDR-H3) are identical to the CDRs in the heavy chain variable region as set forth in SEQ ID NO:22. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 70% homology or identity to the light chain variable region as set forth in SEQ ID NO:23.
  • the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 75% homology or identity to the light chain variable region as set forth in SEQ ID NO:23. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 80% homology or identity to the light chain variable region as set forth in SEQ ID NO:23. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 85% homology or identity to the light chain variable region as set forth in SEQ ID NO:23. In some embodiments, the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 90% homology or identity to the light chain variable region as set forth in SEQ ID NO:23.
  • the antibody or antigen binding fragment provided herein comprises a light chain variable region having more than 95% homology or identity to the light chain variable region as set forth in SEQ ID NO:23.
  • the antibody or antigen binding fragment provided herein comprises a light chain variable region having any of the provided homology or identity to the light chain variable region as set forth in SEQ ID NO:23, wherein the CDRs (CDR-L1, CDR-L2, and CDR-L3) are identical to the CDRs in the light chain variable region as set forth in SEQ ID NO:23.
  • the antibody or antigen binding fragment provided herein comprises any homologous light chain variable region and any homologous heavy chain variable region as provided in this paragraph in any combination or permutation.
  • the anti-nectin-4 antibody provided herein comprises heavy and light chain CDR regions of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light chain CDR regions comprising amino acid sequences that are homologous to the amino acid sequences of the heavy and light chain CDR regions of Ha22- 2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti- nectin-4 antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • ATCC American Type Culture Collection
  • the anti-nectin-4 antibody provided herein comprises heavy and light chain CDR regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light chain CDR regions consisting of amino acid sequences that are homologous to the amino acid sequences of the heavy and light chain CDR regions of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nectin-4 antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • ATC American Type Culture Collection
  • the antibody or antigen binding fragment thereof provided herein comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein: (a) the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR- H3) comprising the amino acid sequences of the heavy chain variable region CDRs set forth in the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267; (b) the light chain variable region comprises CDRs (CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequences of the light chain variable region CDRs set forth in the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR- H3) comprising the amino acid sequences of the heavy chain variable region CDRs set forth in the antibody produced by a hybridoma deposited under the
  • the antibody or antigen binding fragment thereof provided herein comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein: (a) the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR- H3) consisting of the amino acid sequences of the heavy chain variable region CDRs set forth in the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267; (b) the light chain variable region comprises CDRs (CDR-L1, CDR-L2, and CDR-L3) consisting of the amino acid sequences of the light chain variable region CDRs set forth in the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR- H3) consisting of the amino acid sequences of the heavy chain variable region CDRs set forth in the antibody produced by a hybridoma
  • the anti-nectin-4 antibody provided herein comprises heavy and light chain variable regions of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the heavy and light chain variable regions of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nectin-4 antibody provided herein.
  • ATCC American Type Culture Collection
  • the anti-nectin-4 antibody provided herein comprises heavy and light chain variable regions of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light variable regions consisting of amino acid sequences that are homologous to the amino acid sequences of the heavy and light chain variable regions of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nectin-4 antibody provided herein.
  • the constant region of the antibody of the disclosure any subclass of constant region can be chosen.
  • human IgG1 constant region as the heavy chain constant region and human Ig kappa constant region as the light chain constant region can be used.
  • the anti-nectin-4 antibody provided herein comprises heavy and light chains of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light chains comprising amino acid sequences that are homologous to the amino acid sequences of the heavy and light chains of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nectin-4 antibody provided herein.
  • ATCC American Type Culture Collection
  • the anti-nectin-4 antibody provided herein comprises heavy and light chains of an antibody designated Ha22-2(2,4)6.1 produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267, or heavy and light chains consisting of amino acid sequences that are homologous to the amino acid sequences of the heavy and light chains of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nectin-4 antibody provided herein.
  • ATCC American Type Culture Collection
  • the antibody or antigen binding fragment thereof provided herein comprises a heavy chain variable region and a light chain variable region, wherein: (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous or identical to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267; and (b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • ATCC American Type Culture Collection
  • the antibody or antigen binding fragment provided herein comprises a heavy chain variable region having certain homology or identity to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267 and a light chain variable region having certain homology or identity to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • ATC American Type Culture Collection
  • the heavy chain variable region comprises an amino acid sequence that is at least 85% homologous or identical to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267. In other embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 90% homologous or identical to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the heavy chain variable region comprises an amino acid sequence that is at least 95% homologous or identical to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the heavy chain variable region can be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the heavy chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain variable region comprises an amino acid sequence that is at least 85% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267. In other embodiments, the light chain variable region comprises an amino acid sequence that is at least 90% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain variable region comprises an amino acid sequence that is at least 95% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain variable region can be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the antibody or antigen binding fragment provided herein comprises any homologous light chain variable region and any homologous heavy chain variable region as provided in this paragraph in any combination or permutation.
  • the antibody or antigen binding fragment thereof provided herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises an amino acid sequence that is at least 80% homologous or identical to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267; and (b) the light chain comprises an amino acid sequence that is at least 80% homologous or identical to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the antibody or antigen binding fragment provided herein comprises a heavy chain having certain homology or identity to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267 and a light chain having certain homology or identity to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • ATCC American Type Culture Collection
  • the heavy chain comprises an amino acid sequence that is at least 85% homologous or identical to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267. In other embodiments, the heavy chain comprises an amino acid sequence that is at least 90% homologous or identical to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267. In yet other embodiments, the heavy chain comprises an amino acid sequence that is at least 95% homologous or identical to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the heavy chain can be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the heavy chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain comprises an amino acid sequence that is at least 85% homologous or identical to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain comprises an amino acid sequence that is at least 90% homologous or identical to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267. In yet other embodiments, the light chain comprises an amino acid sequence that is at least 95% homologous or identical to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the light chain can be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the light chain amino acid sequence of the antibody produced by a hybridoma deposited under the American Type Culture Collection (ATCC) Accession NO: PTA-11267.
  • the antibody or antigen binding fragment provided herein comprises any homologous light chain and any homologous heavy chain as provided in this paragraph in any combination or permutation. [00400]
  • the antibody or antigen binding fragment thereof provided herein binds to a specific epitope in 191P4D12.
  • the antibody or antigen binding fragment thereof provided herein binds to VC1 domain of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to VC1 domain but not to C1C2 domain of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 1st to 147th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to an epitope located in the 1st to 147th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 1st to 10th amino acid residues of 191P4D12.
  • the antibody or antigen binding fragment thereof provided herein binds to the 11th to 20th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 21st to 30th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 31st to 40th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 41st to 50th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 51st to 60th amino acid residues of 191P4D12.
  • the antibody or antigen binding fragment thereof provided herein binds to the 61st to 70th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 71st to 80th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 81st to 90th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 91st to 100th amino acid residues of 191P4D12.
  • the antibody or antigen binding fragment thereof provided herein binds to the 101st to 110th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 111th to 120th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 121st to 130th amino acid residues of 191P4D12. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to the 131st to 140th amino acid residues of 191P4D12.
  • the antibody or antigen binding fragment thereof provided herein binds to the 141st to 147th amino acid residues of 191P4D12.
  • the binding epitopes of certain embodiments the antibodies or antigen binding fragments thereof provided herein have been determined and described in WO 2012/047724, which is incorporated herein in its entirety by reference. [00401]
  • the antibody or antigen binding fragment thereof provided herein binds to epitopes in 191P4D12 that are common between the 191P4D12 variants observed in human.
  • the antibody or antigen binding fragment thereof provided herein binds to epitopes in 191P4D12 that are common between the 191P4D12 polymorphism observed in human.
  • the antibody or antigen binding fragment thereof provided herein binds to epitopes in 191P4D12 that are common between the 191P4D12 polymorphism observed in human cancers. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to epitopes in 191P4D12 that would bind, internalize, disrupt or modulate the biological function of 191P4Dl2 or 191P4D12 variants. In some embodiments, the antibody or antigen binding fragment thereof provided herein binds to epitopes in 191P4D12 that would disrupt the interaction between 191P4D12 with ligands, substrates, and binding partners.
  • Engineered antibodies provided herein include those in which modifications have been made to framework residues within VH and/or VL (e.g. to improve the properties of the antibody). Typically, such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation can contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.
  • the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis (e.g., “backmutated” from leucine to methionine).
  • site-directed mutagenesis e.g., “backmutated” from leucine to methionine
  • backmutated antibodies are also intended to be encompassed by the disclosure.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T-cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No.2003/0153043 by Carr et al.
  • antibodies of the disclosure can be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • modifications within the Fc region typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • an anti-191P4D12 antibody provided herein can be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No.5,677,425 by Bodmer et al.
  • the number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the anti-191P4D12 antibody.
  • the Fc hinge region of an antibody is mutated to decrease the biological half-life of the anti-191P4D12 antibody.
  • one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • the anti-191P4D12 antibody is modified to increase its biological half-life.
  • mutations can be introduced as described in U.S. Pat. No.6,277,375 to Ward.
  • the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos.5,869,046 and 6,121,022 by Presta et al.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid specific residues can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement.
  • This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • Reactivity of the anti-191P4D12 antibodies with a 191P4D12-related protein can be established by a number of well-known means, including Western blot, immunoprecipitation, ELISA, and FACS analyses using, as appropriate, 191P4D12-related proteins, 191P4D12-expressing cells or extracts thereof.
  • a 191P4D12 antibody or fragment thereof can be labeled with a detectable marker or conjugated to a second molecule.
  • Suitable detectable markers include, but are not limited to, a radioisotope, a fluorescent compound, a bioluminescent compound, chemiluminescent compound, a metal chelator or an enzyme.
  • bi-specific antibodies specific for two or more 191P4D12 epitopes are generated using methods generally known in the art. Homodimeric antibodies can also be generated by cross-linking techniques known in the art (e.g., Wolff et al., Cancer Res.53: 2560-2565).
  • the anti-191P4D12 antibody provided herein is an antibody comprising heavy and light chain of an antibody designated Ha22-2(2,4)6.1.
  • the heavy chain of Ha22-2(2,4)6.1 consists of the amino acid sequence ranging from 20 th E residue to the 466 th K residue of SEQ ID NO:7 and the light chain of Ha22-2(2,4)6.1 consists of amino acid sequence ranging from 23 rd D residue to the 236 th C residue of SEQ ID NO:8 sequence.
  • the hybridoma producing the antibody designated Ha22-2(2,4)6.1 was sent (via Federal Express) to the American Type Culture Collection (ATCC), P.O. Box 1549, Manassas, VA 20108 on 18-August-2010 and assigned Accession number PTA-11267.
  • ATCC American Type Culture Collection
  • P.O. Box 1549 Manassas, VA 20108 on 18-August-2010 and assigned Accession number PTA-11267.
  • Additional embodiments of anti-nectin-4 antibody have been described in US Patent No.8,637,642 and International Application No.
  • the disclosure further provides various embodiments for the cytotoxic agent as part of the ADC for use in the methods.
  • the cytotoxic agent as part of any of the ADCs provided herein for the methods comprises, consists of, or is a tubulin disrupting agent.
  • the cytotoxic agent is a tubulindisrupting agent.
  • the tubulin disrupting agent is selected from the group consisting of a dolastatin, an auristatin, a hemiasterlin, a vinca alkaloid, a maytansinoid, an eribulin, a colchicine, a plocabulin, a phomopsin, an epothilone, a cryptophycin, and a taxane.
  • the tubulin disrupting agent is an auristatin.
  • the auristatin is monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), AFP, or auristain T.
  • the auristatin is monomethyl auristatin E (MMAE).
  • the cytotoxic agent as part of any of the ADCs provided herein for the methods comprises, consists of, or is any agent selected from the cytotoxic agents described in US Patent No.8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are hereby incorporated in their entireties by reference
  • the auristatin is MMAE (wherein the wavy line indicates the covalent attachment to a linker of an antibody drug conjugate).
  • an exemplary embodiment comprising MMAE and a linker component has the following structure (wherein L presents the antibody (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) and p ranges from 1 to 12): [00417] In some embodiments of the formula described in the preceding paragraph, p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.
  • p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3. In some embodiments of the formula described in the preceding paragraph, p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments of the formula described in the preceding paragraph, p is about 1. In some embodiments of the formula described in the preceding paragraph, p is about 2.
  • p is about 3. In some embodiments of the formula described in the preceding paragraph, p is about 4. In some embodiments of the formula described in the preceding paragraph, p is about 3.8. In some embodiments of the formula described in the preceding paragraph, p is about 5. In some embodiments of the formula described in the preceding paragraph, p is about 6. In some embodiments of the formula described in the preceding paragraph, p is about 7. In some embodiments of the formula described in the preceding paragraph, p is about 8. In some embodiments of the formula described in the preceding paragraph, p is about 9. In some embodiments of the formula described in the preceding paragraph, p is about 10. In some embodiments of the formula described in the preceding paragraph, p is about 11.
  • p is about 12. In some embodiments of the formula described in the preceding paragraph, p is about 13. In some embodiments of the formula described in the preceding paragraph, p is about 14. In some embodiments of the formula described in the preceding paragraph, p is about 15. In some embodiments of the formula described in the preceding paragraph, p is about 16. In some embodiments of the formula described in the preceding paragraph, p is about 17. In some embodiments of the formula described in the preceding paragraph, p is about 18. In some embodiments of the formula described in the preceding paragraph, p is about 19. In some embodiments of the formula described in the preceding paragraph, p is about 20.
  • peptide-based drug units can be prepared by forming a peptide bond between two or more amino acids and/or peptide fragments.
  • Such peptide bonds can be prepared, for example, according to the liquid phase synthesis method (see E. Schröder and K. Lübke, “The Peptides”, volume 1, pp 76-136, 1965, Academic Press) that is well-known in the field of peptide chemistry.
  • the auristatin/dolastatin drug units can be prepared according to the methods of: US 5635483; US 5780588; Pettit et al (1989) J. Am. Chem. Soc.
  • the antibody drug conjugates comprise a linker unit between the drug unit (e.g., MMAE) and the antibody unit (e.g., the anti-191P4D12 antibody or antigen binding fragment thereof).
  • the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the drug unit from the antibody in the intracellular environment.
  • the linker unit is not cleavable and the drug is released, for example, by antibody degradation.
  • the linker is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea).
  • the linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
  • a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin-B, which is highly expressed in cancerous tissue can be used (e.g., a Phe- Leu or a Gly-Phe-Leu-Gly linker (SEQ ID NO:15)).
  • the peptidyl linker is at least two amino acids long or at least three amino acids long.
  • the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values.
  • the pH-sensitive linker hydrolyzable under acidic conditions.
  • an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
  • the linker is cleavable under reducing conditions (e.g., a disulfide linker).
  • disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3- (2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB and SMPT.
  • SATA N-succinimidyl-S-acetylthioacetate
  • SPDP N-succinimidyl-3- (2-pyridyldithio)propionate
  • SPDB N-succinimidyl-3-(2-pyridyldithio)butyrate
  • SMPT N-succ
  • a “linker unit” is a bifunctional compound that can be used to link a drug unit and an antibody unit to form an antibody drug conjugate.
  • the linker unit has the formula: wherein:-A- is a stretcher unit, a is 0 or 1, each -W- is independently an amino acid unit, w is an integer ranging from 0 to 12, -Y- is a self-immolative spacer unit, and y is 0, 1 or 2.
  • a is 0 or 1, w is 0 or 1, and y is 0, 1 or 2.
  • a is 0 or 1, w is 0 or 1, and y is 0 or 1.
  • y is 1 or 2. In some embodiments, w is 2 to 12 and y is 1 or 2. In some embodiments, a is 1 and w and y are 0.
  • the linker and each of the stretcher unit, the amino acid unit, and the spacer unit have been described in US Patent No.8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are hereby incorporated in their entireties by reference.
  • Embodiments of the antibody-drug conjugates can include: wherein w and y are each 0, 1 or 2, and, wherein w and y are each 0, 5.3.4 Drug Loading [00424] Drug loading is represented by p and is the average number of drug units per antibody in a molecule. Drug loading can range from 1 to 20 drug units (D) per antibody.
  • the ADCs provided herein include collections of antibodies or antigen binding fragments conjugated with a range of drug units, e.g., from 1 to 20.
  • the average number of drug units per antibody in preparations of ADC from conjugation reactions can be characterized by conventional means such as mass spectroscopy and, ELISA assay.
  • the quantitative distribution of ADC in terms of p can also be determined.
  • the drug loading for an ADC provided herein ranges from 1 to 20. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 18. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 15. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 12. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 10. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 9.
  • the drug loading for an ADC provided herein ranges from 1 to 8. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 7. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 6. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 5. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 4. In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to 3. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 12. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 10. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 9.
  • the drug loading for an ADC provided herein ranges from 2 to 8. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 7. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 6. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 5. In certain embodiments, the drug loading for an ADC provided herein ranges from 2 to 4. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 12. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 10. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 9. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 8.
  • the drug loading for an ADC provided herein ranges from 3 to 7. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 6. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 5. In certain embodiments, the drug loading for an ADC provided herein ranges from 3 to 4. [00426] In certain embodiments, the drug loading for an ADC provided herein ranges from 1 to about 8; from about 2 to about 6; from about 3 to about 5; from about 3 to about 4; from about 3.1 to about 3.9; from about 3.2 to about 3.8; from about 3.2 to about 3.7; from about 3.2 to about 3.6; from about 3.3 to about 3.8; or from about 3.3 to about 3.7.
  • the drug loading for an ADC provided herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or more. In some embodiments, the drug loading for an ADC provided herein is about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, or about 3.9. [00428] In some embodiments, the drug loading for an ADC provided herein ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, or 2 to 13. In some embodiments, the drug loading for an ADC provided herein ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, or 3 to 13.
  • the drug loading for an ADC provided herein is about 1. In some embodiments, the drug loading for an ADC provided herein is about 2. In some embodiments, the drug loading for an ADC provided herein is about 3. In some embodiments, the drug loading for an ADC provided herein is about 4. In some embodiments, the drug loading for an ADC provided herein is about 3.8. In some embodiments, the drug loading for an ADC provided herein is about 5. In some embodiments, the drug loading for an ADC provided herein is about 6. In some embodiments, the drug loading for an ADC provided herein is about 7. In some embodiments, the drug loading for an ADC provided herein is about 8. In some embodiments, the drug loading for an ADC provided herein is about 9.
  • the drug loading for an ADC provided herein is about 10. In some embodiments, the drug loading for an ADC provided herein is about 11. In some embodiments, the drug loading for an ADC provided herein is about 12. In some embodiments, the drug loading for an ADC provided herein is about 13. In some embodiments, the drug loading for an ADC provided herein is about 14. In some embodiments, the drug loading for an ADC provided herein is about 15. In some embodiments, the drug loading for an ADC provided herein is about 16. In some embodiments, the drug loading for an ADC provided herein is about 17. In some embodiments, the drug loading for an ADC provided herein is about 18. In some embodiments, the drug loading for an ADC provided herein is about 19.
  • the drug loading for an ADC provided herein is about 20.
  • fewer than the theoretical maximum of drug units are conjugated to an antibody during a conjugation reaction.
  • An antibody can contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent.
  • antibodies do not contain many free and reactive cysteine thiol groups which can be linked to a drug unit; indeed most cysteine thiol residues in antibodies exist as disulfide bridges.
  • an antibody can be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups.
  • a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP)
  • an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine.
  • the linker unit or a drug unit is conjugated via a lysine residue on the antibody unit.
  • the linker unit or a drug unit is conjugated via a cysteine residue on the antibody unit.
  • the amino acid that attaches to a linker unit or a drug unit is in the heavy chain of an antibody or antigen binding fragment thereof. In some embodiments, the amino acid that attaches to a linker unit or a drug unit is in the light chain of an antibody or antigen binding fragment thereof. In some embodiments, the amino acid that attaches to a linker unit or a drug unit is in the hinge region of an antibody or antigen binding fragment thereof. In some embodiments, the amino acid that attaches to a linker unit or a drug unit is in the Fc region of an antibody or antigen binding fragment thereof.
  • the amino acid that attaches to a linker unit or a drug unit is in the constant region (e.g., CH1, CH2, or CH3 of a heavy chain, or CH1 of a light chain) of an antibody or antigen binding fragment thereof.
  • the amino acid that attaches to a linker unit or a drug unit is in the VH framework regions of an antibody or antigen binding fragment thereof.
  • the amino acid that attaches to a linker unit or a drug unit is in the VL framework regions of an antibody or antigen binding fragment thereof.
  • the loading (drug/antibody ratio) of an ADC can be controlled in different ways, e.g., by: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number and/or position of linker-drug attachments (such as thioMab or thioFab prepared as disclosed herein and in WO2006/034488 (herein incorporated by reference in its entirety)).
  • linker-drug attachments such as thioMab or thioFab prepared as disclosed herein and in WO2006/034488 (herein incorporated by reference in its entirety)
  • the resulting product is a mixture of ADC compounds with a distribution of one or more drug unit attached to an antibody unit.
  • the average number of drugs per antibody can be calculated from the mixture by a dual ELISA antibody assay, which is specific for antibody and specific for the drug.
  • Individual ADC molecules can be identified in the mixture by mass spectroscopy and separated by HPLC, e.g. hydrophobic interaction chromatography (see, e.g., Hamblett, K.J., et al.
  • a homogeneous ADC with a single loading value can be isolated from the conjugation mixture by electrophoresis or chromatography.
  • the antibody drug conjugate for the methods provided herein is AGS-22M6E, which is prepared according to the methods described in US Patent No.8,637,642 and has the following formula: wherein L is Ha22-2(2,4)6.1 and p is from 1 to 20. [00435] In some embodiments, p ranges from 1to 20, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.
  • p ranges from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3. In other embodiments, p is about 1. In other embodiments, p is about 2. In other embodiments, p is about 3. In other embodiments, p is about 4. In other embodiments, p is about 5. In other embodiments, p is about 6. In other embodiments, p is about 7. In other embodiments, p is about 8. In other embodiments, p is about 9. In other embodiments, p is about 10. In some embodiments, p is about 3.1. In some embodiments, p is about 3.2. In some embodiments, p is about 3.3. In some embodiments, p is about 3.4.
  • p is about 3.5. In other embodiments, p is about 3.6. In some embodiments, p is about 3.7. In some embodiments, p is about 3.8. In some embodiments, p is about 3.9. In some embodiments, p is about 4.0. In some embodiments, p is about 4.1. In some embodiments, p is about 4.2. In some embodiments, p is about 4.3. In some embodiments, p is about 4.4. In some embodiments, p is about 4.5. In other embodiments, p is about 4.6. In some embodiments, p is about 4.7. In some embodiments, p is about 4.8. In some embodiments, p is about 4.9. In some embodiments, p is about 5.0.
  • the ADC used in the methods provided herein is enfortumab vedotin.
  • Enfortumab vedotin is an ADC comprised of a fully human immunoglobulin G1 kappa (IgG1 ⁇ ) antibody conjugated to the microtubule-disrupting agent (MMAE) via a protease-cleavable linker (Challita-Eid PM et al, Cancer Res. 2016;76(10):3003-13].
  • Enfortumab vedotin induces antitumor activity by binding to 191P4D12 protein on the cell surface leading to internalization of the ADC-191P4D12 complex, which then traffics to the lysosomal compartment where MMAE is released via proteolytic cleavage of the linker. Intracellular release of MMAE subsequently disrupts tubulin polymerization resulting in G2/M phase cell cycle arrest and apoptotic cell death (Francisco JA et al, Blood.2003 Aug 15;102(4):1458-65). [00437] As described above and in in US Patent No.8,637,642, AGS-22M6E is an ADC derived from a murine hybridoma cell line.
  • Enfortumab vedotin is a Chinese hamster ovary (CHO) cell line-derived equivalent of AGS-22M6E ADC and is an exemplary product used for human treatment.
  • Enfortumab vedotin has the same amino acid sequence, linker and cytotoxic drug as AGS-22M6E.
  • the comparability between enfortumab vedotin and AGS- 22M6E was confirmed through extensive analytical and biological characterization studies, such as binding affinity to 191P4D12, in vitro cytotoxicity, and in vivo antitumor activity.
  • the ADC provided herein is enfortumab vedotin, also known as EV, PADCEV, AGS-22M6E, AGS-22C3E, ASG-22C3E.
  • the enfortumab vedotin includes an anti-191P4D12 antibody, wherein the antibody or antigen binding fragment thereof comprises a heavy chain comprising amino acid residue 20 to amino acid residue 466 of SEQ ID NO:7 and a light chain comprising amino acid residue 23 to amino acid residue 236 of SEQ ID NO:8.
  • Enfortumab vedotin is a Nectin-4 directed antibody -drug conjugate (ADC) comprised of a fully human anti-nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD- 1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1.
  • ADC Nectin-4 directed antibody -drug conjugate
  • ADC Nectin-4 directed antibody -drug conjugate
  • ADC Nectin-4 directed antibody -drug conjugate
  • ADC Nectin-4 directed antibody -drug conjugate
  • ADC Nectin-4 directed antibody
  • Enfortumab vedotin has the following structural formula: [00441] Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis. [00442] Enfortumab vedotin injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use.
  • Enfortumab vedotin is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL.
  • each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg).
  • Each mL of reconstituted solution contains 10 mg of enfortumab vedotin, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0.
  • compositions include an antibody drug conjugate provided herein, and one or more pharmaceutically acceptable or physiologically acceptable excipients.
  • the antibody drug conjugate are provided in combination with, or separate from, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab).
  • the antibody drug conjugate are provided in combination with, or separate from pembrolizumab.
  • compositions comprising the antibody drug conjugate and pembrolizumab and one or more pharmaceutically acceptable or physiologically acceptable excipients.
  • the antibody drug conjugate and pembrolizumab are present in a therapeutically acceptable amount.
  • the antibody drug conjugate and pembrolizumab are provided in combination with, or separate from, one or more additional agents.
  • a composition comprising such one or more additional agents and one or more pharmaceutically acceptable or physiologically acceptable excipients.
  • the antibody drug conjugate and an additional agent(s) are present in a therapeutically acceptable amount.
  • the pharmaceutical compositions can be used in accordance with the methods and uses provided herein.
  • the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice treatment methods and uses provided herein.
  • Pharmaceutical compositions provided herein can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • the pharmaceutical compositions comprising the ADCs and pembrolizumab can further comprise other therapeutically active agents or compounds disclosed herein or known to the skilled artisan which can be used in the treatment or prevention of various diseases and disorders as set forth herein (e.g., a cancer).
  • compositions typically comprise a therapeutically effective amount of at least one of the antibody drug conjugates provided herein and pembrolizumab and one or more pharmaceutically acceptable formulation agents. In certain embodiments, the pharmaceutical composition further comprises one or more additional agents described herein.
  • a pharmaceutical composition comprises an antibody drug conjugate provided herein and pembrolizumab. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of an antibody drug conjugate provided herein and pembrolizumab. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.
  • the antibody drug conjugate in the pharmaceutical composition provided herein is selected from the antibody drug conjugates described in Section 5.3 above.
  • the pharmaceutical composition comprises the antibody drug conjugate provided herein in an amount such that the dosage of antibody drug conjugate administered to a subject is about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg,
  • the pharmaceutical composition comprises the antibody drug conjugate provided herein in an amount such that the dosage of antibody drug conjugate administered to a subject is 0.1 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg.
  • the pharmaceutical composition comprises the antibody drug conjugate provided herein in an amount such that the dosage of the antibody drug conjugate administered to a subject is about 0.1 mg/kg to about 100 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to the patient is about 1 mg/kg to about 75 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to a patient is between about 1 mg/kg and about 20 mg/kg of the subject’s body weight, such as about 1 mg/kg to about 5 mg/kg of the subject’s body weight.
  • the pharmaceutical composition comprises the antibody drug conjugate provided herein in an amount such that the dosage of the antibody drug conjugate administered to a subject is 0.1 mg/kg to 100 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to the patient is 1 mg/kg to 75 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to a patient is between 1 mg/kg and 20 mg/kg of the subject’s body weight, such as 1 mg/kg to 5 mg/kg of the subject’s body weight. [00453] In certain embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of from 0.1 -100 mg/mL.
  • the pharmaceutical composition comprises the antibody drug conjugate at a concentration of from 1 to 20 mg/mL. In other embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of from 5 to 15 mg/mL. In other embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of from 8 to 12 mg/mL. In other embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of from 9 to 11 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 9.5 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 9.6 mg/mL.
  • the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 9.7 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 9.8 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 9.9 mg/mL. In yet other embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10 mg/mL. In yet other embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.1 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.2 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.3 mg/mL.
  • the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.3 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.4 mg/mL. In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate at a concentration of about 10.5 mg/mL. In some embodiments, the pharmaceutical composition provided herein comprises L- histidine, TWEEN-20, and at least one of trehalose dihydrate or sucrose. In some embodiments, the pharmaceutical composition provided herein further comprises hydrochloric acid (HCl) or succinic acid.
  • HCl hydrochloric acid
  • the pharmaceutical composition comprises pembrolizumab in an amount of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg. In particular embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of about 200 mg. [00455] In certain embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, about 400 mg, 450 mg or 500 mg. In particular embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of 200 mg.
  • the pharmaceutical composition comprises pembrolizumab in an amount of about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg.
  • the pharmaceutical composition comprises pembrolizumab in an amount of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg.
  • the pharmaceutical composition comprises pembrolizumab in an amount of about 150 mg to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg. [00457] In certain embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of 100 mg to 500 mg, 150 mg to 500 mg, 200 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, or 450 mg to 500 mg.
  • the pharmaceutical composition comprises pembrolizumab in an amount of 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, or 100 mg to 150 mg. In certain embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of 150 mg to 450 mg, 150 to 400 mg, 150 to 350 mg, 200 mg to 450 mg, 200 mg to 400 mg, 200 mg to 300 mg, or 200 mg to 250 mg. [00458] In some embodiments, the concentration of L-histidine useful in the pharmaceutical compositions provided herein is in the range of between 5 and 50 mM.
  • the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 10 and 40 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 15 and 35 mM. [00459] In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 15 and 30 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 15 and 25 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 15 and 35 mM.
  • the concentration of L-histidine in the pharmaceutical compositions provided herein is about 16 mM. In some embodiments, the concentration of L- histidine in the pharmaceutical compositions provided herein is about 17 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 18 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 19 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 20 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 21 mM.
  • the concentration of L- histidine in the pharmaceutical compositions provided herein is about 22 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 23 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 24 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 25 mM. [00460] In some embodiments, the concentration of TWEEN-20 useful in the pharmaceutical compositions provided herein is in the range of from 0.001 to 0.1% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of from 0.0025 to 0.075% (v/v).
  • the concentration of TWEEN-20 is in the range of from 0.005 to 0.05% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of from 0.0075 to 0.025% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of from 0.0075 to 0.05% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of from 0.01 to 0.03% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.01% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.015% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.016% (v/v).
  • the concentration of TWEEN-20 is about 0.017% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.018% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.019% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.02% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.021% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.022% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.023% (v/v). In one particular embodiment, the concentration of TWEEN-20 is about 0.024% (v/v).
  • the concentration of TWEEN-20 is about 0.025% (v/v).
  • the concentration of trehalose dihydrate useful in the pharmaceutical compositions provided herein is in the range of between 1% and 20% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 2% and 15% (w/v). In one embodiment, the concentration of trehalose dihydrate is in the range of 3% and 10% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4% and 9% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4% and 8% (w/v).
  • the concentration of trehalose dihydrate is in the range of 4% and 7% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4% and 6% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4.5% and 6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.7% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.8% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.9% (w/v).
  • the concentration of trehalose dihydrate is about 5.0% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.1% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.2% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.3% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.4% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.5% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.7% (w/v).
  • the concentration of trehalose dihydrate is about 5.8% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.9% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.0% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.1% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.2% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.3% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.4% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.5% (w/v).
  • the molarity of the trehalose dihydrate is from 50 to 300 mM. In other embodiments, the molarity of the trehalose dihydrate is from 75 to 250 mM. In some embodiments, the molarity of the trehalose dihydrate is from 100 to 200 mM. In other embodiments, the molarity of the trehalose dihydrate is from 130 to 150 mM. In some embodiments, the molarity of the trehalose dihydrate is from 135 to 150 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 135 mM.
  • the molarity of the trehalose dihydrate is about 136 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 137 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 138 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 139 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 140 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 141 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 142 mM.
  • the molarity of the trehalose dihydrate is about 143 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 144 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 145 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 146 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 150 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 151 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 151 mM.
  • the molarity of the trehalose dihydrate is about 152 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 153 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 154 mM. In certain embodiments, the molarity of the trehalose dihydrate is about 155 mM. [00463] In one embodiment, the concentration of sucrose useful in the pharmaceutical compositions provided herein is in the range of between 1% and 20% (w/v). In another embodiment, the concentration of sucrose is in the range of 2% and 15% (w/v). In one embodiment, the concentration of sucrose is in the range of 3% and 10% (w/v).
  • the concentration of sucrose is in the range of 4% and 9% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% and 8% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% and 7% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% and 6% (w/v). In another embodiment, the concentration of sucrose is in the range of 4.5% and 6% (w/v). In another embodiment, the concentration of sucrose is about 4.6% (w/v). In another embodiment, the concentration of sucrose is about 4.7% (w/v). In another embodiment, the concentration of sucrose is about 4.8% (w/v). In another embodiment, the concentration of sucrose is about 4.9% (w/v).
  • the concentration of sucrose is about 5.0% (w/v). In another embodiment, the concentration of sucrose is about 5.1% (w/v). In another embodiment, the concentration of sucrose is about 5.2% (w/v). In another embodiment, the concentration of sucrose is about 5.3% (w/v). In another embodiment, the concentration of sucrose is about 5.4% (w/v). In another embodiment, the concentration of sucrose is about 5.5% (w/v). In another embodiment, the concentration of sucrose is about 5.6% (w/v). In another embodiment, the concentration of sucrose is about 5.7% (w/v). In another embodiment, the concentration of sucrose is about 5.8% (w/v). In another embodiment, the concentration of sucrose is about 5.9% (w/v).
  • the concentration of sucrose is about 6.0% (w/v). In another embodiment, the concentration of sucrose is about 6.1% (w/v). In another embodiment, the concentration of sucrose is about 6.2% (w/v). In another embodiment, the concentration of sucrose is about 6.3% (w/v). In another embodiment, the concentration of sucrose is about 6.4% (w/v). In another embodiment, the concentration of sucrose is about 6.5% (w/v). [00464] In certain embodiments, the molarity of the sucrose is from 50 to 300 mM. In other embodiments, the molarity of the sucrose is from 75 to 250 mM. In some embodiments, the molarity of the sucrose is from 100 to 200 mM.
  • the molarity of the sucrose is from 130 to 150 mM. In some embodiments, the molarity of the sucrose is from 135 to 150 mM. In certain embodiments, the molarity of the sucrose is about 135 mM. In certain embodiments, the molarity of the sucrose is about 136 mM. In certain embodiments, the molarity of the sucrose is about 137 mM. In certain embodiments, the molarity of the sucrose is about 138 mM. In certain embodiments, the molarity of the sucrose is about 139 mM. In certain embodiments, the molarity of the sucrose is about 140 mM.
  • the molarity of the sucrose is about 141 mM. In certain embodiments, the molarity of the sucrose is about 142 mM. In certain embodiments, the molarity of the sucrose is about 143 mM. In certain embodiments, the molarity of the sucrose is about 144 mM. In certain embodiments, the molarity of the sucrose is about 145 mM. In certain embodiments, the molarity of the sucrose is about 146 mM. In certain embodiments, the molarity of the sucrose is about 150 mM. In certain embodiments, the molarity of the sucrose is about 151 mM.
  • the molarity of the sucrose is about 151 mM. In certain embodiments, the molarity of the sucrose is about 152 mM. In certain embodiments, the molarity of the sucrose is about 153 mM. In certain embodiments, the molarity of the sucrose is about 154 mM. In certain embodiments, the molarity of the sucrose is about 155 mM.
  • the pharmaceutical composition provided herein comprises HCl. In other embodiments, the pharmaceutical composition provided herein comprises succinic acid. [00466] In some embodiments, the pharmaceutical composition provided herein has a pH in a range of 5.5 to 6.5.
  • the pharmaceutical composition provided herein has a pH in a range of 5.7 to 6.3. In some embodiments, the pharmaceutical composition provided herein has a pH of about 5.7. In some embodiments, the pharmaceutical composition provided herein has a pH of about 5.8. In some embodiments, the pharmaceutical composition provided herein has a pH of about 5.9. In some embodiments, the pharmaceutical composition provided herein has a pH of about 6.0. In some embodiments, the pharmaceutical composition provided herein has a pH of about 6.1. In some embodiments, the pharmaceutical composition provided herein has a pH of about 6.2. In some embodiments, the pharmaceutical composition provided herein has a pH of about 6.3. [00467] In some embodiments, the pH is taken at room temperature.
  • the pH is taken at 15 o C to 27 o C. In yet other embodiments, the pH is taken at 4 o C. In yet other embodiments, the pH is taken at 25 o C. [00468] In some embodiments, the pH is adjusted by HCl. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in a range of 5.5 to 6.5 at room temperature. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in a range of 5.7 to 6.3 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.7 at room temperature.
  • the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.8 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.9 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.0 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.1 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.2 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.3 at room temperature.
  • the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in a range of 5.5 to 6.5 at 15 o C to 27 o C. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in a range of 5.7 to 6.3 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.7 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.8 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 5.9 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.0 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.1 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.2 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about of 6.3 at 15 o C to 27 o C.
  • the pH is adjusted by succinic acid.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in a range of 5.5 to 6.5 at room temperature.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in a range of 5.7 to 6.3 at room temperature.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.7 at room temperature.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.8 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.9 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.0 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.1 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.2 at room temperature.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.3 at room temperature.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in a range of 5.5 to 6.5 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in a range of 5.7 to 6.3 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.7 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.8 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 5.9 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.0 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.1 at 15 o C to 27 o C.
  • the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.2 at 15 o C to 27 o C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about of 6.3 at 15 o C to 27 o C. [00472] In some specific embodiments, the pharmaceutical composition provided herein comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, and at least one of about 5.5% (w/v) trehalose dihydrate or about 5% (w/v) sucrose. In some embodiments, the pharmaceutical composition provided herein further comprises HCl or succinic acid. In some embodiments, the pH is about 6.0 at room temperature.
  • the pH is about 6.0 at 25 o C.
  • the pharmaceutical composition provided herein comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate and HCl. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25 o C.
  • the pharmaceutical composition provided herein comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5% (w/v) sucrose and HCl. In some embodiments, the pH is about 6.0 at room temperature.
  • the pH is about 6.0 at 25 o C.
  • the pharmaceutical composition provided herein comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate and succinic acid.
  • the pH is about 6.0 at room temperature.
  • the pH is about 6.0 at 25 o C.
  • the pharmaceutical composition provided herein comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5% (w/v) sucrose and succinic acid.
  • the pH is about 6.0 at room temperature.
  • the pH is about 6.0 at 25 o C.
  • an antibody drug conjugate comprising the following structure: wherein L- represents the antibody or antigen binding fragment (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) thereof and p is from 1 to10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and HCl, wherein the antibody drug conjugate is at the concentration of about 10 mg/mL, and wherein the pH is about 6.0 at 25 o C.
  • the pharmaceutical composition provided herein comprises: (a) an antibody drug conjugate comprising the following structure: wherein L- represents the antibody or antigen binding fragment thereof (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) and p is from 1 to10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and succinic acid, wherein the antibody drug conjugate is at the concentration of about 10 mg/mL, and wherein the pH is about 6.0 at 25 o C.
  • L- represents the antibody or antigen binding fragment thereof (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) and p is from 1 to10
  • a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and succinic acid, where
  • the pharmaceutical composition provided herein comprises: (a) an antibody drug conjugate comprising the following structure: wherein L- represents the antibody or antigen binding fragment thereof (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) and p is from 1 to10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.0% (w/v) sucrose, and HCl, wherein the antibody drug conjugate is at the concentration of about 10 mg/mL, and wherein the pH is about 6.0 at 25 o C.
  • L- represents the antibody or antigen binding fragment thereof (e.g. anti-nectin-4 antibody or antigen binding fragment thereof) and p is from 1 to10
  • a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.0% (w/v) sucrose, and HCl, wherein the antibody drug conjugate is at the concentration
  • a primary solvent in a vehicle can be either aqueous or non-aqueous in nature.
  • the vehicle can contain other pharmaceutically acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, sterility or stability of the pharmaceutical composition.
  • the pharmaceutically acceptable vehicle is an aqueous buffer.
  • a vehicle comprises, for example, sodium chloride and/or sodium citrate.
  • compositions provided herein can contain still other pharmaceutically acceptable formulation agents for modifying or maintaining the rate of release of an antibody drug conjugate and/or an additional agent, as described herein.
  • formulation agents include those substances known to artisans skilled in preparing sustained- release formulations.
  • Remington s Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.18042) pages 1435-1712, The Merck Index, 12th Ed. (1996, Merck Publishing Group, Whitehouse, NJ); and Pharmaceutical Principles of Solid Dosage Forms (1993, Technonic Publishing Co., Inc., Lancaster, Pa.).
  • compositions appropriate for administration are known in the art and are applicable in the methods and compositions provided herein.
  • the pharmaceutical composition provided herein is in a liquid form.
  • the pharmaceutical composition provided herein is lyophilized.
  • a pharmaceutical composition can be formulated to be compatible with its intended route of administration.
  • pharmaceutical compositions include excipients suitable for administration by routes including parenteral (e.g., subcutaneous (s.c.), intravenous, intramuscular, or intraperitoneal), intradermal, oral (e.g., ingestion), inhalation, intracavity, intracranial, and transdermal (topical).
  • parenteral e.g., subcutaneous (s.c.), intravenous, intramuscular, or intraperitoneal
  • intradermal e.g., oral (e.g., ingestion), inhalation, intracavity, intracranial, and transdermal (topical).
  • Other exemplary routes of administration are set forth herein.
  • compositions can be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension can be formulated using suitable dispersing or wetting agents and suspending agents disclosed herein or known to the skilled artisan.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • Acceptable diluents, solvents and dispersion media that can be employed include water, Ringer’s solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
  • an agent that delays absorption e.g., aluminum monostearate or gelatin.
  • the pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • the pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, e.g., Remington, The Science and Practice of Pharmacy, supra).
  • the pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles, non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents,
  • suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
  • suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ - cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • the pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration.
  • the single dosage formulations are packaged in an ampoule, a vial, or a syringe.
  • the multiple dosage parenteral formulations can contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • the pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
  • compositions can also include excipients to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including implants, liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a controlled release formulation including implants, liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, can be employed.
  • Prolonged absorption of injectable pharmaceutical compositions can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • the pharmaceutical composition provided herein can be stored at -80 o C, 4 o C, 25 o C or 37 o C.
  • a lyophilized composition can be made by freeze-drying the liquid pharmaceutical composition provided herein.
  • the pharmaceutical composition provided here is a lyophilized pharmaceutical composition.
  • the pharmaceutical formulations are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.
  • preparation of the lyophilized formulation provided herein involves batching of the formulated bulk solution for lyophilization, aseptic filtration, filling in vials, freezing vials in a freeze-dryer chamber, followed by lyophilization, stoppering and capping.
  • a lyophilizer can be used in preparing the lyophilized formulation.
  • a VirTis Genesis Model EL pilot unit can be employed. The unit incorporates a chamber with three working shelves (to a total usable shelf area of ca 0.4 square meters), an external condenser, and a mechanical vacuum pumping system.
  • the lyophilized powder can be prepared by dissolving an antibody drug conjugate provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. In some embodiments, the lyophilized powder is sterile.
  • sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation.
  • the resulting solution will be apportioned into vials for lyophilization.
  • Each vial will contain a single dosage or multiple dosages of the antibody drug conjugate.
  • the lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature.
  • Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration.
  • the lyophilized powder is added to sterile water or other suitable excipient. Such amount can be empirically determined and adjusted according to specific needs.
  • An exemplary reconstitution procedure is illustrated as follows: (1) fit the 5 mL or 3 mL syringe with a with a 18 or 20 Gauge needle and filled the syringe with water of the grade Water for Injection (WFI); (2) measure appropriate amount of WFI using the syringe graduations, ensuring that the syringe was free of air bubbles; (3) inserted the needle through the rubber stopper; (4) dispense the entire contents of the syringe into the container down the vial wall, removed the syringe and needle and put into the sharp container; (4) swirl the vial continuously to carefully solubilize the entire vial contents until fully reconstituted (e.g., about 20-40 seconds) and minimize excessive agitation of the protein solution that could result in foaming.
  • WFI Water for Injection
  • the pharmaceutical composition provided herein is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a subject.
  • the antibody drug conjugate is supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 2 mg, at least 3 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg.
  • the lyophilized antibody drug conjugate can be stored at between 2 and 8° C in its original container and the antibody drug conjugate can be administered within 12 hours, such as within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted.
  • the pharmaceutical composition comprising the antibody drug conjugate provided herein is supplied in liquid form in a hermetically sealed container indicating the quantity and concentration of the antibody drug conjugate.
  • the liquid form of the antibody drug conjugate is supplied in a hermetically sealed container at least 0.1 mg/ml, at least 0.5 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 30 mg/ml, at least 40 mg/ml, at least 50 mg/ml, at least 60 mg/ml, at least 70 mg/ml, at least 80 mg/ml, at least 90 mg/ml, or at least 100 mg/ml. [00504] Additional embodiments for the pharmaceutical compositions have been described in US Patent No.8,637,642 and International Application No.
  • the method for inhibiting growth of tumor cells using the pharmaceutical composition provided herein in combination with chemotherapy or radiation or both comprises administering the present pharmaceutical composition before, during, or after commencing chemotherapy or radiation therapy, as well as any combination thereof (i.e. before and during, before and after, during and after, or before, during, and after commencing the chemotherapy and/or radiation therapy).
  • the method is performed in a manner that will provide the most efficacious treatment and ultimately prolong the life of the patient.
  • the amount of the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab), for the various methods provided herein be determined by standard clinical techniques.
  • a dosage of the checkpoint inhibitor results in a serum titer of from about 0.1 ⁇ g/ml to about 450 ⁇ g/ml, and in some embodiments at least 0.1 ⁇ g/ml, at least 0.2 ⁇ g/ml, at least 0.4 ⁇ g/ml, at least 0.5 ⁇ g/ml, at least 0.6 ⁇ g/ml, at least 0.8 ⁇ g/ml, at least 1 ⁇ g/ml, at least 1.5 ⁇ g/ml, such as at least 2 ⁇ g/ml, at least 5 ⁇ g/ml, at least 10 ⁇ g/ml, at least 15 ⁇ g/ml, at least 20 ⁇ g/ml, at least 25 ⁇ g/ml, at least 30 ⁇ g/ml, at least 35 ⁇ g/ml, at least 40 ⁇ g/ml, at least 50 ⁇ g/ml, at least 75 ⁇ g/ml, at least 100 ⁇ g/ml
  • the dosage of the checkpoint inhibitor (e.g., a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to the patient is about 1 mg/kg to about 75 mg/kg of the subject’s body weight.
  • the dosage administered to a patient is between 1 mg/kg and 20 mg/kg of the subject’s body weight, such as 1 mg/kg to 5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 1 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 1.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 2 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 2.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 3 mg/kg of the subject’s body weight.
  • dosage administered to a patient is about 3.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 4 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 4.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 5.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 6 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 6.5 mg/kg of the subject’s body weight.
  • dosage administered to a patient is about 7 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 7.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 8 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 8.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 9.0 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 10.0 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 15.0 mg/kg of the subject’s body weight.
  • dosage administered to a patient is about 20.0 mg/kg of the subject’s body weight.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the checkpoint inhibitor is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 200 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 200 mg.
  • the pembrolizumab is administered at a dose of about 200 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg.
  • a PD-1 inhibitor or a PD-L1 inhibitor e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of about 150 mg to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of 100 mg to 500 mg, 150 mg to 500 mg, 200 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, or 450 mg to 500 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, or 100 mg to 150 mg.
  • the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered at a dose of 150 mg to 450 mg, 150 to 400 mg, 150 to 350 mg, 200 mg to 450 mg, 200 mg to 400 mg, 200 mg to 300 mg, or 200 mg to 250 mg.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of about 300 mg to about 500 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD- L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of about 350 mg to about 450 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of about 350 mg to about 450 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of 300 mg to 500 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of 350 mg to 450 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of 350 mg to 450 mg mg every 40 to 45 days.
  • the checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab
  • the anti-PD-1 antibody is administered to the subject at a dose of 400 mg every 42 days.
  • pembrolizumab is administered at a dose of about 200 mg.
  • pembrolizumab is administered at a dose of about 200 mg every 3 weeks.
  • pembrolizumab is administered at a dose of about 200 mg on day 1 of each 3 week cycle.
  • pembrolizumab is administered at a dose of about 400 mg. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg on day 1 of each 6 week cycle. [00517] In some embodiment, pembrolizumab is administered at a dose of about 2 mg/kg. In some embodiment, pembrolizumab is administered at a dose of about 2 mg/kg every three weeks. In some embodiment, pembrolizumab is administered at a dose of about 2 mg/kg on day 1 of each 3 week cycle. In particular embodiments, the patient is a pediatric patient.
  • pembrolizumab is administered as a 30 minute (-5 minutes /+10 minutes) intravenous infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes.
  • pembrolizumab in included in a pharmaceutical composition with a pharmaceutically acceptable carrier or diluent and may include additional pharmaceutically acceptable excipients.
  • the patient is an adult patient. In particular embodiments, the patient is an adult patient, wherein the adult patient is 18 years or older.
  • the amount of a prophylactic or therapeutic agent e.g., an antibody drug conjugate provided herein
  • a pharmaceutical composition provided herein that will be effective in the prevention and/or treatment of a cancer can be determined by standard clinical techniques.
  • the ADC of the methods for which the various dosages are described in this Section is enfortumab vedotin (EV).
  • a dosage of an antibody drug conjugate in the pharmaceutical composition that results in a serum titer of from about 0.1 ⁇ g/ml to about 450 ⁇ g/ml, and in some embodiments at least 0.1 ⁇ g/ml, at least 0.2 ⁇ g/ml, at least 0.4 ⁇ g/ml, at least 0.5 ⁇ g/ml, at least 0.6 ⁇ g/ml, at least 0.8 ⁇ g/ml, at least 1 ⁇ g/ml, at least 1.5 ⁇ g/ml, such as at least 2 ⁇ g/ml, at least 5 ⁇ g/ml, at least 10 ⁇ g/ml, at least 15 ⁇ g/ml, at least 20 ⁇ g/ml, at least 25 ⁇ g/ml, at least 30 ⁇ g/ml, at least 35 ⁇ g/ml, at least 40 ⁇ g/ml, at least 50 ⁇ g/ml, at least 75 ⁇ g/ml
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of a cancer in a subject, and should be decided according to the judgment of the practitioner and each patient’s circumstances.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the dosage of the antibody drug conjugate administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to the patient is about 1 mg/kg to about 75 mg/kg of the subject’s body weight.
  • the dosage administered to a patient is between 1 mg/kg and 20 mg/kg of the subject’s body weight, such as 1 mg/kg to 5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 0.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 0.75 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 1 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 1.25 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 1.5 mg/kg of the subject’s body weight.
  • dosage administered to a patient is about 2 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 2.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 3 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 3.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 4 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 4.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 5 mg/kg of the subject’s body weight.
  • dosage administered to a patient is about 5.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 6 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 6.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 7 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 7.5 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 8 mg/kg of the subject’s body weight. In some embodiments, dosage administered to a patient is about 8.5 mg/kg of the subject’s body weight.
  • the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered based on the patient’s actual body weight at baseline and doses will not change unless the patient’s weight changes by ⁇ 10% from baseline of the previous cycle, or the dose adjustment criteria is met.
  • actual weight will be used except for patients weighing greater than 100 kg, in such cases, the dose will be calculated based on a weight of 100 kg.
  • the maximum doses are 100 mg for patients receiving the 1.00 mg/kg dose level and 125 mg for patients receiving the 1.25 mg/kg dose level.
  • the pharmaceutical composition comprising the antibody drug conjugate provided herein is administered about 1-12 times, wherein the doses can be administered as necessary, e.g., weekly, biweekly, monthly, bimonthly, trimonthly, etc., as determined by a physician.
  • a lower dose e.g., 0.1-15 mg/kg
  • a higher dose e.g., 25-100 mg/kg
  • can be administered less frequently e.g., 1-3 times).
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient to prevent and/or treat a cancer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times for every two-week cycle (e.g., about 14 day) over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient to prevent and/or treat a cancer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times for every three-week cycle (e.g., about 21 day) over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient to prevent and/or treat a cancer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times for every four-week cycle (e.g., about 28 day) over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to patient to prevent and/or treat a cancer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times at about monthly (e.g., about 30 day) intervals over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to patient to prevent and/or treat a cancer 1, 2, 3, 4, 5, or 6 times at about bi-monthly (e.g., about 60 day) intervals over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about
  • a single dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to patient to prevent and/or treat a cancer 1, 2, 3 or 4 times at about tri-monthly (e.g., about 120 day) intervals over a time period (e.g., a year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85
  • the route of administration for a dose of an antibody drug conjugate formulated in the pharmaceutical composition provided herein to a patient is intranasal, intramuscular, intravenous, or a combination thereof, but other routes described herein are also acceptable.
  • Each dose may or may not be administered by an identical route of administration.
  • an antibody drug conjugate formulated in the pharmaceutical composition provided herein can be administered via multiple routes of administration simultaneously or subsequently to other doses of one or more additional therapeutic agents.
  • the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered at a dose of about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, or about 1.5 mg/kg of the subject’s body weight by an intravenous (IV) injection or infusion.
  • the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered at a dose of about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, or about 1.5 mg/kg of the subject’s body weight by an intravenous (IV) injection or infusion over about 30 minutes twice every three- week cycle.
  • the antibody drug conjugate formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes on Days 1 and 8 of every three-week cycle.
  • the method further comprises administering an immune checkpoint inhibitor by an intravenous (IV) injection or infusion one or more times in each three-week cycle.
  • the method further comprises administering an immune checkpoint inhibitor by an intravenous (IV) injection or infusion on Day 1 of every three-week cycle.
  • the immune checkpoint inhibitor is pembrolizumab, and wherein pembrolizumab is administered at amount of about 200 mg over about 30 minutes.
  • the antibody drug conjugate is administered to patients with locally advanced urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with another cancer treatment.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered at a dose of about 0.5 mg/kg, about 0.75 mg/kg, 1 mg/kg, about 1.25 mg/kg, or about 1.5 mg/kg of the subject’s body weight by an intravenous (IV) injection or infusion over about 30 minutes three times every four-week cycle.
  • the antibody drug conjugate formulated in the pharmaceutical composition is administered on Days 1, 8 and 15 of every 28-day (four-week) cycle. In some embodiments, the antibody drug conjugate formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes on Days 1, 8 and 15 of every 28-day (four-week) cycle. In some embodiments, the method further comprises administering an immune checkpoint inhibitor by an intravenous (IV) injection or infusion one or more times in each four-week cycle. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In other embodiments, the immune checkpoint inhibitor is atezolizumab.
  • the antibody drug conjugate is administered to patients with urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with another cancer treatment. In some embodiments, the antibody drug conjugate is administered to patients with metastatic urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with another cancer treatment. In some embodiments, the antibody drug conjugate is administered to patients with locally advanced urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with another cancer treatment. In some embodiments, the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • EV enfortumab vedotin
  • the ADC is administered at a dose of about 0.25 to about 10 mg/kg of the subject’s body weight, about 0.25 to about 5 mg/kg of the subject’s body weight, about 0.25 to about 2.5 mg/kg of the subject’s body weight, about 0.25 to about 1.25 mg/kg of the subject’s body weight, about 0.5 to about 10 mg/kg of the subject’s body weight, about 0.5 to about 5 mg/kg of the subject’s body weight, about 0.5 to about 2.5 mg/kg of the subject’s body weight, about 0.5 to about 1.25 mg/kg of the subject’s body weight, about 0.75 to about 10 mg/kg of the subject’s body weight, about 0.75 to about 5 mg/kg of the subject’s body weight, about 0.75 to about 2.5 mg/kg of the subject’s body weight, or about 0.75 to about 1.25 mg/kg of the subject’s body weight.
  • the ADC is administered at a dose of about 1 to about 10 mg/kg of the subject’s body weight. In certain embodiments, the ADC is administered at a dose of about 1 to about 5 mg/kg of the subject’s body weight. In other embodiments, the ADC is administered at a dose of about 1 to about 2.5 mg/kg of the subject’s body weight. In further embodiments, the ADC is administered at a dose of about 1 to about 1.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 0.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 0.5 mg/kg of the subject’s body weight.
  • the ADC is administered at a dose of about 0.75 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 1.0 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 1.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 1.5 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 1.75 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 2.0 mg/kg of the subject’s body weight.
  • the ADC is administered at a dose of about 2.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 2.5 mg/kg of the subject’s body weight. [00539] In certain embodiments of the various methods provided herein, the ADC is administered at a dose of 0.25 to 10 mg/kg of the subject’s body weight, 0.25 to 5 mg/kg of the subject’s body weight, 0.25 to 2.5 mg/kg of the subject’s body weight, 0.25 to 1.25 mg/kg of the subject’s body weight, 0.5 to 10 mg/kg of the subject’s body weight, 0.5 to 5 mg/kg of the subject’s body weight, 0.5 to 2.5 mg/kg of the subject’s body weight, 0.5 to 1.25 mg/kg of the subject’s body weight, 0.75 to 10 mg/kg of the subject’s body weight, 0.75 to 5 mg/kg of the subject’s body weight, 0.75 to 2.5 mg/kg of the subject’s body weight, or 0.75 to
  • the ADC is administered at a dose of 1 to 10 mg/kg of the subject’s body weight. In certain embodiments, the ADC is administered at a dose of 1 to 5 mg/kg of the subject’s body weight. In other embodiments, the ADC is administered at a dose of 1 to 2.5 mg/kg of the subject’s body weight. In further embodiments, the ADC is administered at a dose of 1 to 1.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 0.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 0.5 mg/kg of the subject’s body weight.
  • the ADC is administered at a dose of 0.75 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 1.0 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 1.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 1.5 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 1.75 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 2.0 mg/kg of the subject’s body weight.
  • the ADC is administered at a dose of 2.25 mg/kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of 2.5 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of about 0.25 to about 10 mg/kg of the subject’s body weight, about 0.25 to about 5 mg/kg of the subject’s body weight, about 0.25 to about 2.5 mg/kg of the subject’s body weight, about 0.25 to about 1.25 mg/kg of the subject’s body weight, about 0.5 to about 10 mg/kg of the subject’s body weight, about 0.5 to about 5 mg/kg of the subject’s body weight, about 0.5 to about 2.5 mg/kg of the subject’s body weight, about 0.5 to about 1.25 mg/kg of the subject’s body weight, about 0.75 to about 10 mg/kg of the subject’s body weight, about 0.75
  • the first dose of the ADC is a dose of about 1 to about 10 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of about 1 to about 5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of about 1 to about 2.5 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of about 1 to about 1.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of about 0.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of about 0.5 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 0.75 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of about 1.0 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 1.25 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 1.5 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 1.75 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 2.0 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of about 2.25 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of or about 2.5 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of 0.25 to 10 mg/kg of the subject’s body weight, 0.25 to 5 mg/kg of the subject’s body weight, 0.25 to 2.5 mg/kg of the subject’s body weight, 0.25 to 1.25 mg/kg of the subject’s body weight, 0.5 to 10 mg/kg of the subject’s body weight, 0.5 to 5 mg/kg of the subject’s body weight, 0.5 to 2.5 mg/kg of the subject’s body weight, 0.5 to 1.25 mg/kg of the subject’s body weight, 0.75 to 10 mg/kg of the subject’s body weight, 0.75 to 5 mg/kg of the subject’s body weight, 0.75 to 2.5 mg/kg of the subject’s body weight, or 0.75 to 1.25 mg/kg of the subject’s
  • the first dose of the ADC is a dose of 1 to 10 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of 1 to 5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of 1 to 2.5 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of 1 to 1.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of 0.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the first dose of the ADC is a dose of 0.5 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 0.75 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of 1.0 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 1.25 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 1.5 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 1.75 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 2.0 mg/kg of the subject’s body weight. In some embodiments, the first dose of the ADC is a dose of 2.25 mg/kg of the subject’s body weight.
  • the first dose of the ADC is a dose of 2.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.1 mg/kg to about 2 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.1 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.2 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.3 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.4 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.6 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.7 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 0.8 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 0.9 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.1 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 1.2 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.3 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 1.4 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.6 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 1.7 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 1.8 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by about 1.9 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by about 2 mg/kg of the subject’s body weight. [00543] In certain embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.1 mg/kg to 2 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 0.1 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.2 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 0.3 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.4 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 0.6 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.7 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.75 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 0.8 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 0.9 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 1.1 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.2 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 1.3 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.4 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 1.6 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.7 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.75 mg/kg of the subject’s body weight.
  • the second dose of the ADC is lower than the first dose by 1.8 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 1.9 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is lower than the first dose by 2 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 0.25 to about 10 mg/kg of the subject’s body weight, about 0.25 to about 5 mg/kg of the subject’s body weight, about 0.25 to about 2.5 mg/kg of the subject’s body weight, about 0.25 to about 1.25 mg/kg of the subject’s body weight, about 0.5 to about 10 mg/kg of the subject’s body weight, about 0.5 to about 5 mg/kg of the subject’s body weight, about 0.5 to about 2.5 mg/kg of the subject’s body weight, about 0.5 to about 1.25 mg/kg of the subject’s body weight, about 0.75 to about 10 mg/kg of the subject’s body weight, about 0.75 to about 5 mg/kg of the subject’s body weight, about 0.75 to about 2.5 mg/kg of the subject’s body weight, or about 0.75 to about 1.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 1 to about 10 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 1 to about 5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 1 to about 2.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 1 to about 1.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 0.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 0.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 0.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 1.0 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 1.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 1.5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 1.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 2.0 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of about 2.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of about 2.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 0.25 to 10 mg/kg of the subject’s body weight, 0.25 to 5 mg/kg of the subject’s body weight, 0.25 to 2.5 mg/kg of the subject’s body weight, 0.25 to 1.25 mg/kg of the subject’s body weight, 0.5 to 10 mg/kg of the subject’s body weight, 0.5 to 5 mg/kg of the subject’s body weight, 0.5 to 2.5 mg/kg of the subject’s body weight, 0.5 to 1.25 mg/kg of the subject’s body weight, 0.75 to 10 mg/kg of the subject’s body weight, 0.75 to 5 mg/kg of the subject’s body weight, 0.75 to 2.5 mg/kg of the subject’s body weight, or 0.75 to 1.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 1 to 10 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 1 to 5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 1 to 2.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 1 to 1.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 0.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 0.5 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 0.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 1.0 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 1.25 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 1.5 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 1.75 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 2.0 mg/kg of the subject’s body weight.
  • the second dose of the ADC is a dose of 2.25 mg/kg of the subject’s body weight. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is a dose of 2.5 mg/kg of the subject’s body weight. [00546] In certain embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of the ADC is identical to the first dose of the ADC. [00547] In some embodiments of the methods provided herein, the ADC is administered by an intravenous (IV) injection or infusion.
  • IV intravenous
  • the first dose of the ADC is administered by an IV injection. In another embodiment, the first dose of the ADC is administered by an IV infusion. In yet another embodiment, the second dose of the ADC is administered by an IV injection. In yet another embodiment, the second dose of the ADC is administered by an IV injection infusion. In one embodiment, the first dose of the ADC is administered by an IV injection and the second dose of the ADC is administered by an IV injection. In another embodiment, the first dose of the ADC is administered by an IV infusion and the second dose of the ADC is administered by an IV injection. In yet another embodiment, the second dose of the ADC is administered by an IV injection and the second dose of the ADC is administered by an IV injection infusion.
  • the second dose of the ADC is administered by an IV injection infusion and the second dose of the ADC is administered by an IV injection infusion.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • the ADC is administered by an IV injection or infusion three times every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion three times every four-week cycle.
  • the second dose of the ADC is administered by an IV injection or infusion three times every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion three times every four-week cycle and the second dose of the ADC is administered by an IV injection or infusion three times every four-week cycle.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • EV vedotin
  • the ADC is administered by an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle.
  • the first dose of ADC is administered by an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle.
  • the second dose of ADC is administered by an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle.
  • the first dose of ADC is administered by an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle and the second dose of ADC is administered by an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • EV vedotin
  • the ADC is administered by an IV injection or infusion over about 30 minutes three times every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion over about 30 minutes three times every four-week cycle.
  • the second dose of the ADC is administered by an IV injection or infusion over about 30 minutes three times every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion over about 30 minutes three times every four-week cycle and the second dose of the ADC is administered by an IV injection or infusion over about 30 minutes three times every four-week cycle.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • the ADC is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle.
  • the second dose of the ADC is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle.
  • the first dose of the ADC is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle and the second dose of the ADC is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle.
  • the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered at a dose of about 1 mg/kg, 1.25 mg/kg, or about 1.5 mg/kg of the subject’s body weight by an intravenous (IV) injection or infusion over about 30 minutes three times every 28-day cycle.
  • the antibody drug conjugate formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes on Days 1, 8 and 15 of every 28- day cycle.
  • the method further comprises administering an immune checkpoint inhibitor by an intravenous (IV) injection or infusion one or more times in each four-week cycle.
  • the ADC is administered three times within a 28 day cycle. In some embodiments of the methods provided herein, the ADC is administered on Days 1, 8 and 15 of a 28 day cycle. In some embodiments, the ADC of the methods for which the various dosages are described in this paragraph is enfortumab vedotin (EV).
  • EV vedotin
  • the ADC has the following structure: wherein L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4, the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg/kg of the subject’s body weight, and wherein the dose is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle.
  • L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4
  • the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and
  • combination therapies using an antibody drug conjugate wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE) in combination with a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab) for treating cancer in a subject.
  • a checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab
  • the checkpoint inhibitor may be pembrolizumab.
  • a pharmaceutically effective amount of the antibody drug conjugate is administered.
  • a pharmaceutically effective amount of the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab) is administered.
  • a pharmaceutically effective amount of the antibody drug conjugate is administered and a pharmaceutically effective amount of the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab) is administered.
  • a pharmaceutically effective amount of the antibody drug conjugate is administered and a pharmaceutically effective amount of pembrolizumab is administered.
  • an effective amount of the antibody drug conjugate is administered and an effective amount of the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab) is administered.
  • an effective amount of the antibody drug conjugate is administered and an effective amount of pembrolizumab is administered.
  • the subject is a human.
  • the subject is a subject diagnosed with cancer, e.g., urothelial cancer, bladder cancer, cancer of the renal pelvis, cancer of the ureter, cancer of the urethra, locally advanced cancer, metastatic cancer, locally advanced urothelial cancer, unresectable locally advanced urothelial cancer, metastatic urothelial cancer, locally advanced bladder cancer, or metastatic bladder cancer.
  • cancer e.g., urothelial cancer, bladder cancer, cancer of the renal pelvis, cancer of the ureter, cancer of the urethra
  • locally advanced cancer metastatic cancer
  • locally advanced urothelial cancer unresectable locally advanced urothelial cancer
  • metastatic urothelial cancer locally advanced bladder cancer
  • the amount of the antibody drug conjugate provided herein or pembrolizumab, or a pharmaceutical composition that will be effective in the prevention and/or treatment of cancer can be determined by standard clinical techniques.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • the antibody drug conjugate provided herein is administered to the subject as part a composition.
  • the composition is a pharmaceutical composition described in Section 5.4
  • the antibody drug conjugate and pembrolizumab may be formulated in different pharmaceutical compositions and administered separately to the subject in need thereof.
  • the antibody drug conjugate and pembrolizumab are administered together in the same pharmaceutical composition.
  • the antibody drug conjugate and pembrolizumab are administered simultaneously.
  • the term “simultaneously” means at the same time or within a short period of time, for example, less than 1 hour, less than 2 hours, less than 3 hours, less than 4 hours, or less than 12 hours.
  • the antibody drug conjugate and pembrolizumab are not administered simultaneously, and instead the two compounds are administered at different times.
  • pembrolizumab is administered before the administration of the antibody drug conjugate.
  • pembrolizumab is administered after the administration of the antibody drug conjugate.
  • the subject has been previously treated with pembrolizumab prior to the administration of the antibody drug conjugate.
  • the subject has been previously treated with the antibody drug conjugate prior to the administration of pembrolizumab.
  • the subject has not been previously treated with pembrolizumab prior to the co-administration of the antibody drug conjugate and pembrolizumab.
  • the co-administration of the antibody drug conjugate and pembrolizumab is concomitant administration.
  • the co-administration of the antibody drug conjugate and pembrolizumab is pharmaceutically effective to treat a cancer.
  • Any amount or dose of the antibody drug conjugate disclosed herein may be administered in combination with any amount or dose of pembrolizumab disclosed herein.
  • the antibody drug conjugate and pembrolizumab are administered at least once during a dosing period.
  • a dosing period as used herein is meant a period of time, during which each therapeutic agent has been administered at least once.
  • a dosing cycle can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.
  • a dosing cycle is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks.
  • a dosing period is a dosing cycle.
  • the therapeutic agent (the antibody drug conjugate provided herein and/or pembrolizumab) can be delivered as a single dose (e.g., a single bolus injection), or over time (e.g., continuous infusion over time or divided bolus doses over time).
  • the agent can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.
  • Stable disease or lack is determined by methods known in the art such as evaluation of patient symptoms, physical examination, and visualization of the tumor that has been imaged using X-ray, CAT, PET, MRI scan, or other commonly accepted evaluation modalities.
  • the therapeutic agent (the antibody drug conjugate provided herein and/or pembrolizumab) can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID).
  • the administration can be continuous (i.e., daily for consecutive days or every day) or intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • the term “daily” is intended to mean that a therapeutic compound is administered once or more than once each day, for example, for a period of time.
  • intermittent administration of the compound is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • the frequency of administration is in the range of about a daily dose to about a monthly dose.
  • administration is once a day, twice a day, three times a day, four times a day, once every other day, twice every other day, three times every other day, four times every other day, twice a week, three times a week, four times a week, five times a week, once a week, once every two weeks, once every three weeks, or once every four weeks.
  • the compound is administered once per day, twice a day, three times a day, or four times a day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks.
  • the antibody drug conjugate provided herein is administered in a therapeutically effective amount and pembrolizumab is administered in a therapeutically effective amount.
  • a therapeutically effective amount of the antibody drug conjugate may be any amount or dose of the antibody drug conjugate disclosed herein.
  • a therapeutically effective amount of pembrolizumab may be any amount or dose of pembrolizumab disclosed herein.
  • any amount or dose of the antibody drug conjugate disclosed herein may be administered in combination with any amount or dose of pembrolizumab disclosed herein (see, e.g., Sections 5.2.1.3, 5.4, and 5.7).
  • the antibody drug conjugate and/or pembrolizumab may be administered or dosed according to body weight (mg/kg) or body surface area (BSA) (mg/m 2 ).
  • body weight mg/kg
  • BSA body surface area
  • the average body mass globally has been calculated to be 62 kg. See Walpole et al., 2012, BMC Public Health, 12:439 (doi: 10.1186/1471-2458-12-439).
  • the antibody drug conjugate provided herein is administered at a dose of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg.
  • the antibody drug conjugate provided herein is administered at a dose of about 0.1 mg/kg to about 100 mg/kg of the subject’s body weight. In some embodiments, the antibody drug conjugate provided herein is administered at a dose of about 1 mg/kg to about 75 mg/kg of the subject’s body weight.
  • the antibody drug conjugate provided herein is administered at a dose of between about 1 mg/kg and about 20 mg/kg of the subject’s body weight, such as about 1 mg/kg to about 5 mg/kg of the subject’s body weight, about 1 mg/kg to about 4 mg/kg of the subject’s body weight, about 1 mg/kg to about 3 mg/kg of the subject’s body weight, or about 1 mg/kg to about 2 mg/kg of the subject’s body weight.
  • the pembrolizumab is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg.
  • the pembrolizumab is administered at a dose of about 200 mg.
  • the pembrolizumab is administered at a dose of about 100 mg to about about 500 mg, about 150 mg to about about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg.
  • the pembrolizumab is administered at a dose of about 100 mg to about about 450 mg, about 100 mg to about about 400 mg, about 100 mg to about about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg.
  • the pembrolizumab is administered at a dose of about 150 mg to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.
  • the antibody drug conjugate provided herein is administered daily during each treatment cycle of 14 days, 21 days, 28 days, 35 days, or 42 days. In some embodiments, the antibody drug conjugate is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of a treatment cycle of 14 days. In some embodiments, the antibody drug conjugate is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of a treatment cycle of 21 days (i.e., 3 weeks). In some embodiments, the antibody drug conjugate is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a treatment cycle of 28 days.
  • the antibody drug conjugate is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days of a treatment cycle of 35 days. In some embodiments, the antibody drug conjugate is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days of a treatment cycle of 42 days. In some embodiments, the antibody drug conjugate is administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of a treatment cycle of 21 days.
  • the antibody drug conjugate is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21 of a treatment cycle of 21 days. In particular embodiments, the antibody drug conjugate is administered on days 1 and 8 of a treatment cycle of 21 days. In some embodiments, the antibody drug conjugate is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 treatment cycles. [00581] In some embodiments, the antibody drug conjugate is administered once, two times, three times, or four times daily during each treatment cycle of 14 days, 21 days, 28 days, 35 days, or 42 days.
  • the antibody drug conjugate is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of each treatment cycle of 14 days. In some embodiments, the antibody drug conjugate is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of each treatment cycle of 21 days. In some embodiments, the antibody drug conjugate is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of each treatment cycle of 28 days.
  • the antibody drug conjugate is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days of each treatment cycle of 35 days. In some embodiments, the antibody drug conjugate is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days of each treatment cycle of 42 days.
  • the antibody drug conjugate is administered once, two times, three times, or four times daily for 2 days of each treatment cycle of 21 days. [00582] In certain embodiments, the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg for 2 days in each treatment cycle of 21 days. In certain embodiments, the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg on days 1 and 8 in each treatment cycle of 21 days. In certain embodiments, the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg on days 1 and 8 in each treatment cycle of 21 days by an intravenous injection or infusion.
  • the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg on days 1 and 8 in each treatment cycle of 21 days by intravenous infusion.
  • the antibody drug conjugate is administered intravenously.
  • the antibody drug conjugate is administered by an intravenous injection or infusion.
  • the antibody drug conjugate is administered by intravenous infusion.
  • the antibody drug conjugate is administered as a 30 minute (-5 minutes /+10 minutes) intravenous infusion.
  • the selected dose of the antibody drug conjugate is administered by intravenous infusion over a time period of between 25 and 40 minutes, or about 30 minutes (-5 minutes /+10 minutes).
  • pembrolizumab is administered daily during each treatment cycle of 14 days, 21 days, 28 days, 35 days, or 42 days. In some embodiments, pembrolizumab is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of a treatment cycle of 14 days. In some embodiments, pembrolizumab is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of a treatment cycle of 21 days (i.e., 3 weeks). In some embodiments, pembrolizumab is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a treatment cycle of 28 days.
  • pembrolizumab is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days of a treatment cycle of 35 days. In some embodiments, pembrolizumab is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days of a treatment cycle of 42 days. In some embodiments, pembrolizumab is administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of a treatment cycle of 21 days.
  • pembrolizumab is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21 of a treatment cycle of 21 days. In particular embodiments, pembrolizumab is administered on day 1 of a treatment cycle of 21 days. In some embodiments, pembrolizumab is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 treatment cycles. [00585] In some embodiments, pembrolizumab is administered once, two times, three times, or four times daily during each treatment cycle of 14 days, 21 days, 28 days, 35 days, or 42 days.
  • pembrolizumab is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of each treatment cycle of 14 days. In some embodiments, pembrolizumab is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of each treatment cycle of 21 days. In some embodiments, pembrolizumab is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of each treatment cycle of 28 days.
  • pembrolizumab is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days of each treatment cycle of 35 days. In some embodiments, pembrolizumab is administered once, two times, three times, or four times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days of each treatment cycle of 42 days.
  • pembrolizumab is administered once, two times, three times, or four times daily for 1 day of each treatment cycle of 21 days. [00586] In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg for 1 day in each treatment cycle of 21 days. In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg on day 1 in each treatment cycle of 21 days. In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg on day 1 in each treatment cycle of 21 days as an intravenous infusion. In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg on day 1 in each treatment cycle of 21 days by intravenous infusion.
  • pembrolizumab is administered intravenously. In some embodiments, pembrolizumab is administered as an intravenous infusion. In some embodiments, pembrolizumab is administered by intravenous infusion. In some embodiments, pembrolizumab is administered as a 30 minute (-5 minutes /+10 minutes) intravenous infusion. [00588] In some embodiments, the antibody drug conjugate is administered to the subject up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject on 1 day of the 21-day treatment cycle.
  • the antibody drug conjugate is administered to the subject on days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject on day 1 of the 21-day treatment cycle.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion, and pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on day 1 of the 21-day treatment cycle by intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered at a dose of about 100 mg to about 300 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 100 mg to about 300 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg to about 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of about 100 mg to about 300 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle by intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered at a dose of 100 mg to 300 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of 100 mg to 300 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21- day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion, and pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion, and pembrolizumab is administered at a dose of about 200 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of about 200 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion, and pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion, and pembrolizumab is administered at a dose of 200 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion, and pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of 200 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21- day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21- day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered at a dose of about 200 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of about 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of about 200 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion, and pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg up to 2 days of a 21-day treatment cycle as an intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as an intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle by intravenous infusion, and pembrolizumab is administered at a dose of 200 mg to the subject on day 1 of the 21-day treatment cycle by intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion, and pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg up to 2 days of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on 1 day of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered to the subject at a dose of 200 mg on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after administration of the antibody drug conjugate.
  • the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle as a 30 minute intravenous infusion
  • pembrolizumab is administered at a dose of 200 mg to the subject on day 1 of the 21-day treatment cycle as a 30 minute intravenous infusion 30 minutes after completion of the administration of the antibody drug conjugate.
  • treatment cycle and “cycle” are interchangeable. 5.9 Methods for Determining the Biomarkers [00596] The disclosure provides that the expression of any of the markers provided herein can be determined by various methods known in the field.
  • the expression of the markers can be determined by the amount or relative amount of mRNA transcribed from the marker genes. In one embodiment, the expression of the marker genes can be determined by the amount or relative amount of the protein products encoded by the marker genes. In another embodiment, the expression of the marker genes can be determined by the level of biological or chemical response induced by the protein products encoded by the marker genes. Additionally, in certain embodiments, the expression of the marker genes can be determined by the expression of one or more genes that correlates with the expression of the marker genes. [00597] As described above, levels or amounts of gene transcripts (e.g. mRNA) of the marker genes can be used as a proxy for the expression levels of markers genes.
  • gene transcripts e.g. mRNA
  • Quantitative PCR refers to the direct monitoring of the progress of PCR amplification as it is occurring without the need for repeated sampling of the reaction products.
  • the reaction products can be monitored via a signaling mechanism (e.g., fluorescence) as they are generated and are tracked after the signal rises above a background level but before the reaction reaches a plateau.
  • a signaling mechanism e.g., fluorescence
  • the number of cycles required to achieve a detectable or “threshold” level of fluorescence varies directly with the concentration of amplifiable targets at the beginning of the PCR process, enabling a measure of signal intensity to provide a measure of the amount of target nucleic acid in a sample in real time.
  • PCR methods can be found in the literature (Wong et al., BioTechniques 39:75-85 (2005); D’haene et al., Methods 50:262–270 (2010)), which is incorporated by reference herein in its entirety.
  • PCR assays can also be found in U.S. Patent No.6,927,024, which is incorporated by reference herein in its entirety.
  • RT-PCR methods can be found in U.S. Patent No.7,122,799, which is incorporated by reference herein in its entirety.
  • a method of fluorescent in situ PCR is described in U.S. Patent No.7,186,507, which is incorporated by reference herein in its entirety.
  • RNA transcripts of the marker genes in a sample can also be used for the quantification of RNA transcripts of the marker genes in a sample as the proxy for the expression of the marker genes, including northern blotting and in situ hybridization (Parker & Barnes, Methods in Molecular Biology 106:247-283 (1999)); RNAse protection assays (Hod, Biotechniques 13:852- 854 (1992)); microarrays (Hoheisel et al., Nature Reviews Genetics 7:200-210 (2006); Jaluria et al., Microbial Cell Factories 6:4 (2007)); and polymerase chain reaction (PCR) (Weis et al, Trends in Genetics 8:263-264 (1992)).
  • PCR polymerase chain reaction
  • RNA in situ hybridization is a molecular biology technique widely used to measure and localize specific RNA sequences, for example, messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) within cells, such as circulating tumor cells (CTCs) or tissue sections, while preserving the cellular and tissue context.
  • mRNAs messenger RNAs
  • lncRNAs long non-coding RNAs
  • miRNAs microRNAs
  • CTCs circulating tumor cells
  • ISH is a type of hybridization that uses a directly or indirectly labeled complementary DNA or RNA strand, such as a probe, to bind to and localize a specific nucleic acid, such as DNA or RNA, in a sample, in particular a portion or section of tissue or cells (in situ).
  • the probe types can be double stranded DNA (dsDNA), single stranded DNA (ssDNA), single stranded complimentary RNA (sscRNA), messenger RNA (mRNA), micro RNA (miRNA), ribosomal RNA, mitochondrial RNA, and/or synthetic oligonucleotides.
  • dsDNA double stranded DNA
  • ssDNA single stranded DNA
  • sscRNA single stranded complimentary RNA
  • mRNA messenger RNA
  • miRNA micro RNA
  • ribosomal RNA mitochondrial RNA
  • synthetic oligonucleotides synthetic oligonucleotides.
  • FISH fluorescent in situ hybridization
  • CISH chromogenic in situ hybridization
  • ISH ISH
  • FISH FISH
  • CISH CISH
  • RNA ISH therefore provides for spatial-temporal visualization as well as quantification of gene expression within cells and tissues. It has wide applications in research and in diagnostics (Hu et al., Biomark. Res.2(1):1-13, doi: 10.1186/2050-7771-2-3 (2014); Ratan et al., Cureus 9(6):e1325.
  • RNA transcripts of the marker genes in a sample as the proxy for the expression of the marker genes can be determined by sequencing techniques. Representative methods for sequencing-based gene expression analysis include Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS).
  • SAGE Serial Analysis of Gene Expression
  • MPSS massively parallel signature sequencing
  • expression of the marker genes can be determined by the relative abundance of the RNA transcripts (including for example mRNA) of the marker genes in a pool of total transcribed RNA.
  • RNA transcripts including for example mRNA
  • Such relative abundance of the RNA transcripts of the marker genes can be determined by next generation sequencing, which is known as RNA- seq.
  • RNA-seq RNAs from different sources (blood, tissue, cells) are purified, optionally enriched (e.g. with oligo (dT) primers), converted to cDNA, and fragmented. Millions or even billions of short sequence reads are generated from the randomly fragmented cDNA library. See Zhao et al. BMC genomics 16: 97 (2015); Zhao et al.
  • each mRNA transcript of the marker genes is determined by the total number of mapped fragments upon normalization, which is directly proportional to its abundance level.
  • a few normalization schemes are known and used to facilitate the use of the abundance of the RNA transcripts as the parameter for determining gene expression, including RPKM (Reads Per Kilobase Million), FPKM (Fragments Per Kilobase Million), and/or TPM (Transcripts Per Kilobase Million).
  • RPKM can be calculated as follows: count up the total reads in a sample and divide that number by 1,000,000 – which is the “per million” scaling factor; divide the read counts by the “per million” scaling factor, which normalizes for sequencing depth, giving the reads per million (RPM); and divide the RPM values by the length of the gene, in kilobases, which gives RPKM.
  • FPKM is closely related to RPKM except with fragment replacing read. RPKM was made for single-end RNA-seq, where every read corresponded to a single fragment that was sequenced.
  • FPKM was made for paired-end RNA-seq, in which two reads can correspond to a single fragment, or, if one read in the pair did not map, one read can correspond to a single fragment.
  • TPM is very similar to RPKM and FPKM and is calculated as follows: divide the read counts by the length of each gene in kilobases, which gives the reads per kilobase (RPK); count up all the RPK values in a sample and divide this number by 1,000,000, which gives the “per million” scaling factor; divide the RPK values by the “per million” scaling factor, which gives TPM. See Zhao et al. BMC genomics 16: 97 (2015); Zhao et al.
  • the expression of the marker genes is determined by RNA- seq, for example by TPM, RPKM, and/or FPKM. In some embodiments, the expression of the marker genes is determined by TPM. In some embodiments, the expression of the marker genes is determined by RPKM. In some embodiments, the expression of the marker genes is determined by FPKM. [00603] As described earlier, the expression of the marker genes can be determined in a sample from a subject.
  • the sample is a blood sample, a serum sample, a plasma sample, bodily fluid (e.g. tissue fluid including cancer tissue fluid), or a tissue (e.g. cancer tissue or the tissue surrounding the cancer).
  • the sample is a tissue sample.
  • the tissue sample is tissue fractions isolated or extracted from a mammal, in particular a human.
  • the tissue sample is a population of cells isolated or extracted from a mammal, in particular a human.
  • the tissue sample is a sample obtained from a biopsy.
  • the samples can be obtained from a variety of organs of a subject, including a human subject.
  • the samples are obtained from organs of a subject having a cancer. In some embodiments, the samples are obtained from organs having a cancer in a subject having a cancer. In other embodiments, the samples, for example reference samples, are obtained from normal organs from the patient or from a second human subject.
  • the tissue includes a tissue from bladder, ureter, breast, lung, colon, rectum, ovary, Fallopian tube, esophagus, cervix, uterine endometrium, skin, larynx, bone marrow, salivary gland, kidney, prostate, brain, spinal cord, placenta, adrenal, pancreas, parathyroid, hypophysis, testis, thyroid, spleen, tonsil, thymus, heart, stomach, small intestine, liver, skeletal muscle, peripheral nerve, mesothelium, or eye.
  • the expression of the various marker genes can be detected by a variety of immunoassays known in the art, including an immunohistochemistry (IHC) assay, an immunoblotting assay, a FACS assay, and an ELISA.
  • IHC immunohistochemistry
  • the expression of the various marker genes can be detected by antibodies against the protein products encoded by the marker genes in a variety of IHC assays. IHC staining of tissue sections has been shown to be a reliable method of assessing or detecting the presence of proteins in a sample. IHC techniques utilize an antibody to probe and visualize cellular antigens in situ, generally by chromogenic or fluorescent methods.
  • Primary antibodies or antisera such as polyclonal antisera and monoclonal antibodies that specifically target the protein products encoded by the marker genes, can be used to detect expression of the marker genes in an IHC assay.
  • the tissue sample is contacted with a primary antibody for a specific target for a period of time sufficient for the antibody-target binding to occur.
  • the antibodies can be detected by direct labels on the antibodies themselves, for example, radioactive labels, fluorescent labels, hapten labels such as biotin, or an enzyme such as horse radish peroxidase or alkaline phosphatase.
  • unlabeled primary antibody is used in conjunction with a labeled secondary antibody, comprising antisera, polyclonal antisera or a monoclonal antibody specific for the primary antibody.
  • IHC protocols and kits are well known in the art and are commercially available. Automated systems for slide preparation and IHC processing are available commercially. The Leica BOND Autostainer and Leica Bond Refine Detection system is an example of such an automated system.
  • an IHC assay is performed with an unlabeled primary antibody in conjunction with a labeled secondary antibody in an indirect assay.
  • the indirect assay utilizes two antibodies for the detection of the protein products encoded by the marker genes in a tissue sample.
  • an unconjugated primary antibody was applied to the tissue (first layer), which reacts with the target antigen in the tissue sample.
  • an enzyme- labeled secondary antibody is applied, which specifically recognize the antibody isotype of the primary antibody (second layer).
  • the secondary antibody reacts with the primary antibody, followed by substrate-chromogen application.
  • the second-layer antibody can be labeled with an enzyme such as a peroxidase, which reacts with the chromogen 3, 3’- diaminobenzidine (DAB) to produce brown precipitate at the reaction site.
  • DAB diaminobenzidine
  • a signal amplification system means a system of reagents and methods that can be used to increase the signal from detecting the bound primary or the secondary antibody.
  • a signal amplification system increases the sensitivity of the target protein detection, increases the detected signal, and decreases the lower boundary of the detection limits.
  • There are several types of signal amplification systems including an enzyme labeling system and macrolabeling system. These systems/approaches are not mutually exclusive and can be used in combination for additive effect.
  • Macrolabels or macrolabeling system are collections of labels numbering in the tens (e.g. phycobiliproteins) to millions (e.g. fluorescent microspheres) attached to or incorporated in a common scaffold.
  • the scaffold can be coupled to a target-specific affinity reagent such as an antibody, and the incorporated labels are thereby collectively associated with the target upon binding.
  • the labels in the macrolabels can be any of the labels described herein such as fluorophores, haptens, enzymes, and/or radioisotopes.
  • a labeled chain polymer-conjugated secondary antibody was used.
  • the polymer technology utilized an HRP enzyme-labeled inert “spine” molecule of dextran to which 1, 2, 3, 4, 5, 6, 7, 8, 910, 15, 20, 25, 30, 50 or more molecules of secondary antibodies can be attached, making the system even more sensitive.
  • Signal amplification system based on an enzyme labeling system utilizes the catalytic activity of enzymes, such as horseradish peroxidase (HRP) or alkaline phosphatase to generate high-density labeling of a target protein or nucleic acid sequence in situ.
  • enzymes such as horseradish peroxidase (HRP) or alkaline phosphatase to generate high-density labeling of a target protein or nucleic acid sequence in situ.
  • tyramide can be used to increase the signal of HRP.
  • HRP enzymatically converts the labeled tyramide derivative into highly reactive, short-lived tyramide radicals.
  • the labeled active tyramide radicals then covalently couple to residues (principally the phenol moiety of protein tyrosine residues) in the vicinity of the HRP- antibody–target interaction site, resulting amplification of the number of labels at the site with minimal diffusion-related loss of signal localization. Consequently, the signal can be amplified 1, 2, 3, 4, 5, 6, 7, 8, 910, 15, 20, 25, 30, 50, 75, or 100 folds.
  • the labels on the tyramide can be any labels described herein, including fluorophores, enzymes, haptens, radioisotopes, and/or photophores. Other enzyme-based reactions can be utilized to create signal amplification as well.
  • Enzyme-Labeled Fluorescence (ELF) signal amplification is available for alkaline phosphatase, wherein the alkaline phosphatase enzymatically cleaves a weakly blue-fluorescent substrate (ELF 97 phosphate) and converts it into a bright yellow-green-fluorescent precipitate that exhibits an unusually large Stokes shift and excellent photostability.
  • ELF Enzyme-Labeled Fluorescence
  • the specimen is then counterstained to identify cellular and subcellular elements.
  • the expression level of the protein products encoded by the marker genes can also be detected with antibodies against the protein products encoded by the marker genes using an immunoblotting assay.
  • proteins are often (but do not have to be) separated by electrophoresis and transferred onto membranes (usually nitrocellulose or PVDF membrane).
  • primary antibodies or antisera such as polyclonal antisera and monoclonal antibodies that specifically target the protein products encoded by the marker genes, can be used to detect expression of the marker genes.
  • the membrane is contacted with a primary antibody for a specific target for a period of time sufficient for the antibody-antigen binding to occur and the bound antibodies can be detected by direct labels on the primary antibodies themselves, e.g. with radioactive labels, fluorescent labels, hapten labels such as biotin, or enzymes such as horseradish peroxidase or alkaline phosphatase.
  • unlabeled primary antibody is used in an indirect assay as described above in conjunction with a labeled secondary antibody specific for the primary antibody.
  • the secondary antibodies can be labeled, for example, with enzymes or other detectable labels such as fluorescent labels, luminescent labels, colorimetric labels, or radioisotopes.
  • Immunoblotting protocols and kits are well known in the art and are commercially available. Automated systems for immunoblotting, e.g. iBind Western Systems for Western blotting (ThermoFisher, Waltham, MA USA 02451), are available commercially. Immunoblotting includes, but is not limited to, Western blot, in-cell Western blot, and dot blot. Dot blot is a simplified procedure in which protein samples are not separated by electrophoresis but are spotted directly onto a membrane. In cell Western blot involves seeding cells in microtiter plates, fixing/permeabilizing the cells, and subsequent detection with a primary labeled primary antibody or unlabelled primary antibody followed by labeled secondary antibody as described herein.
  • the expression levels of the protein products encoded by the marker genes can also be detected with the antibodies described herein in a flow cytometry assay, including a fluorescence-activated cell sorting (FACS) assay.
  • FACS fluorescence-activated cell sorting
  • primary antibodies or antisera such as polyclonal antisera and monoclonal antibodies that specifically target the protein products encoded by the marker genes, can be used to detect protein expression in a FACS assay.
  • cells are stained with primary antibodies against specific target protein for a period of time sufficient for the antibody-antigen binding to occur and the bound antibodies can be detected by direct labels on the primary antibodies, for example, fluorescent labels or hapten labels such as biotin on the primary antibodies.
  • unlabeled primary antibody is used in an indirect assay as described above in conjunction with a fluorescently labeled secondary antibody specific for the primary antibody.
  • FACS provides a method for sorting or analyzing a mixture of fluorescently labeled biological cells, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell. The flow cytometer thus detects and reports the intensity of the fluorichrome-tagged antibody, which indicates the expression level of the target protein. Therefore, the expression level of the protein products encoded by the marker genes can be detected using antibodies against such protein products. Non-fluorescent cytoplasmic proteins can also be observed by staining permeablized cells.
  • the expression levels of the protein products encoded by the marker genes can also be detected using immunoassays such as an Enzyme Immune Assay (EIA) or an ELISA. Both EIA and ELISA assays are known in the art, e.g. for assaying a wide variety of tissues and samples, including blood, plasma, serum or bone marrow.
  • EIA Enzyme Immune Assay
  • ELISA Enzyme Immune Assay
  • ELISA assay formats are available, see, e.g., U.S. Pat. Nos. 4,016,043, 4,424,279, and 4,018,653, which are hereby incorporated by reference in their entireties. These include both single-site and two-site or “sandwich” assays of the non- competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labeled antibody to a target protein. Sandwich assays are commonly used assay format. A number of variations of the sandwich assay technique exist. For example, in a typical forward assay, an unlabelled antibody is immobilized on a solid substrate, and the sample to be tested brought into contact with the bound molecule.
  • a second antibody specific to the antigen, labeled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labeled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results can either be qualitative, by simple observation of the visible signal, or can be quantitated by comparing with a control sample containing known amounts of target protein. [00615] In some embodiments of the EIA or ELISA assays, an enzyme is conjugated to the second antibody.
  • fluorescently labeled secondary antibodies can be used in lieu of the enzyme-labeled secondary antibody to produce a detectable signal an ELISA assay format.
  • the fluorochrome-labeled antibody When activated by illumination with light of a particular wavelength, the fluorochrome-labeled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope.
  • the fluorescent labeled antibody is allowed to bind to the first antibody-target protein complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength; the fluorescence observed indicates the presence of the target protein of interest.
  • any of a number of enzymes or non- enzyme labels can be utilized so long as the enzymatic activity or non-enzyme label, respectively, can be detected.
  • the enzyme thereby produces a detectable signal, which can be utilized to detect a target protein.
  • Particularly useful detectable signals are chromogenic or fluorogenic signals.
  • particularly useful enzymes for use as a label include those for which a chromogenic or fluorogenic substrate is available.
  • Such chromogenic or fluorogenic substrates can be converted by enzymatic reaction to a readily detectable chromogenic or fluorescent product, which can be readily detected and/or quantified using microscopy or spectroscopy.
  • Such enzymes are well known to those skilled in the art, including but not limited to, horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, glucose oxidase, and the like (see Hermanson, Bioconjugate Techniques, Academic Press, San Diego (1996)).
  • Other enzymes that have well known chromogenic or fluorogenic substrates include various peptidases, where chromogenic or fluorogenic peptide substrates can be utilized to detect proteolytic cleavage reactions.
  • chromogenic and fluorogenic substrates are also well known in bacterial diagnostics, including but not limited to the use of ⁇ - and ⁇ -galactosidase, ⁇ -glucuronidase,6-phospho- ⁇ -D-galatoside 6- phosphogalactohydrolase, ⁇ -gluosidase, ⁇ -glucosidase, amylase, neuraminidase, esterases, lipases, and the like (Manafi et al., Microbiol. Rev.55:335-348 (1991)), and such enzymes with known chromogenic or fluorogenic substrates can readily be adapted for use in methods of the present disclosure.
  • chromogenic or fluorogenic substrates to produce detectable signals are well known to those skilled in the art and are commercially available.
  • Exemplary substrates that can be utilized to produce a detectable signal include, but are not limited to, 3,3’-diaminobenzidine (DAB), 3,3’,5,5’-tetramethylbenzidine (TMB), Chloronaphthol (4- CN)(4-chloro-1-naphthol), 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), o-phenylenediamine dihydrochloride (OPD), and 3-amino-9-ethylcarbazole (AEC) for horseradish peroxidase; 5-bromo-4-chloro-3-indolyl-1-phosphate (BCIP), nitroblue tetrazolium (NBT), Fast Red (Fast Red TR/AS-MX), and
  • fluorogenic substrates include, but are not limited to, 4-(Trifluoromethyl)umbelliferyl phosphate for alkaline phosphatase; 4-Methylumbelliferyl phosphate bis (2-amino- 2-methyl- 1,3-propanediol), 4-Methylumbelliferyl phosphate bis (cyclohexylammonium) and 4- Methylumbelliferyl phosphate for phosphatases; QuantaBlu TM and QuantaRed TM for horseradish peroxidase; 4-Methylumbelliferyl ⁇ -D-galactopyranoside, Fluorescein di( ⁇ -D- galactopyranoside) and Naphthofluorescein di-( ⁇ -D-galactopyranoside) for ⁇ -galactosidase; 3-Acetylumbelliferyl ⁇ -D-glucopyranoside and 4-Methylumbelliferyl- ⁇ - D-glucopyranoside for ⁇ -glucopy
  • Exemplary enzymes and substrates for producing a detectable signal are also described, for example, in US publication 2012/0100540.
  • Various detectable enzyme substrates including chromogenic or fluorogenic substrates, are well known and commercially available (Pierce, Rockford IL; Santa Cruz Biotechnology, Dallas TX; Invitrogen, Carlsbad CA; 42 Life Science; Biocare).
  • the substrates are converted to products that form precipitates that are deposited at the site of the target nucleic acid.
  • exemplary substrates include, but are not limited to, HRP-Green (42 Life Science), Betazoid DAB, Cardassian DAB, Romulin AEC, Bajoran Purple, Vina Green, Deep Space BlackTM, Warp RedTM, Vulcan Fast Red and Ferangi Blue from Biocare (Concord CA; biocare.net/products/detection/chromogens).
  • a detectable label can be directly coupled to either the primary antibody or the secondary antibody that detects the unlabeled primary antibody can have.
  • Exemplary detectable labels are well known to those skilled in the art, including but not limited to chromogenic or fluorescent labels (see Hermanson, Bioconjugate Techniques, Academic Press, San Diego (1996)).
  • fluorophores useful as labels include, but are not limited to, rhodamine derivatives, for example, tetramethylrhodamine, rhodamine B, rhodamine 6G, sulforhodamine B, Texas Red (sulforhodamine 101), rhodamine 110, and derivatives thereof such as tetramethylrhodamine- 5-(or 6), lissamine rhodamine B, and the like; 7-nitrobenz-2-oxa-1,3-diazole (NBD); fluorescein and derivatives thereof; napthalenes such as dansyl (5-dimethylaminonapthalene- 1-sulfonyl); coumarin derivatives such as 7-amino-4-methylcoumarin-3-acetic acid (AMCA), 7-diethylamino-3-[(4’-(iodoacetyl)amino)phenyl]-4-methylcoumarin (DCIA),
  • Exemplary chromophores include, but are not limited to, phenolphthalein, malachite green, nitroaromatics such as nitrophenyl, diazo dyes, dabsyl (4- dimethylaminoazobenzene-4’-sulfonyl), and the like.
  • Methods well known to a person skilled in the art such as microscopy or spectroscopy can be utilized to visualize chromogenic or fluorescent detectable signals associated with the bound primary or secondary antibodies.
  • the methods provided in this Section (Section 5.8) can be used with various cancer models known in the art. In one embodiment, mouse xenograft cancer models are used.
  • T-24 and UM-UC-3 cells are purchased from ATCC and cultured using the recommended media conditions.
  • the T-24 hNectin-4 (human nectin-4) and the UM-UC-3 Nectin-4 cells are generated by transducing parental cells with lentivirus containing the human Nectin-4 using the pRCDCMEP-CMV-hNectin-4 EF1-Puro construct and selected using puromycin.
  • T-24 Nectin-4 (clone 1A9) cells are implanted into nude mice and passaged via trocar, allowed to reach approximately 200mm 3 tumor volume, and subsequently treated with a single intraperitoneal (IP) dose of enfortumab vedotin (3mg/kg) or non-binding ADC (3 mg/kg) with 7 animals per treatment group.
  • IP intraperitoneal
  • enfortumab vedotin 3mg/kg
  • ADC non-binding ADC
  • the immunohistochemically stained slides sections are scanned with a Leica AT2 digital whole slide scanner, and the images are analyzed with Visiopharm software by use of custom-made algorithms for Nectin 4, CD11c and F4/80 staining.
  • the algorithms are optimized on the basis of staining intensity and background staining. Percent positive staining is calculated for Nectin 4 and positive cells per mm 2 is calculated for F480 and CD11c.
  • RNA from flash frozen tumors is isolated using the TRIZOL Plus RNA Purification Kit (Life Technologies) according to the manufacturer’s protocol yielding high quality RNA (average RNA integrity number > 8).
  • RNA selection method is using Poly(A) selection and the mRNA Library Prep Kit from Illumina and read on the Hi-Seq 2 x 150bp, single index (Illumina). The sequence reads are mapped to the human and mouse transcriptome and total reads per million were determined.
  • the disclosure is generally provided using affirmative language to describe the numerous embodiments.
  • the disclosure also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, procedures, assays or analysis.
  • particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, procedures, assays or analysis.
  • aspects that are not expressly included in the disclosure are nevertheless disclosed herein.
  • Particular embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Upon reading the foregoing description, variations of the disclosed embodiments can become apparent to individuals working in the art, and it is expected that those skilled artisans can employ such variations as appropriate.
  • Enfortumab vedotin is a Nectin-4 targeted monoclonal antibody (AGS-22C3) covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE).
  • AGS-22C3 Nectin-4 targeted monoclonal antibody
  • MMAE microtubule-disrupting agent monomethyl auristatin E
  • Enfortumab vedotin consists of three functional subunits: • A fully human IgG1 ⁇ antibody (AGS-22C3); • The microtubule-disrupting agent MMAE; • A protease-cleavable maleimidocaproyl-valine-citrulline (vc) linker that covalently attaches MMAE to AGS-22C3. [00629] Enfortumab vedotin binds the V domain of Nectin-4 (Challita-Eid et al., Cancer Res (2016); 76(10): 3003-13.).
  • the drug binds Nectin-4 protein on the cell surface and is internalized, causing proteolytic cleavage of the vc linker and intracellular release of MMAE. Free MMAE subsequently disrupts tubulin polymerization and leads to mitotic arrest.
  • Patients must also be ⁇ 18 years of age, must have an anticipated life expectancy of ⁇ 3 months as assessed by the investigator, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with adequate baseline hematologic, hepatic, and renal function.
  • ECOG Eastern Cooperative Oncology Group
  • Patients must not have ongoing sensory or motor neuropathy (Grade 2 or higher), or active central nervous system (CNS) metastases. Patients must not have received previous treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) for urothelial cancer.
  • MMAE monomethyl auristatin E
  • HbA1c hemoglobin A1c
  • GFR glomerular filtration rate
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • NYHA New York Heart Association
  • Patients must not have received prior systemic treatment for locally advanced or metastatic disease. Patients may not have previously received adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • EV Mono arm enfortumab vedotin monotherapy
  • EV+Pembro arm enfortumab vedotin in combination with pembrolizumab
  • the EV Mono arm included approximately 75 patients. Patients received enfortumab vedotin on Days 1 and 8 of every 3-week cycle. • The EV+Pembro arm included approximately 75 patients. Patients received enfortumab vedotin on Days 1 and 8, and pembrolizumab on Day 1 of every 3-week cycle.
  • test Product, Dose, and Mode of Administration [00647] Enfortumab vedotin administered as an IV infusion at 1 or 1.25 mg/kg over approximately 30 minutes on Days 1 and 8 of every 3-week cycle. A dose level of 1.25 mg/kg IV enfortumab vedotin on Days 1 and 8 of every 3-week cycle has been determined.
  • Table 8 shows the Enfortumab vedotin step-down dose levels for the study.
  • Table 8 Enfortumab vedotin step-down dose levels
  • Enfortumab vedotin doses were calculated on the basis of a patient’s actual body weight at baseline. Doses were recalculated when a patient’s body weight changed by ⁇ 10% of baseline or the previous cycle or when dose adjustment criteria were met. Actual weight was used except for patients weighing >100 kg; in such cases, the dose was calculated based on a weight of 100 kg.
  • the maximum dose permitted in this study component was 125 mg.
  • pembrolizumab 200 mg was administered as an IV infusion approximately 30 minutes after completion of enfortumab vedotin.
  • (ix) Duration of Treatment [00651] Patients were continued on study treatment until radiographically confirmed disease progression, unacceptable toxicity, investigator decision, consent withdrawal, start of a subsequent anticancer therapy, pregnancy, or study termination by the sponsor. Patients in the EV+Pembro arm with a response assessment of iUPD were permitted to continue on treatment until iCPD was confirmed by the investigator with a subsequent scan 4 to 9 weeks after iUPD.
  • Pembrolizumab was administered for up to a total of 35 cycles.
  • Patients who experienced unacceptable toxicity that was attributable only to pembrolizumab were continued on enfortumab vedotin monotherapy until radiographically confirmed disease progression, unacceptable toxicity, investigator decision, consent withdrawal, start of a subsequent anticancer therapy, pregnancy, or study termination by the sponsor.
  • Patients who experienced toxicity that was attributable only to enfortumab vedotin were continued on pembrolizumab monotherapy (for up to 35 cycles) until disease progression, unacceptable toxicity, investigator decision, consent withdrawal, start of a subsequent anticancer therapy, pregnancy, or study termination by the sponsor.
  • PK samples were collected and archived for possible analysis of concomitant drug levels or other enfortumab vedotin-related species, such as circulating metabolites of MMAE.
  • a validated assay was used to determine the levels of ATA for enfortumab vedotin in plasma.
  • PK and ATA samples for pembrolizumab were collected and archived for potential subsequent analysis the EV+Pembro arm.
  • Biomarker Assessments [00656] Peripheral blood, urine, and tumor biopsies were collected at protocol specified time points. Exploratory, predictive, and prognostic biomarkers associated with response, resistance, or safety observations were monitored before and during study treatment.
  • Tumor samples obtained at RC+PLND were used to characterize the clinical mechanisms of action and resistance.
  • Tumor tissue from diagnostic TURBT specimens and RC+PLND was required (fine needle aspiration is not adequate) to identify novel biomarkers. If additional post- treatment biopsies were done as part of SOC, the samples were also be used to further identify biomarkers of response and mechanism of action and resistance to treatment.
  • Biomarker assessments in tumor tissue may include, but may not be limited to, measurement of gene expression (GE) and mutation burden, characterization of the tumor microenvironment (TME) and tumor subtype, and drug effects.
  • Assays may include, but may not be limited to, immunohistochemistry (IHC) for Nectin-4 and PD-L1, and Next Generation Sequencing (NGS) of RNA and DNA.
  • Biomarker assessments in blood samples may include, but may not be limited to, measurement of baseline and drug induced changes in circulating blood cell subpopulations, immunoassays, and circulating disease markers.
  • Blood and urine assays may include, but may not be limited to, circulating tumor DNA, proteomic methodologies such as enzyme-linked immunosorbent assay (ELISA), immunoassays as a marker of tumor response or therapy resistance, and markers of immune function, including abundance of immune cell subsets and cytokines.
  • ELISA enzyme-linked immunosorbent assay
  • tissue e.g., skin
  • biomarkers including tissue levels of drug and drug products, nucleic acids, and protein to investigate possible associations with mechanisms of resistance or sensitivity to treatments as well as dynamic changes associated with treatments.
  • PRO assessments included QoL measures, both general and oncology specific (EuroQOL-5 Dimensions [EQ 5D-5L] and European Organisation for Research and Treatment of Cancer [EORTC] Core QoL Assessment [QLQ C30], respectively), as well as outcome-specific PROs around pain (Brief Pain Inventory Short Form [BPI-SF]).
  • a health resource utilization (HRU) questionnaire also aimed to measure clinical burden outside of the clinical trial setting.
  • PRO assessments were completed on an electronic device (preferred medium for reporting) on Day 1 prior to dosing, once weekly for the first 3 cycles, and once every cycle for the remainder of the treatment portion of the study. On dosing visit days, assessments were completed prior to dosing. PRO assessments were completed at each follow-up visit and each long term follow-up contact. PRO assessments were reported on paper or by clinic staff by telephone only if the use of an electronic device is not feasible.
  • Safety assessments were based on the information collected through the safety surveillance process and included the data from recorded AEs, including serious adverse events (SAEs), concomitant medications, physical examination findings, cardiac monitoring, and laboratory tests. Safety was monitored over the course of the study by the SMC.

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Abstract

La présente invention concerne des méthodes de traitement de cancers avec des conjugués anticorps-médicament (CAM) qui se lient à la protéine 191P4D12 (Nectine-4) et du pembrolizumab.
EP23847474.6A 2022-07-25 2023-07-24 Méthodes de traitement de patients atteints d'un cancer urothélial localement avancé ou métastatique avec des conjugués anticorps-médicament (cam) qui se lient à des protéines 191p4d12 en combinaison avec du pembrolizumab Pending EP4561624A1 (fr)

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US202263392067P 2022-07-25 2022-07-25
US202263402830P 2022-08-31 2022-08-31
US202363504183P 2023-05-24 2023-05-24
PCT/US2023/070812 WO2024026253A1 (fr) 2022-07-25 2023-07-24 Méthodes de traitement de patients atteints d'un cancer urothélial localement avancé ou métastatique avec des conjugués anticorps-médicament (cam) qui se lient à des protéines 191p4d12 en combinaison avec du pembrolizumab

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CN120754270A (zh) 2025-10-10
IL318220A (en) 2025-03-01
CN119907684A (zh) 2025-04-29
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KR20250051672A (ko) 2025-04-17

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