WO2026025013A2 - Polythérapie utilisant des inhibiteurs de cdk4 pour des traitements contre le cancer - Google Patents

Polythérapie utilisant des inhibiteurs de cdk4 pour des traitements contre le cancer

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Publication number
WO2026025013A2
WO2026025013A2 PCT/US2025/039221 US2025039221W WO2026025013A2 WO 2026025013 A2 WO2026025013 A2 WO 2026025013A2 US 2025039221 W US2025039221 W US 2025039221W WO 2026025013 A2 WO2026025013 A2 WO 2026025013A2
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cancer
cdr
seq
amino acid
acid sequence
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WO2026025013A3 (fr
Inventor
Lars ANDERS
Danan Li
Na Li
Kelsi Ray WILLIS
Jing Tang YUAN
Lianglin Edward ZHANG
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Remegen Co Ltd
Pfizer Inc
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Remegen Co Ltd
Pfizer Inc
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Publication of WO2026025013A2 publication Critical patent/WO2026025013A2/fr
Publication of WO2026025013A3 publication Critical patent/WO2026025013A3/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/6855—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 breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present disclosure relates to combination therapies useful for treating cancer.
  • the disclosure relates to combination therapies which comprise administering a CDK4 inhibitor in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody drug-conjugate (‘ADC’), optionally in further combination with an additional an endocrine therapy agent.
  • ADC anti-HER2 monoclonal antibody or an anti-HER2 antibody drug-conjugate
  • the disclosure also relates to associated methods of treatment, pharmaceutical compositions, and pharmaceutical uses.
  • Cyclin-dependent kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation.
  • the CDK catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312).
  • Cyclin B/CDK1 , cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and likely other heterodynes are important regulators of cell cycle progression.
  • cyclin/CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK4/6 inhibitors including palbociclib, ribociclib and abemaciclib, have been approved for treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced or metastatic breast cancer in combination with endocrine therapy, based on enhanced efficacy in prolonging PFS when compared to patients treated with endocrine therapy alone (Serra et al, Palbociclib in metastatic breast cancer: current evidence and real-life data, Drugs Context. (2019), 8:212579).
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • HR+/HER2- human epidermal growth factor receptor 2
  • CDK4/6 inhibitors have demonstrated substantial clinical effectiveness in treating HRpositive, HER2-negative advanced or metastatic breast cancer. However, similar to other kinase-targeting drugs, their efficacy may diminish over time due to the emergence of primary or acquired resistance. A notable limitation is that neutropenia, being a common adverse event, can interrupt treatment and require dose reductions. This highlights the need for therapies that can maintain efficacy while minimizing adverse effects.
  • PF-07220060 a novel CDK4 selective inhibitor
  • This compound offers a more selective inhibition profile, potentially translating into a reduced risk of neutropenia and other side effects associated with CDK6 inhibition.
  • This present disclosure relates to methods, combinations, uses, pharmaceutical compositions and kits for treating cancer, comprising a CDK4 inhibitor in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate, optionally in further combination with an additional anti-cancer agent.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a CDK4 inhibitor in combination with an anti-HER2 therapeutic agent comprising a monoclonal antibody or an antibody-drug conjugate (ADC); and optionally with an endocrine therapy agent; wherein the CDK4 inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each of R 5 and R 6 is independently OH, F, or C1-C2 alkoxy; wherein the monoclonal antibody is trastuzumab (Herceptin®), trastuzumab-qyyp (Trazimera®), pertuzumab (Perjeta®), margetuximab (Margenza®), zanidatamab, zenocutuzumab, or combinations thereof; wherein the ADC has the general formula Ab-(Linker-D) p , in which Ab represents the antibody or functional fragments thereof (e.g., Ab1 , Ab2 described herein), Linker represents a linker described herein, D represents a drug payload described herein, and p is 1 to 8 (e.g., 1 to 4). [11] In some embodiments, the ADC has the formula: wherein Ab1 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1 , CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively;
  • the ADC comprises Ab2 which is conjugated with a drug payload (D2) via a linker (Linker2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37 and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2, optionally through thiol, and Linker2 is selected from mc-vc-pAB and me.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject: an amount of a CDK4 inhibitor that is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol or a pharmaceutically acceptable salt thereof; and an amount of an anti-HER2 therapeutic agent that is an antibody-drug conjugate (ADC) that has the formula: wherein Ab1 is an antibody that binds to HER2 and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 6 or 14, and comprises a light chain comprising the amino acid sequence of SEQ ID NO: 12, 16, 45, or 46, wherein p is 4, and optionally wherein the amounts together are effective in treating
  • a method of treating cancer in a subject in need thereof comprising administering to the subject: an amount of a CDK4 inhibitor that is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol or a pharmaceutically acceptable salt thereof; and an amount of an anti-HER2 therapeutic agent that is an antibody-drug conjugate (ADC) that comprises Ab2 which is conjugated with MMAE via mc-vc-pAB, wherein Ab2 is an antibody that binds to HER2 and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 or 42, and comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43, and optionally
  • FIG. 1 illustrates the structure of the anti-HER2 immunoglobulin G1 ADC, T(kK183C+K290C)-vc0101 (PF-06804103), which comprises the anti-HER2 antibody T(kK183C+K290C) and 0101 payload connected via a vc linker.
  • Each black circle represents a linker/payload that is conjugated to the monoclonal antibody.
  • the underlined entity denotes the specific amino acid residue on the antibody to which conjugation occurs.
  • FIG. 2 illustrates the structure of an ADC according to certain embodiments of the present description. As shown is RC48-vc-MMAE (disitamab vedotin (DV)) , an embodiment of ADC2.
  • RC48-vc-MMAE diisitamab vedotin (DV)
  • FIG. 3 illustrates the structure of an ADC according to certain embodiments of the present description. As shown is RC48-vc-MMAF, an embodiment of ADC2.
  • FIG. 4 illustrates the structure of an ADC according to certain embodiments of the present description. As shown is RC48-mc-MMAF, an embodiment of ADC2.
  • FIG. 5 shows dose-dependent growth inhibition by Trazimera, palbociclib, PF-07220060 as single agents, combination of palbociclib + Trazimera, and enhanced growth inhibition by combination of PF-07220060 + Trazimera, in HR+ HER2+ BT474 breast cancer spheroid in vitro growth as spheroid diameter (pm) versus time of treatment.
  • FIG. 7 illustrates the schematic of an assay and sequential dosing procedure for a CDK inhibitor and an anti-HER2-ADC, disitamab vedotin (DV), according to certain embodiments of the present disclosure.
  • FIGs. 8A-8C show the dose response curves illustrating the single agent activity of PF- 07220060 (FIG.8A) and DV (FIG. 8B), along with the combined effect of DV + PF-07220060 (FIG. 8C).
  • FIG. 9 shows an isobologram for CAMA1 cells treated with PF-07220060 and DV in vitro.
  • E1 A method of treating cancer in a subject in need thereof comprising administering to the subject an amount of a CDK4 inhibitor in combination with an amount of an anti-HER2 therapeutic agent selected from the group consisting of (1) a monoclonal antibody or (2) an antibody-drug conjugate; and optionally with an endocrine therapy agent; wherein the CDK4 inhibitor is a compound of Formula (I): wherein:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each of R 5 and R 6 is independently OH, F, or C1-C2 alkoxy; wherein the monoclonal antibody is trastuzumab (Herceptin®), trastuzumab-qyyp (Trazimera®), pertuzumab (Perjeta®), margetuximab (Margenza®), zanidatamab, zenocutuzumab, or combinations thereof.
  • the antibody-drug conjugate is selected from ADC1 or ADC2: wherein ADC1 has the formula: wherein Ab1 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively;
  • ADC2 comprises Ab2 which is conjugated with a drug payload (D2) via a linker (Linker2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1 , CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequence of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; wherein Linker2 is linked with Ab2 through thiol and is selected from mc-vc-pAB and me; and wherein the amounts together are effective in treating cancer.
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively;
  • E6 The method of any one of embodiments E1-E2, wherein the anti-HER2 therapeutic agent is a monoclonal antibody selected from the group consisting of trastuzumab, trastuzumab-qyyp, pertuzumab, and margetuximab, zanidatamab, and zenocutuzumab.
  • the anti-HER2 therapeutic agent is a monoclonal antibody selected from the group consisting of trastuzumab, trastuzumab-qyyp, pertuzumab, and margetuximab, zanidatamab, and zenocutuzumab.
  • E7 The method of any one of embodiments E1-E3, wherein the anti-HER2 therapeutic agent is a monoclonal antibody which is trastuzumab-qyyp.
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively;
  • E10 The method of any one of embodiments E1-E9, wherein the endocrine therapy agent is selected from the group consisting of letrozole, anastrozole, exemestane, fulvestrant, elacestrant, amcenestrant, giredestrant, RG6171, camizestrant, AZD9496, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, adoxifene, and afimoxifene.
  • the endocrine therapy agent is selected from the group consisting of letrozole, anastrozole, exemestane, fulvestrant, elacestrant, amcenestrant, giredestrant, RG6171, camizestrant, AZD9496, rintodestrant, ZN
  • E12 The method of any one of embodiments E1-E11 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.
  • the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.
  • E13 The method of any one of embodiments E1-E12, wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+) breast cancer, hormone receptor negative (HR-) breast cancer, human epidermal growth factor receptor 2 negative (HER2-) breast cancer, human epidermal growth factor receptor 2 positive (HER2+) breast cancer, HR+/HER2- breast cancer, estrogen receptor negative (ER-)/HR+ breast cancer, estrogen receptor positive (ER+)/HER2- breast cancer, and triple negative breast cancer (TNBC).
  • HR+ hormone receptor positive
  • HR- hormone receptor negative
  • HER2- human epidermal growth factor receptor 2 negative
  • HER2+ human epidermal growth factor receptor 2 positive
  • HR+/HER2- breast cancer HR+/HER2- breast cancer
  • estrogen receptor negative (ER-)/HR+ breast cancer estrogen receptor positive (ER+)/HER2- breast cancer
  • TNBC triple negative breast cancer
  • a combination for use in treating cancer comprising:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each R 5 and R 6 is independently OH, F or C1-C2 alkoxy; and
  • a heavy chain variable region comprising a CDR-H1 , CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively; and (2) a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 8, 9, and 10, respectively; and wherein p is 1 to 4.
  • a combination for use in treating cancer comprising:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each R 5 and R 6 is independently OH, F or C1-C2 alkoxy; and
  • an antibody-drug conjugate comprising Ab2 which is conjugated with a drug payload (D2) via a linker (Linker2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2 through thiol and is selected from mc-vc-pAB and me.
  • E16 The combination of any one of embodiments E14-E15, wherein the compound of Formula (I) is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1/7- benz-imidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-f/7reo-pentitol.
  • E17 The combination of any one of embodiments E14-E16, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.
  • the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.
  • E18 The combination of any one of embodiments E14-E17, wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+) breast cancer, hormone receptor negative (HR-) breast cancer, human epidermal growth factor receptor 2 negative (HER2-) breast cancer, human epidermal growth factor receptor 2 positive (HER2+) breast cancer, HR+/HER2- breast cancer, estrogen receptor negative (ER-)/HR+ breast cancer, estrogen receptor positive (ER+)/HER2- breast cancer, and triple negative breast cancer (TNBC).
  • HR+ hormone receptor positive
  • HR- hormone receptor negative
  • HER2- human epidermal growth factor receptor 2 negative
  • HER2+ human epidermal growth factor receptor 2 positive
  • HR+/HER2- breast cancer HR+/HER2- breast cancer
  • estrogen receptor negative (ER-)/HR+ breast cancer estrogen receptor positive (ER+)/HER2- breast cancer
  • TNBC triple negative breast cancer
  • the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter.
  • a dose of about 100 mg should be understood to mean that the dose may vary between 90 mg and 110 mg.
  • the terms “antibody-drug conjugate” or “ADC” refers to a molecule composed of an antibody linked to an anti-cancer drug.
  • the antibody specifically binds to a certain tumor antigen, such as HER2.
  • the antibodies used in an ADC may be full-length antibodies, antigen-binding fragments of a full-length antibody, or antibody derivatives.
  • the anti-cancer drug is conjugated to the antibody via a linker.
  • the ADC provided by the present disclosure comprises an antibody, or antigenbinding fragment thereof, that binds to HER2, and a linker-drug moiety.
  • HER2 refers to a transmembrane tyrosine kinase receptor that belongs to the EGFR family. HER2 is also known as ErbB2, p185 and CD340. This family of receptors includes four members (EGFR/HER1, HER2, HER3 and HER4) that function by stimulating growth factor signaling pathways such as the PI3K-AKT-mT0R pathway. Amplification and/or overexpression of HER2 is associated with multiple human malignancies. The wild type human HER2 protein is described, for example, in Semba et al., 1985, PNAS 82:6497-6501 and Yamamoto et al., 1986, Nature 319:230-4 and Genbank Accession Number X03363.
  • HER2 includes variants, isoforms, homologs, orthologs and paralogs.
  • antibodies and antibody-drug conjugates cross-react with HER2 from species other than human, such as HER2 of mouse, rat, or primate, as well as different forms of HER2 (e.g., glycosylated HER2).
  • the antibodies and antibody-drug conjugates may be completely specific for human HER2 and may not exhibit species or other types of cross-reactivity.
  • HER2 refers to naturally occurring human HER2 unless contextually dictated otherwise.
  • HER2 antibody means an antibody that associates, binds, or reacts with the HER2 type ligand or isoform, or fragment or derivative thereof. These terms are used interchangeably.
  • HER2 antibody-drug conjugate refers to an antibody-drug conjugate or ADC (as defined herein) that comprises an anti-HER2 antibody as defined herein. These terms are used interchangeably.
  • Native or naturally occurring antibodies, and native immunoglobulins are typically heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V H ) followed by a number of constant domains.
  • V H variable domain
  • Each light chain has a variable domain at one end (V L ) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • V L variable domain at one end
  • variable domain refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies.
  • Linker describes the direct or indirect linkage of the antibody to the drug payload (D). Attachment of a linker to an antibody can be accomplished in a variety of ways, such as through surface lysines, reductive-coupling to oxidized carbohydrates, cysteine residues liberated by reducing interchain disulfide linkages, reactive cysteine residues engineered at specific sites, and acyl donor glutamine-containing tag or an endogenous glutamine made reactive by polypeptide engineering in the presence of transglutaminase and an amine.
  • the present disclosure uses site specific methods to link the antibody to the drug payload. In one embodiment, conjugation occurs through cysteine residues that have been engineered into the antibody constant region.
  • conjugation occurs through acyl donor glutamine residues that have either been a) added to the antibody constant region via a peptide tag, b) engineered into the antibody constant region or c) made accessible/reactive by engineering surrounding residues.
  • Linkers can be cleavable (i.e. , susceptible to cleavage under intracellular conditions) or non-cleavable. In some embodiments, the linker is a cleavable linker.
  • drug refers to drug payload having a cytotoxic effect on tumors including the depletion, elimination and/or the killing of tumor cells.
  • drug, payload, and drug payload are used interchangeably.
  • the drug payload is a cytotoxic agent.
  • examples of drug payloads include but are not limited to monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF).
  • linker-drug moiety refers to the molecule resulting from a drug linked or conjugated to a linker.
  • an “antibody” or “Ab” is an immunoglobulin molecule capable of recognizing and binding to a specific target or antigen, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • a specific target or antigen such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.
  • the term “antibody” encompasses any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, antigenbinding fragments (or portion), such as Fab, Fab’, F(ab’)2, Fd, Fv, Fc, etc., of intact antibodies that retain the ability to specifically bind to a given antigen (e.g.
  • HER2 an isolated complementarity determining region (CDR)
  • bispecific antibodies heteroconjugate antibodies, mutants thereof, fusion proteins having an antibody, or antigen-binding fragment thereof, (e.g., a domain antibody), single chain (ScFv) and single domain antibodies (e.g., shark and camelid antibodies), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Holliger and Hudson, 2005, Nature Biotechnology 23(9): 1126-1136), humanized antibodies, chimeric antibodies and any other modified configuration of the immunoglobulin molecule that includes an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies.
  • CDR complementarity determining region
  • the antibodies may be of murine, rat, human, or any other origin (including chimeric or humanized antibodies).
  • the antibody, or antigen-binding fragment thereof, of the disclosed anti-HER2 antibody-drug conjugates is a chimeric, humanized, or a recombinant human antibody, or HER2-binding fragment thereof.
  • variable region of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.
  • variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions.
  • FR framework regions
  • CDRs complementarity determining regions
  • the CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies.
  • There are at least two techniques for determining CDRs (1) an approach based on cross-species sequence variability (i.e. , Kabat et al.
  • a CDR may refer to CDRs defined by either approach or by a combination of both approaches.
  • a CDR of a variable domain are comprised of amino acid residues within the variable region that are identified in accordance with the definitions of Kabat, Chothia, IMGT, the accumulation of both Kabat and Chothia, VBASE2, AbM, contact, and/or conformational definitions or any method of CDR determination well known in the art.
  • Antibody CDRs may be identified as the hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. The positions of the CDRs may also be identified as the structural loop structures originally described by Chothia and others.
  • the CDR positions may also be derived from an analysis of the VBASE2 database. (See, e.g. Retter et al., Nucleic Acids Res. 33(Database Issue): D671-D674, 2005).
  • Antibodies, antibody domains, and antigen-binding fragments thereof may be described as “polypeptides”, “oligopeptides”, “peptides” and “proteins”, i.e., chains of amino acids of any length, preferably, relatively short (e.g., 10-100 amino acids).
  • the chain may be linear or branched, it may comprise modified amino acids, and/or may be interrupted by non-amino acids.
  • the terms also encompass an amino acid chain that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component.
  • polypeptides containing one or more analogs of an amino acid including, for example, unnatural amino acids, etc.
  • polypeptides can occur as single chains or associated chains.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Commission on Biochemical Nomenclature.
  • humanized antibody or “CDR grafted antibody” refers to forms of nonhuman (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab’, F(ab')2 or other antigen binding subsequences of antibodies) that contain minimal sequences derived from a non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from one or more complementarity determining regions (CDRs) of the recipient are replaced by residues from one or more CDRs of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity.
  • recipient antibody complementarity determining regions
  • donor antibody non-human species
  • angiogenesis refers to blood vessel formation. Tumor angiogenesis is the growth of new blood vessels that tumors need to grow. This process is caused by the release of chemicals by the tumor and by host cells near the tumor.
  • apoptosis refers to the death of cells that occurs as a normal and controlled part of an organism's growth or development. Apoptosis is a type of cell death in which a series of molecular steps in a cell lead to its death. Apoptosis is one method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth.
  • cancer refers to solid tumors named for the type of cells that form them, as well as cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include but are not limited to sarcomas and carcinomas. Examples of cancers of the blood include but are not limited to leukemias, lymphomas and myeloma.
  • cancer includes but is not limited to a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from latter one.
  • the term “patient” or “subject” refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs and cats. In some embodiments, the subject is a human.
  • the terms “treat” or “treating” or “treatment” of a cancer as used herein means to administer a combination therapy according to the present disclosure to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as "treating” is defined immediately above.
  • the term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and/or prolonging survival of patients having the cancer.
  • Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S-10S (2009).
  • the treatment achieved by a combination therapy of the disclosure is any of the partial response (PR), complete response (CR), overall response (OR), objective response rate (ORR), progression free survival (PFS), radiographic PFS, metastasis fee survival (MFS), disease free survival (DFS) and overall survival (OS).
  • PR partial response
  • CR complete response
  • OR overall response
  • ORR objective response rate
  • PFS progression free survival
  • MFS metastasis fee survival
  • DFS disease free survival
  • OS overall survival
  • the term "sustained response" refers to the sustained effect on reducing tumor growth after cessation of a treatment.
  • the tumor size may be the same size or smaller as compared to the size at the beginning of the medicament administration phase.
  • the sustained response has a duration of at least the same as the treatment duration, at least 1.5x, 2x, 2.5x, or 3x length of the treatment duration, or longer.
  • the anti-cancer effect of the method of treating cancer including “objective response,” “complete response,” “partial response,” “progressive disease,” “stable disease,” “progression free survival,” “duration of response,” as used herein, may be defined and assessed by the investigators using RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Eur J of Cancer, 2009; 45(2):228-47).
  • the therapeutic effect achieved by the compound of Formula (I), e.g., PF-07220060, in combination with a monoclonal antibody or an antibody-drug conjugate, and optionally in further combination with endocrine therapy agent is defined by reference to any of the following: complete response (CR), disease free survival (DFS), duration of response (DoR), overall response rate (ORR), overall survival (OS), partial response (PR), or progression free survival (PFS).
  • response to a combination therapy of the disclosure is any of PR, CR, PFS, DFS, OR OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.
  • the disclosure relates to neoadjuvant therapy, adjuvant therapy, first-line therapy, second-line therapy, second-line or later lines of therapy, or third-line or later lines of therapy.
  • the cancer may be localized, advanced or metastatic, and the intervention may occur at point along the disease continuum (i.e. , at any stage of the cancer).
  • the treatment achieved by a combination therapy of the disclosure is measured by the time to PSA progression, the time to initiation of cytotoxic chemotherapy, or the proportion of patients with PSA response greater than or equal to 50%.
  • the treatment regimen for a method, combination or use of the disclosure that is effective to treat cancer in a subject may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as, but not limited to, the Cox log-rank test, the Cochran-Mantel-Haenszel log-rank test, the Student’s t- test, the chi2-test, the ll-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-test and the Wilcon on-test.
  • any statistical test known in the art such as, but not limited to, the Cox log-rank test, the Cochran-Mantel-Haenszel log-rank test, the Student’s t- test, the chi2-test, the ll-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-test and the Wilcon on-test.
  • treatment regimen may be used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.
  • ameliorate or “ameliorating” refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease. “Ameliorating” also includes shortening or reduction in duration of a symptom. “Symptom” refers to any subjective evidence of disease or of a subject's condition.
  • an “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured).
  • Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome.
  • therapeutically effective amount also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.
  • Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and/or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.
  • beneficial or desired outcomes provided by the disclosure may include: (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) reducing the incidence or ameliorating (that is, reducing to some extent, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dosage of another medication required to treat the cancer, (6) enhancing the efficacy or safety of another medication used to treat the cancer, and/or (7) delaying the time to progression of the cancer.
  • An effective dosage can be administered in one or more administrations.
  • Combination therapy involves administering each of the component drugs in the combination therapy in an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.
  • the effective amount of a compound or pharmaceutical composition when used as part of a combination therapy may be less than the amount of the compound or pharmaceutical composition if used as a single agent to treat the same disorder.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas.
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor.
  • Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using callipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CR or MRI scans.
  • imaging techniques e.g., bone scan, ultrasound, CR or MRI scans.
  • additive is used to mean that the result of the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent individually.
  • synergistic or “synergistic” are used to mean that the result of the combination of two or more compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect and combinations providing a synergistic effect may be referred to as synergistic combinations.
  • a “synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein.
  • the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, or dose ratios to patients in need of treatment.
  • the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species to measure a synergistic effect.
  • the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic or pharmacodynamics methods.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)).
  • Sigmoid-Emax equation Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)
  • Loewe additivity Li. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)
  • the median-effect equation Chou, T. C. and Tala
  • endocrine therapy or “hormone therapy” means an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).
  • endocrine therapy includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.
  • an antiestrogen refers to a class of drugs that prevent estrogens like estradiol from mediating the biological effects in the body. Antiestrogens act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production.
  • an antiestrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD) or a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • an aromatase inhibitor include, but are not limited to, anastrozole.
  • a SERD include, but are not limited to, fulvestrant.
  • Additional SERDs include elacestrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine).
  • SERM include, but are not limited to, tamoxifen, clomifene and raloxifene.
  • Additional SERMS include toremifene, lasofoxifene, apeledoxifene and afimoxifene.
  • the aromatase inhibitor includes letrozole, exemestane, and anastrozole.
  • the SERM includes tamoxifen, clomifene and raloxifene.
  • an antiestrogen of the present disclosure includes fulvestrant and letrozole. In an embodiment, an antiestrogen of the present disclosure includes fulvestrant. In an embodiment, an antiestrogen of the present disclosure includes letrozole.
  • Palbociclib or 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8/7- pyrido[2,3-c(]pyrimidin-7-one (referred to herein as “palbo”) is a potent and selective inhibitor of CDK4 and CDK6, having the structure: [89] Palbociclib is described in WHO Drug Information, Vol. 27, No. 2, page 172 (2013).
  • the disclosure relates to methods, combinations, and uses comprising a CDK4 inhibitor, wherein the CDK4 inhibitor is a compound of Formula (I), which includes hydrates (e.g., monohydrate), salts, and polymorphs thereof: wherein:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each of R 5 and R 6 is independently OH, F, or C1-C2 alkoxy.
  • CDK4 selective inhibitors of the present disclosure include “PF- 07220060” which refers to 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-t/7reo-pentitol or atirmociclib, which has the following chemical structure, including hydrates (e.g., monohydrate), salts and polymorphs thereof:
  • PF-07220060 is disclosed in International Publication No. WO 2019/207463, U.S. Patent No. 10,766,884, and International Publication No. WO 2022/058871, the contents of which are incorporated herein by reference in their entirety. Unless indicated otherwise, all references herein to PF-07220060 include references to salts, solvates, hydrates, and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.
  • PF-07220060 can be prepared as described in Example A94 of U.S. Publication No. 2019/0330196 and as described in WO 2022/058871 , the contents of which are incorporated herein by reference in their entirety.
  • the anti-HER2 therapeutic agents of the disclosure include monoclonal antibodies and antibody-drug-conjugates which target the HER2 protein.
  • the disclosure relates to methods, combinations, and uses comprising an anti-HER2 monoclonal antibody that targets the HER2 protein (also refers to as ‘HER2 antibody’).
  • HER2 antibodies include, but are not limited to, trastuzumab (Herceptin®), trastuzumab-qyyp (Trazimera®), pertuzumab (Perjeta® disclosed in WO9123894), margetuximab (Margenza® as disclosed in WO01002244, zanidatamab as disclosed in WO1 8190924, zenocutuzumab as disclosed in WO18182422 and WO15130173), and combinations thereof, the contents of which are incorporated herein by reference in their entirety.
  • ADCs Antibody Drug Conjugates
  • ADCs include an antibody component conjugated to a drug payload (D) through the use of a linker (Linker).
  • ADCs have a formula of Ab-(Linker-D) p , wherein (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to HER2, (b) Linker-D is a linker-drug moiety, wherein Linker is a linker, and D is a drug and (c) p is the average number of linker/drug moieties that are attached to the antibody.
  • the Ab is Ab1 described herein.
  • the Ab is Ab2 described herein.
  • p indicates the average number of units of the linker-drug conjugated per antibody molecule in the ADC.
  • p is a whole number due to the homogeneous nature of the ADC. In some embodiments, p is from about 1 to about 8. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4. In other embodiments, p is greater than 4, such as 5, 6, 7, or 8. p can also be referred to as the drug-to- antibody ratio (DAR) or drug loading, which indicates the number of drug (D) molecules that are conjugated per antibody.
  • DAR drug-to- antibody ratio
  • the ADCs of the present disclosure use site specific conjugation such that there is essentially a homogeneous population of ADCs having one DAR in a composition of ADCs. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In other embodiments, the DAR is 3. In other embodiments, the DAR is 4. In other embodiments, the DAR is greater than 4, such as 5, 6, 7, or 8.
  • the antibody in the ADC used in the present disclosure specifically binds to HER2. In some embodiments, the antibody specifically binds to human HER2.
  • the binding activity of the antibody against cancer cells can be confirmed using flow cytometry.
  • the internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol.
  • the ADC is ADC1 which includes an antibody (e.g., Ab1) that comprises three complementarity-determining regions (CDRs) (/.e., CDR-H1 , CDR-H2, and CDR-H3) from a heavy chain protein having the amino acid sequence shown in SEQ ID NO: 6 or 14 and three CDRs (/.e., CDR-L1 , CDR-L2, and CDR-L3) from a light chain protein having the amino acid sequence shown in SEQ ID NO: 12, 16, 45, or 46.
  • an antibody e.g., Ab1 that comprises three complementarity-determining regions (CDRs) (/.e., CDR-H1 , CDR-H2, and CDR-H3) from a heavy chain protein having the amino acid sequence shown in SEQ ID NO: 6 or 14 and three CDRs (/.e., CDR-L1 , CDR-L2, and CDR-L3) from a light chain protein having the amino acid sequence shown in SEQ ID NO: 12, 16, 45,
  • the ADC1 includes an antibody (e.g., Ab1) that comprises a CDR-H1 having the amino acid sequence shown in SEQ ID NO: 2, a CDR-H2 having the amino acid sequence shown in SEQ ID NO: 3, and a CDR-H3 having the amino acid sequence shown in SEQ ID NO: 4, and/or a CDR-L1 having the amino acid sequence shown in SEQ ID NO: 8, a CDR-L2 having the amino acid sequence shown in SEQ ID NO: 9, and a CDR-L3 having the amino acid sequence shown in SEQ ID NO: 10.
  • Ab1 that comprises a CDR-H1 having the amino acid sequence shown in SEQ ID NO: 2, a CDR-H2 having the amino acid sequence shown in SEQ ID NO: 3, and a CDR-H3 having the amino acid sequence shown in SEQ ID NO: 4, and/or a CDR-L1 having the amino acid sequence shown in SEQ ID NO: 8, a CDR-L2 having the amino acid sequence shown in SEQ ID NO: 9, and
  • the ADC1 includes an antibody (e.g., Ab1) that comprises the CDRs from a VH having the amino acid sequence shown in SEQ ID NO: 1 and the CDRs from a VL having the amino acid sequence shown in SEQ ID NO: 7 or 44.
  • Ab1 an antibody that comprises the CDRs from a VH having the amino acid sequence shown in SEQ ID NO: 1 and the CDRs from a VL having the amino acid sequence shown in SEQ ID NO: 7 or 44.
  • the ADC1 includes an antibody (e.g., Ab1) that comprises the CDRs from a heavy chain protein comprising the amino acid sequence of SEQ ID NO: 6 or 14 and the CDRs from a light chain protein comprising the amino acid sequence of SEQ ID NO: 12, 16, 45, or 46.
  • Ab1 an antibody that comprises the CDRs from a heavy chain protein comprising the amino acid sequence of SEQ ID NO: 6 or 14 and the CDRs from a light chain protein comprising the amino acid sequence of SEQ ID NO: 12, 16, 45, or 46.
  • the ADC1 includes an antibody (e.g., Ab1) comprising a heavy chain variable region that comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1, and comprising a light chain variable region that comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 7 or 44.
  • Ab1 an antibody comprising a heavy chain variable region that comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 7 or 44.
  • the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 1.
  • the heavy chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7 or 44.
  • the light chain variable region comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 7 or 44.
  • the light chain variable region comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 7 or 44. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1 , and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 7 or 44.
  • the ADC1 includes an antibody (e.g., Ab1) that comprises a heavy chain comprising a heavy chain variable region and a heavy chain constant region, and comprises a light chain comprising a light chain variable region and a light chain constant region.
  • Ab1 an antibody that comprises a heavy chain comprising a heavy chain variable region and a heavy chain constant region, and comprises a light chain comprising a light chain variable region and a light chain constant region.
  • the heavy chain comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 6 or 14, and the light chain comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 6 or 14.
  • the heavy chain comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 6 or 14.
  • the heavy chain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 6 or 14. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 12, 16, 45, or 46.
  • the light chain comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 12, 16, 45, or 46.
  • the light chain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 12, 16, 45, or 46. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 12.
  • the light chain comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 6 or 14, and the light chain comprises the amino acid sequence of SEQ ID NO: 12, 16, 45, or 46.
  • the ADC1 includes an antibody (e.g., Ab1) designated T(kK183C+K290C), which is described in US 2017/0151341 and WO 2017/093844, each of which is herein incorporated by reference in its entirety.
  • the antibody T(kK183C+K290C) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO:16 or 46.
  • the ADC includes an antibody that comprises a heavy chain protein having the amino acid sequence shown in SEQ ID NO: 14 and a light chain protein having the amino acid sequence shown in SEQ ID NO: 16 or 46.
  • the antibodies are conjugated to the Linker-D complexes via cysteine residues.
  • the site-specific conjugation occurs through one or more cysteine residues that have been engineered into an antibody constant region. Methods of preparing HER2 antibodies for site specific conjugation through cysteine residues can be performed as described in PCT Publication No. WQ2013/093809, which is incorporated by reference in its entirety.
  • positions 290 on the heavy chain constant region and position 183 on the light chain constant region are altered to cysteine for conjugation.
  • the antibodies bind to the same epitope on HER2 as trastuzumab (Herceptin®).
  • the antibodies have the same variable region CDRs as trastuzumab (Herceptin®).
  • the antibodies have the same variable regions (i.e. , VH and VL) as trastuzumab (Herceptin®).
  • Trastuzumab (Herceptin®) is a recombinant humanized monoclonal antibody, selectively targeting on the extracellular domain of human epidermal growth factor receptor-2 (HER2).
  • Trastuzumab-qyyp (Trazimera®) is a biosimilar to trastuzumab (Herceptin®).
  • Tables 1 and 2 provide the amino acid (protein) sequences and associated nucleic acid (DNA) sequences of certain humanized HER2 antibodies that may be used in constructing the site-specific ADCs described herein.
  • the CDRs shown are defined by Kabat numbering scheme.
  • the antibody heavy chains and light chains shown in Table 1 contain the trastuzumab heavy chain variable region (VH) and light chain variable region (VL).
  • the heavy chain constant region and light chain constant region shown in Table 1 are derivatized from trastuzumab and contain one or more modifications (relative to the respective sequences of trastuzumab) to allow for site specific conjugation when making the ADCs used in the disclosure. Modifications to the amino acid sequences in the antibody constant region to allow for site specific conjugation are underlined and bolded.
  • T for trastuzumab
  • kK183C denotes that position 183 on the light (kappa) chain has been modified from a lysine to a cysteine.
  • the positions of the amino acids of modifications, such as “K290C” and “kK183C,” are numbered according to the numbering of Ell index of Kabat.
  • the ADC is ADC2 which comprises Ab2 which is conjugated with a drug payload (D2) via a linker (Linker2), and Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2, optionally through thiol, and is selected from mc-vc-pAB and me.
  • the ADC2 comprises Ab2 (e.g., RC48) which is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • the ADC2 comprises Ab2 comprising a heavy chain variable region that comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 39, and comprising a light chain variable region that comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 40.
  • the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 39.
  • the heavy chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 39. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 40.
  • the light chain variable region comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 40.
  • the light chain variable region comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 40. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 40.
  • the ADC2 comprises Ab2 that comprises a heavy chain comprising a heavy chain variable region and a heavy chain constant region, and comprises a light chain comprising a light chain variable region and a light chain constant region.
  • the heavy chain comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 41 or 42
  • the light chain comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 43.
  • the heavy chain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 41 or 42.
  • the heavy chain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 or 42. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 42s.
  • the light chain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 43.
  • the light chain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 43. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 or 42, and the light chain comprises the amino acid sequence of SEQ ID NO: 43.
  • Ab2 is humanized antibody RC48 (also known as disitamab) described in U.S. Patent No. 10,087,260, the content of which is herein incorporated by reference in its entirety.
  • RC48 is a recombinant human HER2 antibody, which is able to bind to the extracellular domain of HER2 with high affinity.
  • the ADC2 is disitamab vedotin, as described in U.S. Patent No. 10,087,260.
  • the antibody heavy chains and light chains shown in Table 2 contain the disitamab heavy chain variable region (VH) and disitamab light chain variable region (VL).
  • Additional HER2 ADCs of the disclosure include but are not limited to ado-trastuzumab emtasine (Kadcyla®, as disclosed in WO15115091) and Fam-trastuzumab-deruxtecan (Enhertu®, as disclosed in WO0100245).
  • the drug component of the ADCs of the disclosure is an anti-mitotic drug, which is an auristatin drug, such as 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1- ⁇ (2S)-2- [(1 R,2R)-1-methoxy-2-methyl-3-oxo-3- ⁇ [(1S)-2-phenyl-1-(1 ,3-thiazol-2- yl)ethyl]amino ⁇ propyl]pyrrolidin-1-yl ⁇ -5-methyl-1 -oxoheptan-4-yl]-N-methyl-L-valinamide (also known as “0101”), having the following structure:
  • Auristatins inhibit cell proliferation by inhibiting the formation of microtubules during mitosis through inhibition of tubulin polymerization.
  • PCT International Publication No. WO 2013/072813 which is incorporated by reference in its entirety, discloses auristatins that are useful in the manufacture of the ADCs of the disclosure and provides methods of producing those auristatins.
  • the drug component of the ADCs of the disclosure is monomethyl auristatin E (‘MMAE’).
  • the drug component of the ADCs of the disclosure is monomethyl auristatin F (‘MMAF’).
  • the drug-to-antibody ratio (DAR) or drug loading indicates the number of drug (D) molecules that are conjugated per antibody.
  • the ADCs of the present disclosure use site specific conjugation such that there is essentially a homogeneous population of ADCs having one DAR in a composition of ADCs.
  • the DAR is 1.
  • the DAR is 2.
  • the DAR is 3.
  • the DAR is 4.
  • the DAR is greater than 4.
  • compositions of ADCs prepared in this way include a plurality of antibodies, each antibody conjugated to a particular number of drug molecules. As such, the compositions have an average DAR.
  • a linker is a bifunctional compound which can be used to link a drug and an antibody to form an antibody-drug conjugate (ADC). Such conjugates allow the selective delivery of drugs to tumor cells.
  • Suitable linkers include, for example, cleavable and non-cleavable linkers.
  • a cleavable linker is typically susceptible to cleavage under intracellular conditions.
  • Major mechanisms by which a conjugated drug is cleaved from an antibody include hydrolysis in the acidic pH of the lysosomes (hydrazones, acetals, and cis-aconitate-like amides), peptide cleavage by lysosomal enzymes (the cathepsins and other lysosomal enzymes), and reduction of disulfides.
  • hydrolysis in the acidic pH of the lysosomes hydrolysis in the acidic pH of the lysosomes (hydrazones, acetals, and cis-aconitate-like amides)
  • peptide cleavage by lysosomal enzymes the cathepsins and other lysosomal enzymes
  • reduction of disulfides As a result of these cleavage, mechanisms of linking the drug to the antibody also vary widely and any suitable linker can be used.
  • the linker is a cleavable linker such that the payload can induce a bystander effect once the linker is cleaved.
  • the bystander effect is when a membrane permeable drug is released from the antibody (i.e. , by cleaving of a cleavable linker) and crosses the cellular membrane and, upon diffusion, induces killing of cells surrounding the cell that initially internalized the ADC.
  • Suitable cleavable linkers include, but are not limited to, a peptide linker cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease, such as maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (also known as “mc-vc-pAB” or simply “vc”), which is used in the ADCs shown in Figs. 2 and 3 and which has the following structure:
  • Linkers are attached to the monoclonal antibody via the left side of the molecule and the drug via the right side of the molecule (see example of linker mc-vc-pAB as depicted above).
  • the linker is an uncleavable, such as maleimidocaproyl (‘me’).
  • the ADC is ADC1 which is a site specific HER2 antibody drug conjugate as described in U.S. Patent Publication No. 2017/0151341 and International Publication No. WO2017/093844, the content of each of which is herein incorporated by reference in its entirety.
  • ADCs conjugate the drug payload to the antibody at particular engineered residues on the antibody heavy and/or light chain.
  • the ADC is ADC1 having the following formula:
  • Ab1 is an HER2 antibody, or antigen-binding fragment thereof, that binds to HER2.
  • Ab1 comprises (1) a heavy chain comprising SEQ ID NO: 6 or 14; and (2) a light chain comprising SEQ ID NO: 12, 16, 45, or 46.
  • the partial structure consisting of a linker and a drug in ADC1 is referred to as “linker-drug” or “L-D.”
  • the L-D is conjugated to the antibody via a thioether bond (i.e. , via the S atom of a cysteine residue).
  • the ADC1 is T(kK183C+K290C)-vc-0101 ADC, as shown in FIG. 1.
  • the ADC is ADC2 which comprises Ab2 that is conjugated with a therapeutic agent (D2) via a linker (L2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR- H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively.
  • the ADC is ADC2 which comprises Ab2 that is conjugated with a therapeutic agent (D2) via a linker (L2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • the ADC is ADC2 which comprises Ab2 that is conjugated with a therapeutic agent (D2) via a linker (L2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • the ADC2 is RC48-vc-MMAE, as shown in FIG. 2.
  • the ADC2 is RC48-vc-MMAF, as shown in FIG. 3.
  • the ADC2 is RC48-mc-MMAF, as shown in FIG. 4.
  • the ADC2 disclosed herein is HER2 antibody drug conjugate as described in U.S. Patent No. 10,087,260, the content of each of which is herein incorporated by reference in its entirety.
  • the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound.
  • pharmaceutically acceptable salt(s) includes salts of acidic or basic groups which may be present in the compounds of the formulae disclosed herein.
  • the compounds of the disclosure that are basic in nature may be capable of forming a wide variety of salts with various inorganic and organic acids.
  • anions suitable for mono- and di- acid addition salts include, but are not limited to, acetate, asparatate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, decanoate, edetate, edislyate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate (embonate), pantothenate,
  • compounds that are acidic in nature may be capable of forming base salts with various pharmacologically acceptable cations which form non-toxic base salts.
  • non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • salts examples include alkali metal or alkaline-earth metal salts and other cations, including aluminium, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethyamine and zinc.
  • Salts may be prepared by conventional techniques. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts are known to those of skill in the art.
  • the present disclosure provides methods, combinations and uses for treating cancer. Some embodiments provided herein result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; (5) inhibiting angiogenesis; or (6) overcoming one or more resistance mechanisms relating to a cancer treatment.
  • the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer (including non-small cell lung cancer, NSCLC, and small cell lung cancer, SCLC), liver cancer (including hepatocellular carcinoma, HCC), kidney cancer (including renal cell carcinoma, RCC), bladder cancer (including urothelial carcinomas, such as upper urinary tract urothelial carcinoma, UUTUC), ovarian cancer (including epithelial ovarian cancer, EOC), peritoneal cancer (including primary peritoneal cancer, PPC), fallopian tube cancer, cervical cancer, uterine cancer (including endometrial cancer), pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer, and salivary gland cancer), testicular cancer, adrenal cancer, skin cancer (including basal cell carcinoma and melanoma), brain cancer (including astrocytoma), testicular cancer, adrenal cancer, skin cancer (including basal cell carcinoma
  • the cancer is androgen-dependent.
  • the cancer expresses androgen receptors, which may sometimes be referred to as androgen receptor (AR)-positive or AR+ cancer.
  • AR androgen receptor
  • the cancer is advanced or metastatic cancer. In some embodiments of the methods, combinations and uses described herein, the cancer is early stage or non-metastatic cancer. [155] In some embodiments of the methods, combinations and uses described herein, the cancer is characterized by deleterious germline mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) (i.e. , is germline BRCA1- or BRCA2- mutated). In some such embodiments, the BRCA1- or BRCA2-mutated cancer is prostate cancer, breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, or pancreatic cancer.
  • BRCA1- or BRCA2-mutated cancer is prostate cancer, breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, or pancreatic cancer.
  • the cancer is characterized by amplification or overexpression of CDK4, CDK6 or cyclin D1 (CCND1).
  • the cancer is retinoblastoma protein (RB)-positive or RB- proficient.
  • the cancer is resistant to a therapeutic agent or class of agents, such as a standard of care agent or class for the particular cancer.
  • the cancer is characterized by innate or acquired resistance to a therapeutic agent or class of agents.
  • the cancer is resistant to treatment with antiandrogens, taxanes, platinum agents, aromatase inhibitors, selective estrogen receptor degraders (SERDs), selective estrogen receptor modulators (SERMs), or CDK4/6 inhibitors.
  • the cancer is resistant to treatment with a taxane (i.e., the cancer is a taxane resistant cancer). In some embodiments of each of the methods, combinations and uses described herein, the cancer is resistant to treatment with a platinum agent (i.e., the cancer is a platinum resistant cancer).
  • the cancer is resistant to treatment with an aromatase inhibitor, a SERD, or a SERM.
  • the cancer is resistant to treatment with a CDK4 inhibitor or a CDK4/6 inhibitor.
  • the cancer is resistant to treatment with a CDK4/6 inhibitor selected from the group consisting of palbociclib, ribociclib or abemaciclib, or a pharmaceutically acceptable salt thereof.
  • the cancer is resistant to treatment with palbociclib, or a pharmaceutically acceptable salt thereof.
  • the cancer is refractory, i.e., the cancer does not respond at all to treatment with a therapeutic agent or class (including a standard of care agent or class for the particular cancer) or initially responds but starts to grow again in a very short period of time.
  • the cancer is breast cancer.
  • the breast cancer is androgendependent breast cancer.
  • the breast cancer is AR+ breast cancer.
  • the breast cancer is advanced or metastatic breast cancer. In some embodiments of the methods, combinations and uses described herein, the breast cancer is early stage or non-metastatic breast cancer.
  • the breast cancer is characterized by amplification or overexpression of CDK4, CDK6 or cyclin D1 (CCND1).
  • the breast cancer is characterized as RB-positive, RB- proficient, or RB wild type.
  • the breast cancer is BRCA1- or BRCA2-mutated breast cancer.
  • the breast cancer is P I K3CA- mutated cancer breast cancer.
  • the breast cancer is refractory or resistant to treatment with, or has progressed on, one or more standard of care agents.
  • the breast cancer is refractory or resistant to treatment with, or has progressed on, an antiestrogen, such as an aromatase inhibitor, SERD, or a SERM.
  • the breast cancer is refractory or resistant to treatment with, or has progressed on, a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof.
  • the breast cancer is refractory or resistant to treatment with, or has progressed on, treatment with antineoplastic chemotherapeutic agents such as taxanes, platinum agents, anthracyclines or anti-metabolites.
  • the breast cancer is hormone receptor (HR)-positive (HR+) breast cancer, i.e. , the breast cancer is estrogen receptor (ER)-positive (ER+) and/or progesterone receptor (PR)-positive (PR+).
  • HR hormone receptor
  • ER estrogen receptor
  • PR progesterone receptor
  • the breast cancer is hormone receptor (HR)-negative (HR-), i.e., the breast cancer is estrogen receptor (ER)-negative (ER-) and progesterone receptor (PR)- negative (PR-).
  • HR- hormone receptor
  • ER estrogen receptor
  • PR progesterone receptor
  • the breast cancer is human epidermal growth factor receptor 2 (HER2)-positive (HER2+).
  • HER2 human epidermal growth factor receptor 2
  • HER2+ human epidermal growth factor receptor 2
  • the breast cancer is human epidermal growth factor receptor 2 (HER2)-negative (HER2-).
  • the breast cancer is is estrogen receptor alpha (ERa)-negative.
  • the breast cancer is triple negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR- and HER2-.
  • the breast cancer is selected from the group consisting of HR+/HER2- breast cancer, HR+/HER2+ breast cancer, HR-/HER2+ breast cancer, and triple negative breast cancer (TNBC).
  • the breast cancer is androgendependent or AR+ breast cancer.
  • the breast cancer is BRCA1- or BRCA2-mutated breast cancer.
  • the breast cancer is HR+/HER2- breast cancer.
  • the HR+/HER2- breast cancer is advanced or metastatic HR+/HER2- breast cancer.
  • the HR+/HER2- breast cancer is early or non-metastatic HR+/HER2- breast cancer.
  • the HR+/HER2- breast cancer is characterized by amplification or overexpression of CDK4, CDK6 or cyclin D1 (CCND1). In some embodiments, the HR+/HER2- breast cancer is characterized as RB-positive, RB-proficient, or RB wild type.
  • the HR+/HER2- breast cancer is BRCA1- or BRCA2-mutated breast cancer.
  • the HR+/HER2- breast cancer is PIK3CA-mutated cancer breast cancer.
  • the HR+/HER2- breast cancer is refractory or resistant to treatment with, or has progressed on, a standard of care agent, e.g., an antiestrogen such as an aromatase inhibitor, a SERD, or a SERM.
  • a standard of care agent e.g., an antiestrogen such as an aromatase inhibitor, a SERD, or a SERM.
  • the HR+/HER2- breast cancer is refractory or resistant to treatment with, or has progressed on, a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof.
  • the HR+/HER2- breast cancer is refractory or resistant to treatment an antiestrogen such as an aromatase inhibitor, a SERD, or a SERM.
  • the HR+/HER2- breast cancer is refractory or resistant to treatment with a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof.
  • the HR+/HER2- breast cancer is refractory or resistant to treatment with a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof, in further combination with an antiestrogen, e.g., letrozole or fulvestrant.
  • the HR+/HER2- breast cancer is resistant to treatment an antiestrogen such as an aromatase inhibitor, a SERD, or a SERM.
  • the HR+/HER2- breast cancer is resistant to treatment with a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof.
  • the HR+/HER2- breast cancer is resistant to treatment with a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof, in further combination with an antiestrogen, e.g., letrozole or fulvestrant.
  • the breast cancer is HR+/HER2+ breast cancer. In some embodiments, the breast cancer is HR-/HER2+ breast cancer.
  • the methods, combinations and uses described herein further comprise an additional anti-cancer agent.
  • the additional anti-cancer agent is an antiestrogen, such as an aromatase inhibitor, a SERD, or a SERM.
  • the antiestrogen is letrozole or fulvestrant.
  • the additional anti-cancer agent is a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof.
  • the additional anti-cancer agent is a CDK4/6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof, in further combination with an antiestrogen, e.g., letrozole or fulvestrant.
  • the additional anti-cancer agent is a PI3K inhibitor, e.g., alepelisib.
  • the methods, combinations and uses described herein further comprise an additional anti-cancer agent.
  • the additional anti-cancer agent is a HER2-targeted agent, e.g., trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib or tucatinib, or an agent targeting the PI3K/AKT/mTOR molecular pathway, e.g., ipatasertib.
  • the breast cancer is triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • the TNBC is androgen-dependent or AR+ TNBC.
  • the TNBC is RN+ or RB-proficient.
  • the TNBC is AR+, RB+ or AR+, RB-proficient TNBC.
  • the TNBC is locally recurrent/advanced or metastatic TNBC. In some such embodiments, the TNBC is advanced or metastatic TNBC. In some such embodiments, the TNBC is early or non-metastatic TNBC.
  • the TNBC is characterized by amplification or overexpression of CDK4, CDK6 or cyclin D1 (CCND1).
  • the TNBC is BRCA1- or BRCA2-mutated TNBC.
  • the TNBC is refractory or resistant to treatment with, or has progressed on, a standard of care agent, e.g., an antineoplastic chemotherapeutic agent such as a taxane, platinum agent, anthracycline or anti-metabolite.
  • a standard of care agent e.g., an antineoplastic chemotherapeutic agent such as a taxane, platinum agent, anthracycline or anti-metabolite.
  • the cancer is lung cancer.
  • the lung cancer is non-small_cell lung cancer (NSCLC).
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is advanced or metastatic lung cancer.
  • the cancer is liver cancer.
  • the liver cancer is hepatocellular carcinoma (HCC).
  • the liver cancer is advanced or metastatic liver cancer.
  • the cancer is kidney cancer.
  • the kidney cancer is renal cell carcinoma (RCC).
  • the kidney cancer is advanced or metastatic kidney cancer.
  • the cancer is bladder cancer.
  • the bladder cancer is a urothelial carcinoma, including an upper urinary tract urothelial carcinoma (UUTIIC).
  • UUTIIC upper urinary tract urothelial carcinoma
  • the bladder cancer is advanced or metastatic bladder cancer.
  • the cancer is ovarian cancer, including epithelial ovarian cancer (EOC).
  • EOC epithelial ovarian cancer
  • the ovarian cancer is advanced or metastatic ovarian cancer.
  • the cancer is peritoneal cancer, including primary peritoneal cancer (PPC).
  • PPC primary peritoneal cancer
  • the peritoneal cancer is advanced or metastatic peritoneal cancer.
  • the cancer is fallopian tube cancer.
  • the fallopian tube cancer is advanced or metastatic fallopian tube cancer.
  • the cancer is cervical cancer.
  • the cervical cancer is advanced or metastatic cervical cancer.
  • the cancer is uterine cancer, including endometrial cancer.
  • the uterine cancer is advanced or metastatic uterine cancer.
  • the cancer is pancreatic cancer.
  • the pancreatic cancer is advanced or metastatic pancreatic cancer.
  • the pancreatic cancer is resistant to antineoplastic chemotherapeutic agents such as taxanes, platinum agent, a nth racy clines or anti-metabolites.
  • the pancreatic cancer is resistant to gemcitabine or nab-paclitaxel.
  • the cancer is stomach cancer (or gastric cancer).
  • the stomach cancer is adenocarcinoma.
  • the stomach cancer is advanced or metastatic stomach cancer.
  • the cancer is colorectal cancer.
  • the colorectal cancer is advanced or metastatic colorectal cancer.
  • the cancer is esophageal cancer.
  • the esophageal cancer is advanced or metastatic esophageal cancer.
  • the cancer is head and neck cancer.
  • the head and neck cancer is advanced or metastatic head and neck cancer.
  • the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer, or salivary gland cancer.
  • the head and neck cancer is salivary gland cancer.
  • the cancer is testicular cancer.
  • the testicular cancer is advanced or metastatic testicular cancer.
  • the cancer is adrenal cancer.
  • the adrenal cancer is advanced or metastatic adrenal cancer.
  • the cancer is skin cancer.
  • the skin cancer is basal cell carcinoma or melanoma.
  • the skin cancer is advanced or metastatic skin cancer.
  • the cancer is brain cancer.
  • the brain cancer is astrocytoma, meningioma, or glioblastoma.
  • the brain cancer is advanced or metastatic brain cancer.
  • the cancer is sarcoma.
  • the sarcoma is osteosarcoma or liposarcoma
  • the cancer is lymphoma.
  • the lymphoma is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • this disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a CDK4 inhibitor of Formula (I), and a monoclonal antibody or an antibody-drug conjugate, and a pharmaceutically acceptable carrier.
  • compositions, medicaments and kits comprising a compound of Formula (I), having the structure:
  • R 1 is H, F, or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each of R 5 and R 6 is independently OH, F, or C1-C2 alkoxy.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a CDK4 inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof, an antiandrogen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the disclosure provides a first pharmaceutical composition comprising a CDK4 inhibitor of Formula (I), and a pharmaceutically acceptable carrier or excipient, and a second pharmaceutical composition comprising a monoclonal antibody or an antibody-drug conjugate, and a pharmaceutically acceptable carrier or excipient, wherein the first and second pharmaceutical compositions are administered sequentially, simultaneously or concurrently.
  • the disclosure provides a combination comprising a CDK4 inhibitor of Formula (I), and a monoclonal antibody or an antibody-drug conjugate, for use in the manufacture of a medicament for treating cancer in a subject.
  • the disclosure provides use of a combination comprising a CDK4 inhibitor of Formula (I), and a monoclonal antibody or an antibody-drug conjugate, in the manufacture of a medicament for treating cancer in a subject.
  • the compound of Formula (I) is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan- 2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-f/7reo-pentitol (PF-07220060).
  • the CDK4 inhibitor of Formula (I) is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol (PF-07220060), and the antibody-drug conjugate has the general formula Ab-(L- D)p, in which Ab represents the antibody or functional fragments thereof (e.g., Ab1, Ab2 described herein), L represents a linker, D represents a therapeutic agent, and p is 1 to 8.
  • the CDK4 inhibitor of Formula (I) is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol (PF-07220060), and the antibody-drug conjugate has the formula: wherein Ab1 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively;
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 8, 9, and 10, respectively; and wherein p is 1 to 4.
  • the CDK4 inhibitor of Formula (I) is 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol (PF-07220060), and the antibody-drug conjugate comprises Ab2 which is conjugated with a therapeutic agent (D2) via a linker (Linker2), wherein Ab2 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2, optionally through thiol, and is selected from mc-vc- pAB and me.
  • the disclosure provides a kit comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a CDK4 inhibitor of Formula (I) as described herein; the second container comprises at least one dose of a monoclonal antibody or an antibody-drug conjugate as described herein; and the package insert comprises instructions for treating cancer in a subject using the medicaments.
  • the first container comprises at least one dose of a CDK4 inhibitor of Formula (I) as described herein
  • the second container comprises at least one dose of a monoclonal antibody or an antibody-drug conjugate as described herein
  • the package insert comprises instructions for treating cancer in a subject using the medicaments.
  • the CDK4 inhibitor of Formula (I) is 1,5- anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6- yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-f/7reo-pentitol (PF-07220060), and the antibody-drug conjugate has the formula: wherein Ab1 is an antibody that binds to HER2 and comprises:
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequences of SEQ ID NOs: 2, 3, and 4, respectively;
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 8, 9, and 10, respectively; and wherein p is 1 to 4.
  • the CDK4 inhibitor of Formula (I) is 1 ,5- anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6- yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-f/7reo-pentitol (PF-07220060), and the antibody-drug conjugate comprises Ab2 which is conjugated with a drug payload (D2) via a linker (Linker2), wherein Ab2 is an antibody that binds to HER2 and comprises: (1) a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid
  • a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2, optionally through thiol, and is selected from mc-vc- pAB and me.
  • the additional anti-cancer agent is an endocrine therapeuticagent, such as an aromatase inhibitor, a SERD, or a SERM.
  • the antiestrogen is letrozole or fulvestrant.
  • compositions, medicaments and kits described herein may be useful for treating the cancers described above with respect to the methods, combinations and uses of the disclosure.
  • Each therapeutic agent of the methods and combination therapies of the present disclosure may be administered either alone, or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, or diluents, according to pharmaceutical practice.
  • combination or “combination therapy” refer to the administration of two or more therapeutic agents of the combination therapy of the disclosure, either alone or in the form of a pharmaceutical composition or medicament, either sequentially, concurrently or simultaneously.
  • sequences refers to the administration of each therapeutic agent of the combination therapy of the disclosure, either alone or in a medicament, one after the other, or one or more doses of one therapeutic agent of the combination therapy after one or more doses of another therapeutic agent of the combination therapy, wherein each therapeutic agent can be administered in any order.
  • Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and/or the agents are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
  • the term “concurrent” or “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the disclosure, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order. In an embodiment, the therapeutic agents are administered concurrently.
  • the term “simultaneous” or “simultaneously” refers to the administration of each therapeutic agent of the combination therapy of the disclosure in the same medicament, for example as a fixed dose combination comprising two or more drugs in a single dosage form.
  • PF-07220060 is administered before administration of the monoclonal antibody or antibody-drug conjugate.
  • the monoclonal antibody or antibody-drug conjugate is administered before administration of PF-07220060.
  • PF-07220060 is administered concurrently with the monoclonal antibody or antibody-drug conjugate.
  • PF-07220060 is administered simultaneously with the monoclonal antibody or antibody-drug conjugate.
  • the combination therapy may be usefully administered to a subject during different stages of their treatment.
  • the combination therapy is administered to a subject who is previously untreated, i.e. the subject is treatment naive.
  • the combination therapy is administered to a subject who has previously received a CDK4 or CDK4/6 inhibitor. In some such embodiments, the combination therapy is administered to a subject who has previously received a CDK4 or CDK4/6 inhibitor, but whose cancer has since progressed.
  • Dosage regimens may be adjusted to provide the optimum desired response.
  • a therapeutic agent of the combination therapy of the present disclosure may be administered as a single bolus, as several divided doses administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be particularly advantageous to formulate a therapeutic agent in a dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure may be dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a detectable therapeutic benefit to a subject may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the subject. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present disclosure.
  • dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compounds or pharmaceutical compositions, taking into consideration factors such as the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compound or pharmaceutical composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present disclosure encompasses intrapatient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein
  • At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as a monotherapy for treating the same cancer.
  • the subject received a lower total amount of at least one of the therapeutic agents in the combination therapy than when the same agent is used as a monotherapy, for example a lower dose of therapeutic agent, a reduced frequency of dosing and / or a shorter duration of dosing.
  • the CDK4 inhibitor 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D- f/ireo-pentitol, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of from about 1 mg to about 1000 mg per day. In another embodiment, the CDK4 inhibitor is administered at a daily dosage from about 10 mg to about 500 mg per day. In another embodiment, the CDK4 inhibitor is administered at a dosage of from about 25 mg to about 300 mg per day.
  • the CDK4 inhibitor is administered at dosages of about: 1 , 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 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, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg on a single dose (QD), twice daily (BID), three times daily (TID) or four times daily (QID) schedule.
  • QD twice daily
  • TID three times daily
  • QID four times daily
  • a “continuous dosing schedule”, as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule.
  • the compounds of the combination of the present disclosure may be administered in a continuous dosing schedule. In an embodiment, the compounds of the combination of the present disclosure may be administered concurrently in a continuous dosing schedule.
  • PF-07220060 and the monoclonal antibody or the antibody-drug conjugate as described herein are dosed in amounts which together are effective in treating the cancer.
  • PF-07220060 the monoclonal antibody or the antibody-drug conjugate as described herein, are dosed in amounts which together are synergistic.
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 , CDR-H2, and CDR-H3 comprise the amino acid sequence of SEQ ID NOs: 2, 3, and 4, respectively; and (2) a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 8, 9, and 10, respectively; and wherein p is 1 to 4; are dosed in amounts which together are synergistic.
  • a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3, in which the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 31, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 33, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 34 or 35; and
  • a light chain variable region comprising a CDR-L1 , CDR-L2, and CDR-L3, in which the CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 36, 37, and 38, respectively; wherein D2 is selected from MMAE and MMAF; and wherein Linker2 is linked with Ab2, optionally through thiol, and is selected from mc-vc- pAB and me; are dosed in amounts which together are synergistic.
  • a "pharmaceutical composition” refers to a mixture of one or more of the therapeutic agents described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.
  • a "pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound or therapeutic agent.
  • the pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient.
  • the choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates).
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid pharmaceutical compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Non-limiting examples of materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository.
  • Exemplary parenteral administration forms include solutions or suspensions of an active compound in a sterile aqueous solution, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise amounts.
  • compositions suitable for the delivery of the therapeutic agents of the combination therapies of the present disclosure, and methods for their preparation will be readily apparent to those skilled in the art. Such pharmaceutical compositions and methods for their preparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.
  • Therapeutic agents of the combination therapies of the disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the therapeutic agent enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the therapeutic agent enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Therapeutic agents of the combination therapies of the present disclosure may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.
  • the therapeutic agent may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant may comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Exemplary tablets may contain from about 1 wt% to about 80 wt% active agent, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the therapeutic agent, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Therapeutic agents of the combination therapies of the disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of therapeutic agents used in the preparation of parenteral solutions may potentially be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • therapeutic agents of the combination therapies of the disclosure may potentially be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • kits may comprise one or both of the active agents in the form of a pharmaceutical composition, which pharmaceutical composition comprises an active agent, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the kit may contain means for separately retaining said pharmaceutical compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • kits described herein may be particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate pharmaceutical compositions at different dosage intervals, or for titrating the separate pharmaceutical compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • the kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes, and the like.
  • dispensed cells were centrifuged at 220 x g for 6 minutes in the ultralow attachment plates and allowed to form compact spheroids for 4 days prior to the initiation of treatment. After spheroids were formed, 150 pL of medium was aspirated from each well without disturbing the spheroid, and fresh RPMI medium of the same volume was added containing single agent compounds (palbociclib, PF-07220060, fulvestrant, or Trazimera®), or selected combinations thereof.
  • single agent compounds palbociclib, PF-07220060, fulvestrant, or Trazimera®
  • DMSO 0.01 % was used as the vehicle control. DMSO and all compounds were diluted in cell medium. Medium and compounds were replenished twice per week, with 3 and 4-day intervals. Replenishment was executed by aspirating 150 pL of medium per well without disturbing the spheroid and then adding the same volume of premixed medium/compound solution to spheroids. In some cases, an extended phase of treatment was followed by a ‘recovery’ phase where medium was replenished without addition of compounds. Spheroid diameter was quantified immediately following each medium change twice a week (on every 3 rd or 4 th day) throughout the duration of the assay.
  • a sequential treatment schedule was implemented for experiments involving HER2 ADC (PF-06804103) treatment of BT474 spheroids. It was added at Day 0 and Day 24 and medium change was performed twice each week without re-addition of HER2-ADC. Palbociclib or PF- 07220060 was then added for 2 weeks (with each medium change every 2-3 days) one week after each dosing of HER2-ADC in all combination arms. The diameter of the spheroids during and after treatment was measured (Celigo 200-BFFL-S, Nexcelom) at each medium change.
  • arrows indicate the addition of PF-06804103 to spheroids (on day 0 and 24), and CDK inhibitors were administered within two treatment phases only (2 weeks each, grey boxes).
  • Table 3 shows the percent of spheroid growth inhibition (SGI%). The results indicated that the BT474 SGI increased from 70% HER2-ADC as a single agent to 84% when treated with an alternating treatment schedule that included PF-07220060. [284] Table 3. SGI% for single agent and combination treatments
  • SGI (1-AUC treatment/AUC DMSO) x 100%.
  • Example 3 CDK4 Inhibitor Synergized with HER2 Antibody-Drug Conjugate (ADC) disitamab vedotin to inhibit proliferation of HR+ cells
  • FIG.7 illustrates the schematic of the assay and sequential dosing procedure for PF-07220060 an DV.
  • the cell lines were treated with a five-point dose titration of PF-07220060 at 31.25 nM, 125 nM, 500 nM, 2,000 nM, and 8,000 nM, with control wells being treated with a relevant volume of DMSO.
  • FIGs. 8A-8C show the dose response curves illustrating the single agent activity of PF- 07220060 (FIG.8A) and DV (FIG. 8B), along with the combined effect of DV + PF-07220060 (FIG. 8C).
  • Mean +/- SEM, n 3.
  • FIG. 9 shows an isobologram for CAMA1 cells treated with PF-07220060 and DV in vitro.
  • the x-axis indicates the concentration of PF-07220060 in pM.
  • the y-axis indicates the concentration of DV in ng/ml.
  • Additional HR+ breast cancer cell lines e.g., T47D, ZR751 and JIMT1 were used according to the same assay and sequential dosing procedure described above.
  • CDK4 inhibitor disclosed herein e.g., PF- 07220060
  • PF- 07220060 can increase the sensitivity of HR+ breast cancer cells to treatment with HER2 antibody and/or HER2-ADC.

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Abstract

La présente divulgation concerne des polythérapies faisant intervenir un inhibiteur de kinase 4 dépendante des cyclines (CDK4) de formule (I) selon la divulgation, et un anticorps monoclonal ou un conjugué anticorps-médicament, éventuellement en combinaison supplémentaire avec un agent de thérapie endocrine, et des méthodes de traitement associées, des compositions pharmaceutiques et leurs utilisations.
PCT/US2025/039221 2024-07-26 2025-07-25 Polythérapie utilisant des inhibiteurs de cdk4 pour des traitements contre le cancer Pending WO2026025013A2 (fr)

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