WO2025128652A1 - Méthodes de traitement du cancer de l'endomètre avec des anticorps anti-cd3 x anti-muc16 bispécifiques seuls ou en association avec des anticorps anti-pd-1 - Google Patents

Méthodes de traitement du cancer de l'endomètre avec des anticorps anti-cd3 x anti-muc16 bispécifiques seuls ou en association avec des anticorps anti-pd-1 Download PDF

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WO2025128652A1
WO2025128652A1 PCT/US2024/059495 US2024059495W WO2025128652A1 WO 2025128652 A1 WO2025128652 A1 WO 2025128652A1 US 2024059495 W US2024059495 W US 2024059495W WO 2025128652 A1 WO2025128652 A1 WO 2025128652A1
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seq
muc16
antibody
amino acid
acid sequence
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Thomas Smith ULDRICK JR.
Elizabeth Miller
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Regeneron Pharmaceuticals Inc
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Regeneron Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3076—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
    • C07K16/3092—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated mucins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity

Definitions

  • the present disclosure relates to methods for treating endometrial cancer with a bispecific antibody that binds to mucin 16 (MUC16) and CD3, alone or in combination with an anti-PD-1 antibody.
  • Mucin 16 also known as cancer antigen 125, carcinoma antigen 125, carbohydrate antigen 125, or CA-125, is a single transmembrane domain highly glycosylated integral membrane glycoprotein that is expressed in many cancer types.
  • MUC16 consists of three major domains: an extracellular N-terminal domain, a large tandem repeat domain interspersed with sea urchin sperm, enterokinase, and agrin (SEA) domains, and a carboxyl terminal domain that comprises a segment of the transmembrane region and a short cytoplasmic tail. Proteolytic cleavage results in shedding of the extracellular portion of MUC16 into the bloodstream.
  • MUC16 is overexpressed in cancers including endometrial cancer, ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer, intrahepatic cholangiocarcinoma-mass forming type, adenocarcinoma of the uterine cervix, and adenocarcinoma of the gastric tract, and in diseases and conditions including inflammatory bowel disease, liver cirrhosis, cardiac failure, peritoneal infection, and abdominal surgery. (Haridas, D. et al., 2014, FASEB J., 28:4183-4199).
  • CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation.
  • Functional CD3 is formed from the dimeric association of two of four different chains: epsilon, zeta, delta and gamma.
  • the CD3 dimeric arrangements include gamma/epsilon, delta/epsilon and zeta/zeta.
  • Antibodies against CD3 have been shown to cluster CD3 on T cells, thereby causing T cell activation in a manner similar to the engagement of the TCR by peptide-loaded MHC molecules.
  • anti-CD3 antibodies have been proposed for therapeutic purposes involving the activation of T cells.
  • bispecific antibodies that are capable of binding CD3 and a target antigen have been proposed for therapeutic uses involving targeting T cell immune responses to tissues and cells expressing the target antigen.
  • PD-1 signaling in the tumor microenvironment plays a key role in allowing tumor cells to escape immune surveillance by the host immune system.
  • Blockade of the PD-1 signaling pathway has demonstrated clinical activity in patients with multiple tumor types, and antibody therapeutics that block PD-1 (e.g., nivolumab and pembrolizumab) have been approved for the treatment of metastatic melanoma and metastatic squamous non-small cell lung cancer.
  • Recent data has demonstrated the clinical activity of PD- 1 blockade in patients with aggressive NHL and Hodgkin's lymphoma (Lesokhin, et al. 2014, Abstract 291 , 56th ASH Annual Meeting and Exposition, San Francisco, Calif.; Ansell et al. 2015, N. Engl. J. Med. 372(4) :311 -9).
  • Endometrial cancer has an annual incidence of 66,000 cases and causes 13,000 deaths per year in the US (SEER, 2022). In the National Cancer Database, 34.1% of Black women and 19.1% of White women present with advanced disease (Kucera, 2023). Until recently, the standard of care for the 1 st line therapy for women with advanced endometrial cancer, including cancer that has progressed after surgery and/or radiation, has been carboplatin and paclitaxel. This line of therapy is based on a study that showed non-inferior overall survival with this regimen compared to the more toxic regimen of doxorubicin, cisplatin and paclitaxel (Miller, 2020).
  • pembrolizumab O’Malley, 2022
  • dostarlimab Oaknin, 2022
  • pembrolizumab O’Malley, 2022
  • dostarlimab Oaknin, 2022
  • the overall response rate with anti-PD-1 in this setting is approximately 45% with responses being durable in a majority of patients.
  • pembrolizumab and lenvatinib was FDA approved in 2022 based on demonstration of improved PFS compared to chemotherapy in the KEYNOTE - 775 study (Makker, 2022).
  • the present disclosure includes a method of treating endometrial cancer in a subject in need thereof, comprising administering to the subject a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds mucin 16 (MUC16), and a second antigen-binding domain that specifically binds human CD3.
  • the bispecific antibody or antigen-binding fragment thereof is administered to the subject at a dose of at least 1 mg e.g., weekly).
  • the subject has previously been treated with a platinum-based chemotherapy. In some embodiments, the subject has previously been treated with an antibody that binds human programmed death receptor-1 (PD-1 ). In some embodiments, the subject has previously been treated with a platinum-based chemotherapy, and an antibody that binds human PD-1 . In some embodiments, the subject has received at least two prior lines of therapy to treat the endometrial cancer. In some embodiments, the endometrial cancer is advanced or recurrent endometrial cancer. In some embodiments, the endometrial cancer is MUC16- expressing cancer.
  • the present disclosure provides methods, as discussed herein, wherein the bispecific antibody or antigen-binding fragment thereof comprises a first antigenbinding domain comprising three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 ; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
  • HCVR heavy chain complementarity determining regions
  • LCDR1 , LCDR2 and LCDR3 contained within a light chain variable region
  • the first antigen-binding domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a HCDR3 comprising the amino acid sequence of SEO ID NO: 10.
  • the first antigen-binding domain comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 13.
  • the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 , and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
  • the bispecific antibody or antigen-binding fragment thereof comprises a second antigen-binding domain comprising three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 3; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
  • HCDR1 , HCDR2 and HCDR3 contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 3
  • LCDR1 , LCDR2 and LCDR3 contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.
  • the second antigen-binding domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the second antigen-binding domain comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 11 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 13.
  • the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 3, and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
  • the bispecific antibody comprises a human IgG heavy chain constant region.
  • the human IgG heavy chain constant region is isotype IgG 1 .
  • the human IgG heavy chain constant region is isotype lgG4.
  • the bispecific antibody comprises a chimeric hinge that reduces Fey receptor binding relative to a wild-type hinge of the same isotype.
  • the first heavy chain or the second heavy chain but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.
  • the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the bispecific antibody comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 31 . In some embodiments, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 29, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 31 , and a common light chain comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the bispecific antibody is REGN4018 (ubamatamab).
  • the present disclosure provides the methods disclosed herein where the subject has a serum CA-125 level equal to or greater than 60 U/ml. In some cases, the subject’s serum CA-125 level is greater than 65 U/ml, 70 U/ml, 75 U/ml, 80 U/ml, 85 U/ml, 90 U/ml, or 95 U/ml.
  • the methods further comprise administering a second therapeutic agent or therapeutic regimen.
  • the second therapeutic agent or therapeutic regimen comprises an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 33; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 34.
  • the anti-PD-1 antibody or antigen-binding fragment comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 35, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 37.
  • the anti-PD-1 antibody or antigen-binding fragment comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 38, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.
  • the anti-PD-1 antibody or antigenbinding fragment comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 33, and a LCVR comprising the amino acid sequence of SEQ ID NO: 34.
  • the anti-PD-1 antibody or antigen-binding fragment is an anti-PD-1 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42.
  • the anti-PD-1 antibody is cemiplimab
  • the present disclosure provides methods wherein the bispecific antibody (or fragment thereof) is administered in a dosing regimen comprising a split initial dose.
  • the bispecific antibody (or fragment thereof) is administered to the subject at a dose of from 10 mg to 1000 mg weekly.
  • the bispecific antibody (or fragment thereof) is administered to the subject at a dose of about 250 mg weekly, optionally wherein the dose is split into a first fraction of about 50 mg, and a second fraction of about 200 mg.
  • the bispecific antibody (or fragment thereof) is administered to the subject at a dose of about 800 mg weekly, optionally wherein the dose is split into a first fraction of about 50 mg, and a second fraction of about 750 mg.
  • the bispecific antibody (or fragment thereof) is administered to the subject at a dose of from 10 mg to 1000 mg once every three weeks. In some embodiments, the bispecific antibody (or fragment thereof) is administered to the subject at a dose of about 250 mg once every three weeks, optionally wherein the dose is split into a first fraction of about 50 mg, and a second fraction of about 200 mg. In some embodiments, the bispecific antibody (or fragment thereof) is administered to the subject at a dose of about 800 mg once every three weeks, optionally wherein the dose is split into a first fraction of about 50 mg, and a second fraction of about 750 mg.
  • the present disclosure provides methods wherein the bispecific antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: (i) administering 1 mg of the bispecific antibody (or fragment thereof) in week 1 , optionally wherein the dose is split into a first fraction of about 0.5 mg and a second fraction of about 0.5 mg; (ii) administering 20 mg of the bispecific antibody (or fragment thereof) in week 2, optionally wherein the dose is split into a first fraction of about 10 mg and a second fraction of about 10 mg; and (iii) administering 250 mg of the bispecific antibody (or fragment thereof) in week 3, optionally wherein the dose is split into a first fraction of about 50 mg, and a second fraction of about 200 mg.
  • the methods further comprises administration of the bispecific antibody (or fragment thereof) at a dose of about 250 mg once every week from week 4 onwards. In some embodiments, the methods further comprise administration of the bispecific antibody (or fragment thereof) at a dose of about 250 mg once every three weeks from week 4 onwards. In some embodiments, the methods further comprises administration of the bispecific antibody (or fragment thereof) at a dose of about 800 mg once every three weeks from week 4 onwards.
  • the present disclosure provides methods wherein an anti-PD-1 antibody is administered to the subject at a dose of from 300 to 400 mg once every three weeks. In some embodiments, the anti-PD-1 antibody is administered to the subject at a dose of 350 mg once every three weeks. [0021] In one aspect, the present disclosure provides methods wherein the subject has stable disease, a partial response, or a complete response following administration of the bispecific antibody (or fragment thereof) for at least one week at a dose of 1-800 mg. In some embodiments, the subject has stable disease, a partial response, or a complete response following administration of the bispecific antibody (or fragment thereof) for at least one week at a dose of 20-800 mg.
  • the present disclosure provides methods where the bispecific antibody (or fragment thereof) is administered to the subject at a dose sufficient to achieve a serum concentration of at least 4 mg/L.
  • the present disclosure provides methods wherein MUC16 is expressed on >25% of tumor cells in the subject, as determined by immunohistochemical staining.
  • the subject has a baseline MUC16 immunohistochemical staining score of
  • a MUC16-expressing tumor or a tumor with MUC16-expression in > 25% of tumor cells; or a tumor with MUC16-expression in > 30% of tumor cells; or a tumor with MUC16-expression in > 35% of tumor cells; or a tumor with MUC16-expression in > 40% of tumor cells; or a tumor with MUC16-expression in > 45% of tumor cells; or a tumor with MUC16-expression in > 50% of tumor cells; or a tumor with MUC16-expression in > 55% of tumor cells; or a tumor with MUC16-expression in > 60% of tumor cells; or a tumor with MUC16-expression in > 65% of tumor cells; or a tumor with MUC16-expression in > 70% of tumor cells; or a tumor with MUC16-expression in > 75% of tumor cells.
  • the present disclosure provides methods wherein MUC16 is expressed on tumor cells in the subject, as determined by immunohistochemical staining.
  • the subject has: an H-score >100; an H-score >105; an H-score >110; an Flscore >115; an H-score >120; an H-score >125; an H-score >130; an H-score >135; an H-score >140; an H-score >145; an H-score >150; an H-score >155; an H-score >160; an H-score >165; an H-score >170; an H-score >175; an H-score >180; an H-score >185; an H-score >190; an H- score >195; or an H-score >200, as determined by immunohistochemical staining discussed in Example 6.
  • the subject has a serous subtype of endometrial cancer. In some cases, the subject has a carcinosarcoma subtype of endometrial cancer. In some cases, the subject has a grade 3 endometrial cancer. In some cases, the subject has a mixed serous and endometrioid subtype of endometrial cancer. In some cases, the subject has a mixed serous and clear cell subtype of endometrial cancer. In some cases, the subject has a mixed clear cell and grade 3 endometrial cancer.
  • the present disclosure provides methods wherein the bispecific antibody (or fragment thereof) is administered intravenously.
  • the bispecific antibody (or fragment thereof) is administered subcutaneously.
  • the anti- PD-1 antibody or antigen-binding fragment is administered intravenously.
  • Figure 1 shows a schema of a monotherapy study design with intravenous dosing of REGN4018.
  • Figure 2 shows a schema of a combination therapy study design with intravenous dosing of REGN4018 and cemiplimab.
  • Figure 3 shows a schema of a monotherapy study design with subcutaneous initial and transitional dosing of REGN4018, followed by second transitional IV dosing and subsequent full IV dosing of REGN4018. Where CRS is not observed in initial patients, the second transitional IV dosing may be omitted for additional patients.
  • Figure 4 shows the variability of MUC16 expression by histology, with H-scores across pathology diagnosis categories, as determined in Example 6.
  • the present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of a cancer (e.g., endometrial cancer) in a subject.
  • the methods according to this aspect of the disclosure comprise administering a therapeutically effective amount of a bispecific antibody or antigenbinding fragment thereof against MUC16 and CD3 as monotherapy, or in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds PD-1 to a subject in need thereof.
  • the terms “treat”, “treating”, or the like mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, to delay or inhibit tumor growth, to reduce tumor cell load or tumor burden, to promote tumor regression, to cause tumor shrinkage, necrosis and/or disappearance, to prevent tumor recurrence, and/or to increase duration of survival of the subject.
  • a subject in need thereof means a human or nonhuman mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including an endometrial cancer and who needs treatment for the same.
  • the term "subject” may be interchangeably used with the term “patient”.
  • a human subject may be diagnosed with a primary or a metastatic tumor and/or with one or more symptoms or indications including, but not limited to, enlarged lymph node(s), swollen abdomen, chest pain/pressure, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, enlargement of spleen, itching.
  • the expression includes subjects with primary or established endometrial tumors.
  • the expression includes human subjects that have and need treatment for endometrial cancer or another tumor expressing MUC16, for example, endometrial cancer.
  • the expression includes subjects with MUC16+ tumors e.g., a tumor with MUC16 expression as determined by flow cytometry or immunohistochemistry).
  • the expression includes human subjects with a tumor that shows high expression of MUC16 in >50%, >55%, >60%, >65%, >70% or >75% of tumor cells.
  • the expression of MUC16 may be determined and evaluated by any method known in the art (see e.g., Shimizu et al 2012, Cancer Sci.
  • the expression includes human subjects with a baseline MUC16 immunohistochemical staining score of 2+ (e.g., 2, 3, 4 or 5) in a MUC16- expressing tumor. In certain embodiments, the expression includes human subjects with a baseline MUC16 immunohistochemical staining score of 2, 2+, 3, 3+, 4, 4+, or 5 in a MUC16- expressing tumor.
  • Immunohistochemical staining scores incorporate the percentage of cells, and the intensity and pattern of the staining according to the following standards: score 1 ( ⁇ 5% strong or weak); score 2 (5-50% strong or weak); score 3 (51 -75% strong or 51 -100% weak); score 4 (76-99% strong); and score 5 (100% strong staining).
  • score 1 ⁇ 5% strong or weak
  • score 2 5-50% strong or weak
  • score 3 51 -75% strong or 51 -100% weak
  • score 4 76-99% strong
  • score 5 (100% strong staining).
  • the expression "a subject in need thereof” includes patients with an endometrial cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with an anti-cancer agent).
  • the expression includes subjects who have been treated with chemotherapy, such as a platinum-based chemotherapeutic agent (e.g., cisplatin) or a taxol compound (e.g., docetaxel).
  • chemotherapy such as a platinum-based chemotherapeutic agent (e.g., cisplatin) or a taxol compound (e.g., docetaxel).
  • the expression also includes subjects with an endometrial tumor for which conventional anti-cancer therapy is inadvisable, for example, due to toxic side effects.
  • the expression includes patients who have received one or more cycles of chemotherapy with toxic side effects.
  • the expression "a subject in need thereof" includes patients with an endometrial tumor which has been treated but which has subsequently relapsed or metastasized.
  • patients with an endometrial tumor that may have received treatment with one or more anti-cancer agents leading to tumor regression; however, subsequently have relapsed with cancer resistant to the one or more anti-cancer agents (e.g., chemotherapy-resistant cancer) are treated with the methods of the present disclosure.
  • one or more anti-cancer agents leading to tumor regression
  • cancer resistant to the one or more anti-cancer agents e.g., chemotherapy-resistant cancer
  • a subject in need thereof also includes subjects who are at risk of developing endometrial cancer, e.g., persons with a family history of endometrial cancer, persons with a past history of infections associated with endometrial cancer, persons with mutations in the BRCA1/2 genes, or persons with an immune system compromised due to HIV infection or due to immunosuppressive medications.
  • the methods of the present disclosure may be used to treat patients that show elevated levels of one or more cancer-associated biomarkers (e.g., programmed death ligand 1 (PD-L1 ), Mild 6, CA125, human epididymis protein 4 (HE4), and/or carcinoembryonic antigen (CEA)).
  • cancer-associated biomarkers e.g., programmed death ligand 1 (PD-L1 ), Mild 6, CA125, human epididymis protein 4 (HE4), and/or carcinoembryonic antigen (CEA)
  • the methods of the present disclosure comprise administering a therapeutically effective amount of an anti-PD-1 antibody or antigenbinding fragment thereof in combination with a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof to a patient with an elevated level of MUC16 and/or CA125.
  • Methods to determine MUC16 and/or CA125 expression are well-known in the art.
  • the expression of MUC16 in tumor tissue is determined by an immunohistochemistry (IHC) assay (see e.g., Bast et al 1981 , J. Clin. Invest. 68: 1331-1337). MUC16 expression may be evaluated by any method known in the art (e.g., Shimizu et al 2012, Cancer Sci. 103: 739-746). In certain embodiments, the expression of MUC16 is determined by imaging with a labeled anti-MUC16 antibody, for example, by immuno-positron emission tomography or iPET (described elsewhere herein).
  • IHC immunohistochemistry
  • the methods of the present disclosure are used in a subject with an endometrial cancer.
  • tumor refers to tumors of the uterus and includes adenocarcinoma (e.g., endometrioid), uterine carcinosarcoma, squamous cell carcinoma, small cell carcinoma, transitional carcinoma, and serous carcinoma.
  • adenocarcinoma e.g., endometrioid
  • uterine carcinosarcoma e.g., uterine carcinosarcoma
  • squamous cell carcinoma e.g., small cell carcinoma, transitional carcinoma, and serous carcinoma.
  • Endometrioid cancers include adenocarcimona, adenoacanthoma, adenosquamous, secretory carcinoma, ciliated carcinoma, and villoglandular adenocarcinoma.
  • Advanced or recurrent endometrial cancer refers to those tumors, respectively, that cannot be treated with surgery or radiation alone, or that have recurred following prior therapy.
  • the present disclosure includes methods for treating, or delaying or inhibiting the growth of a tumor.
  • the present disclosure includes methods to promote tumor regression.
  • the present disclosure includes methods to reduce tumor cell load or to reduce tumor burden.
  • the present disclosure includes methods to prevent tumor recurrence.
  • the methods comprise administering a therapeutically effective amount of a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof as monotherapy, or in combination with an anti-PD-1 antibody or antigen-binding fragment thereof to a subject in need thereof, wherein each antibody is administered to the subject in multiple doses, e.g., as part of a specific therapeutic dosing regimen.
  • the therapeutic dosing regimen may comprise administering one or more doses of an anti- MUC16 x CD3 antibody or antigen-binding fragment thereof to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently.
  • the one or more doses of anti-PD-1 antibody or antigen-binding fragment thereof are administered in combination with one or more doses of a therapeutically effective amount of a bispecific anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof, wherein the one or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof are administered to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently.
  • each dose of the anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof is administered in more than 1 fractions, e.g., in 2-5 fractions ("split dosing") within the given dosing period.
  • the anti-MUC16/anti-CD3 bispecific antibody or antigen-binding fragment thereof may be administered in split doses to reduce or eliminate the cytokine "spikes" induced in response to administration of the antibody. Cytokine spikes refer to the clinical symptoms of the cytokine release syndrome ("cytokine storm”) and infusion related reactions.
  • the methods of the present disclosure comprise administering one or more doses of anti-PD-1 antibody or antigen-binding fragment thereof in combination with one or more doses of a bispecific anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof to a subject in need thereof, wherein a dose of the bispecific antibody or antigen-binding fragment thereof is administered as split doses, or in more than 1 fractions, e.g., as 2 fractions, as 3 fractions, as 4 fractions or as 5 fractions within the given dosing period.
  • a dose of the bispecific antibody or antigen-binding fragment thereof is split into 2 or more fractions, wherein each fraction comprises an amount of the antibody or antigen-binding fragment thereof equal to the other fractions.
  • a dose of anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof comprising 1000 micrograms may be administered once a week, wherein the dose is administered in 2 fractions within the week, each fraction comprising 500 micrograms.
  • a dose of the bispecific antibody or antigen-binding fragment thereof is administered split into 2 or more fractions, wherein the fractions comprise unequal amounts of the antibody, e.g., more than or less than the first fraction.
  • a dose of anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof comprising 1000 micrograms may be administered once a week, wherein the dose is administered in 2 fractions within the week, wherein the first fraction comprises 700 micrograms and the second fraction comprises 300 micrograms.
  • a dose of anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof comprising 1000 micrograms may be administered once in 2 weeks, wherein the dose is administered in 3 fractions within the 2-week period, wherein the first fraction comprises 400 micrograms, the second fraction comprises 300 micrograms and the third fraction comprises 300 micrograms.
  • the present disclosure provides a method of treating a MUC16-expressing cancer (e.g., endometrial cancer, including cancers refractory to multiple rounds of prior therapy as discussed herein) in a subject in need thereof, comprising administering to the subject a bispecific antibody comprising a first antigen-binding domain that specifically binds mucin 16 (MUC16), and a second antigen-binding domain that specifically binds human CD3, wherein the bispecific antibody is administered in a dosing regimen comprising: (i) administering 1 mg of the bispecific antibody in week 1 , optionally wherein the dose is split into a first fraction of about 0.5 mg and a second fraction of about 0.5 mg; (ii) administering 20 mg of the bispecific antibody in week 2, optionally wherein the dose is split into a first fraction of about 10 mg and a second fraction of about 10 mg; and (iii) administering 250 mg of the bispecific antibody in week 3, optionally wherein the dose is split into a MUC16-expressing cancer (e
  • the method further comprises administering the bispecific antibody at a dose of about 250 mg once every week from week 4 onwards. In some cases, the method further comprises administering the bispecific antibody at a dose of about 250 mg once every three weeks from week 4 onwards. In some cases, the method further comprises administering the bispecific antibody at a dose of about 800 mg once every three weeks from week 4 onwards. In some cases, the method further comprises administering an anti-PD-1 antibody to the subject at a dose of from 300 to 400 mg (e.g., 350 mg) once every three weeks.
  • the present disclosure includes methods to inhibit, retard or stop tumor metastasis or tumor infiltration into peripheral organs.
  • the methods comprise administering a therapeutically effective amount of a bispecific anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD-1 antibody or antigen-binding fragment thereof to a subject in need thereof.
  • the present disclosure provides methods for increased antitumor efficacy or increased tumor inhibition.
  • the methods comprise administering to a subject with an endometrial cancer a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof prior to administering a therapeutically effective amount of a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof, wherein the anti-PD- 1 antibody or antigen-binding fragment thereof may be administered about 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days prior to the bispecific antibody or antigen-binding fragment thereof.
  • the methods provide for increased tumor inhibition, e.g., by about 20%, more than 20%, more than 30%, more than 40% more than 50%, more than 60%, more than 70% or more than 80% as compared to a subject administered with the bispecific antibody or antigenbinding fragment thereof prior to the anti-PD- 1 antibody or antigen-binding fragment thereof.
  • the methods of the present disclosure comprise administering a therapeutically effective amount of a bispecific anti-CD3xMUC16 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD- 1 antibody or antigen-binding fragment thereof to a subject with an endometrial cancer.
  • the endometrial cancer is serous cancer.
  • the endometrial cancer is indolent or aggressive.
  • the subject is not responsive to prior therapy or has relapsed after prior therapy ⁇ e.g., platinum-based therapy).
  • the subject has a CA-125 level that is equal to or greater than 2 times the upper limit of normal (ULN) ⁇ e.g., equal to or greater than about 60 U/ml).
  • the subject’s serum CA-125 level (prior to treatment) is at or greater than 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650 or 700 U/ml.
  • the methods of the present disclosure further comprise administering an additional therapeutic agent to the subject.
  • the methods of the present disclosure comprise administering a therapeutically effective amount of a bispecific anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof to a subject with a MUC16+ cancer.
  • the cancer is an endometrial cancer.
  • the endometrial cancer is indolent or aggressive.
  • the cancer is a platinum-resistant endometrial cancer.
  • the cancer is a taxol-resistant endometrial cancer.
  • the cancer is fallopian tube cancer.
  • the cancer is primary peritoneal cancer, optionally in which the patient has elevated levels of serum CA-125 ⁇ e.g., at least 2x ULN).
  • the subject is not responsive to prior therapy or has relapsed after prior therapy ⁇ e.g., chemotherapy).
  • the methods of the present disclosure comprise administering an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a bispecific anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof to a subject in need thereof as a "first line" treatment (e.g., initial treatment).
  • a bispecific anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof is administered as a "second line” treatment (e.g., after prior therapy).
  • an anti-PD- 1 antibody or antigen-binding fragment thereof in combination with a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof is administered as a "second line" treatment to a subject that has relapsed after prior therapy with, e.g., chemotherapy (e.g., platinum-based chemotherapy).
  • chemotherapy e.g., platinum-based chemotherapy
  • the methods of the present disclosure are used to treat a patient with a MRD-positive disease.
  • Minimum residual disease refers to small numbers of cancer cells that remain in the patient during or after treatment, wherein the patient may or may not show symptoms or signs of the disease. Such residual cancer cells, if not eliminated, frequently lead to relapse of the disease.
  • the present disclosure includes methods to inhibit and/or eliminate residual cancer cells in a patient upon MRD testing. MRD may be assayed according to methods known in the art (e.g., MRD flow cytometry).
  • the methods comprise administering a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD-1 antibody or antigen-binding fragment thereof to a subject in need thereof.
  • the methods of the present disclosure comprise administering to a subject a therapeutically effective amount of a bispecific anti-MUC16/anti- CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD-1 antibody or antigen-binding fragment thereof and, optionally, a third therapeutic agent.
  • the third therapeutic agent may be an agent selected from the group consisting of, e.g., radiation, chemotherapy, surgery, a cancer vaccine, a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), a LAG3 inhibitor (e.g., an anti-LAG3 antibody), a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), a TIM3 inhibitor, a BTLA inhibitor, a TIG IT inhibitor, a CD47 inhibitor, an indoleamine-2,3- dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an Ang2 inhibitor, a transforming growth factor beta (TGF.beta.) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen (e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-
  • the antibodies may be administered in combination with therapy including a chemotherapeutic agent (e.g., paclitaxel, carboplatin, doxorubicin, cyclophosphamide, cisplatin, gemcitabine or docetaxel), radiation and surgery.
  • a chemotherapeutic agent e.g., paclitaxel, carboplatin, doxorubicin, cyclophosphamide, cisplatin, gemcitabine or docetaxel
  • the phrase “in combination with” means that the antibodies are administered to the subject at the same time as, just before, or just after administration of the third therapeutic agent.
  • the third therapeutic agent is administered as a co-formulation with the antibodies.
  • the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-MUC16/anti- CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti- PD-1 antibody or antigen-binding fragment thereof. Where the combination is administered, the administration of the antibodies (or fragments) leads to increased inhibition of tumor growth. In certain embodiments, tumor growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% as compared to an untreated subject or a subject administered with either antibody (or fragment) as monotherapy.
  • the administration of an anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof leads to increased tumor regression, tumor shrinkage and/or disappearance.
  • the administration of an anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof leads to delay in tumor growth and development, e.g., tumor growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years as compared to an untreated subject or a subject treated with either antibody (or fragment) as monotherapy.
  • administration of an anti-PD-1 antibody or antigenbinding fragment thereof in combination with a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof prevents tumor recurrence and/or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months than an untreated subject or a subject which is administered either antibody (or fragment) as monotherapy.
  • administration of the antibodies in combination increases progression-free survival or overall survival.
  • administration of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof increases response and duration of response in a subject, e.g., by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40% or more than 50% over an untreated subject or a subject which has received either antibody (or fragment) as monotherapy.
  • administration of an anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof to a subject with an endometrial cancer leads to complete disappearance of all evidence of tumor cells ("complete response").
  • administration of an anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof to a subject with an endometrial cancer leads to at least 30% or more decrease in tumor cells or tumor size ("partial response").
  • administering leads to complete or partial disappearance of tumor cells/lesions including new measurable lesions.
  • Tumor reduction can be measured by any of the methods known in the art, e.g., X-rays, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analyses.
  • administering produces a synergistic anti-tumor effect that exceeds the combined effects of the two agents when administered alone.
  • the combination of administered antibodies (or fragments) is safe and well-tolerated by a patient wherein there is no increase in an adverse side effect (e.g., increased cytokine release ("cytokine storm") or increased T-cell activation) as compared to a patient administered with the bispecific antibody (or fragment) as monotherapy.
  • an adverse side effect e.g., increased cytokine release ("cytokine storm") or increased T-cell activation
  • the response of a subject to therapy is categorized as a complete response (CR), a partial response (PR), progressive disease (PD), or as stable disease (SD).
  • a CR is defined as disappearance of all target lesions, and a reduction in short axis of any pathological lymph nodes (whether target or non-target) to ⁇ 10 mm ( ⁇ 1 cm).
  • a PR is defined as an at least 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • PD is defined as an at least 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
  • the sum In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also considered a progression). SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
  • the methods comprise administering a therapeutically effective amount of an anti-PD-1 antibody or antigenbinding fragment thereof.
  • anti-PD-1 antibody or antigen-binding fragment thereof refers to and is used interchangeably with the term “antibody or antigen-binding fragment thereof that specifically binds to PD-1 .”
  • antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
  • each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V ) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, CH1 , CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
  • the light chain constant region comprises one domain (CL1).
  • the V and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • Each VH and L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the anti-l L-4R antibody may be identical to the human germline sequences, or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
  • the term "antibody,” as used herein, also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain- deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the V H and V domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain V H -V H , V H -V L or V L -V dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigenbinding fragment of an antibody of the present disclosure include: (i) V H -CH1 ; (ii) V H -CH2; (iii) V H - CH3; (iv) VH-CH1 -CH2; (V) VH-CH1 -CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1 ; (ix) VL-CH2; (x) V L -CH3; (xi) V L -CH1 -CH2; (xii) V -CH1 -CH2-CH3; (xiii) V L -CH2-CH3; and (xiv) V -CL.
  • variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody of the present disclosure may comprise a homodimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or V L domain (e.g., by disulfide bond(s)).
  • antibody also includes multispecific (e.g., bispecific) antibodies.
  • a multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format may be adapted for use in the context of an antibody or antigenbinding fragment of an antibody of the present disclosure using routine techniques available in the art.
  • the present disclosure includes methods comprising the use of bispecific antibodies wherein one arm of an immunoglobulin is specific for PD-1 or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety.
  • Exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, lgG1/lgG2, dual acting Fab (DAF)-lgG, and Mab.sup.2 bispecific formats (see, e.g., Klein et al.
  • Bispecific antibodies can also be constructed using peptide/nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).
  • the antibodies used in the methods of the present disclosure may be human antibodies.
  • the term "human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the disclosure may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or sitespecific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • the term "human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the antibodies used in the methods of the present disclosure may be recombinant human antibodies.
  • the term "recombinant human antibody,” as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • the antibodies used in the methods of the present disclosure specifically bind PD-1 .
  • the term "specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
  • an antibody that "specifically binds" PD- 1 includes antibodies that bind PD-1 or portion thereof with a K D of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay.
  • An isolated antibody that specifically binds human PD-1 may, however, have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.
  • the anti-PD-1 antibody, or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-PD-1 antibodies as set forth in US Patent No. 9,987,500.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • CDRs complementarity determining regions
  • HCDRs heavy chain complementarity determining regions
  • LCDRs light chain complementarity determining regions of a light chain variable region
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 35; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 37; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 38; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 40.
  • the anti-PD-1 antibody or antigenbinding fragment thereof comprises an HCVR comprising SEQ ID NO: 33 and an LCVR comprising SEQ ID NO: 34.
  • the methods of the present disclosure comprise the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 .
  • the anti-PD-1 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 42.
  • An exemplary antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 33 and a LCVR comprising the amino acid sequence of SEQ ID NO: 34 is the fully human anti-PD- 1 antibody known as REGN2810 (also known as cemiplimab, LIBTAYO®).
  • REGN2810 also known as cemiplimab, LIBTAYO®
  • the methods of the present disclosure comprise the use of REGN2810, or a bioequivalent thereof.
  • bioequivalent refers to anti- PD-1 antibodies or PD-1 -binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and/or extent of absorption do not show a significant difference with that of REGN2810 when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose.
  • the term refers to antigen-binding proteins that bind to PD-1 which do not have clinically meaningful differences with REGN2810 in their safety, purity and/or potency.
  • the anti-PD-1 antibodies used in the context of the methods of the present disclosure may have pH-dependent binding characteristics.
  • an anti-PD-1 antibody for use in the methods of the present disclosure may exhibit reduced binding to PD-1 at acidic pH as compared to neutral pH.
  • an anti-PD-1 antibody of the disclosure may exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH.
  • the expression "acidic pH” includes pH values less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1 , 5.05, 5.0, or less.
  • neutral pH means a pH of about 7.0 to about 7.4.
  • neutral pH includes pH values of about 7.0, 7.05, 7.1 , 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.
  • "reduced binding to PD-1 at acidic pH as compared to neutral pH” is expressed in terms of a ratio of the K D value of the antibody binding to PD-1 at acidic pH to the K D value of the antibody binding to PD-1 at neutral pH (or vice versa).
  • an antibody or antigen-binding fragment thereof may be regarded as exhibiting "reduced binding to PD-1 at acidic pH as compared to neutral pH” for purposes of the present disclosure if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral KD ratio of about 3.0 or greater.
  • the acidic/neutral KD ratio for an antibody or antigen-binding fragment of the present disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or greater.
  • Antibodies with pH-dependent binding characteristics may be obtained, e.g., by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modifications of the antigen-binding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain ⁇ e.g., within a CDR) with a histidine residue, an antibody with reduced antigen-binding at acidic pH relative to neutral pH may be obtained.
  • the expression "acidic pH” means a pH of 6.0 or less.
  • the methods comprise administering a therapeutically effective amount of a bispecific antibody or antigenbinding fragment thereof that specifically binds CD3 and MUC16.
  • a bispecific antibody or antigenbinding fragment thereof that specifically binds CD3 and MUC16.
  • Such antibodies and fragments may be referred to herein as, e.g., "anti-MUC16/anti-CD3," or "anti-MUC16xCD3" or “MUC16xCD3" bispecific antibodies or antigen-binding fragments thereof, or other similar terminology.
  • the expression "bispecific antibody” refers to an immunoglobulin protein comprising at least a first antigen-binding domain and a second antigen-binding domain.
  • the first antigen-binding domain specifically binds a first antigen (e.g., MUC16)
  • the second antigen-binding domain specifically binds a second, distinct antigen (e.g., CD3).
  • Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR), each comprising three CDRs.
  • the CDRs of the first antigenbinding domain may be designated with the prefix "A” and the CDRs of the second antigenbinding domain may be designated with the prefix "B".
  • the CDRs of the first antigenbinding domain may be referred to herein as A-HCDR1 , A-HCDR2, and A-HCDR3; and the CDRs of the second antigen-binding domain may be referred to herein as B-HCDR1 , B-HCDR2, and B-HCDR3.
  • the first antigen-binding domain and the second antigen-binding domain are each connected to a separate multimerizing domain.
  • a "multimerizing domain” is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution.
  • the multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3 domain), e.g., an Fc domain of an IgG selected from the isotypes IgG 1 , lgG2, lgG3, and lgG4, as well as any allotype within each isotype group.
  • Bispecific antibodies of the present disclosure typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain.
  • the first and second multimerizing domains may be of the same IgG isotype such as, e.g., lgG1/lgG1 , lgG2/lgG2, lgG4/lgG4.
  • the first and second multimerizing domains may be of different IgG isotypes such as, e.g., lgG1/lgG2, lgG1/lgG4, lgG2/lgG4, etc.
  • any bispecific antibody format or technology may be used to make the bispecific antigen-binding molecules of the present disclosure.
  • an antibody or fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigen-binding specificity to produce a bispecific antigen-binding molecule.
  • bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into- holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, lgG1/lgG2, dual acting Fab (DAF)-lgG, and Mab2 bispecific formats (see, e.g., Klein et al.
  • Fc domains may comprise one or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain.
  • the disclosure includes bispecific antigen-binding molecules comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction e.g., enhanced or diminished) between Fc and FcRn.
  • the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype.
  • a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human IgG 1 , human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human IgG 1 , human lgG2 or human lgG4.
  • a chimeric Fc domain can also contain a chimeric hinge region.
  • a chimeric hinge may comprise an "upper hinge" sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region, combined with a "lower hinge” sequence, derived from a human IgG 1 , a human lgG2 or a human lgG4 hinge region.
  • a particular example of a chimeric Fc domain that can be included in any of the antigen-binding molecules set forth herein comprises, from N- to C-terminus: [lgG4 Cn1]-[lgG4 upper hinge]-[lgG2 lower hinge]-[lgG4 CH2]-[lgG4 CH3].
  • chimeric Fc domains that can be included in any of the antigen-binding molecules of the present disclosure are described in US Patent Publication No. 20140243504, which is herein incorporated in its entirety. Chimeric Fc domains having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.
  • the bispecific anti-MUC16/anti-CD3 antibody, or antigen-binding fragment thereof comprises heavy chain variable regions (A-HCVR and B-HCVR), light chain variable regions (A-LCVR and B-LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the bispecific anti-MUC16/anti-CD3 antibodies as set forth in US Patent Publication No. 20180112001.
  • the bispecific anti- MUC16/anti-CD3 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen-binding arm comprising the heavy chain complementarity determining regions (A-HCDR1 , A-HCDR2 and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (A-LCDR1 , A-LCDR2 and A-LCDR3) of a light chain variable region (A-LCVR) comprising the amino acid sequence of SEQ ID NO: 2; and (b) a second antigen-binding arm comprising the heavy chain CDRs (B-HCDR1 , B-HCDR2 and B-HCDR3) of a HCVR (B-HCVR) comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 or SEQ
  • the A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; the A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 9; the A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 10; the A-LCDR1 comprises the amino acid sequence of SEQ ID NO: 11 ; the A-LCDR2 comprises the amino acid sequence of SEQ ID NO: 12; the A-LCDR3 comprises the amino acid sequence of SEQ ID NO: 13; the B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, or SEQ ID NO: 26; the B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 21 , SEQ ID NO: 24, or SEQ ID NO: 27; and the B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 19, SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 28
  • the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof comprises: (a) a first antigen-binding arm comprising a HCVR (A-HCVR) comprising SEQ ID NO: 1 and a LCVR (A-LCVR) comprising SEQ ID NO: 2; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, and a LCVR (B-LCVR) comprising SEQ ID NO: 2.
  • the bispecific anti-CD3xMUC16 antibody comprises a MUC16-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 30.
  • the bispecific anti-CD3xMUC16 antibody comprises a MUC16-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 30.
  • An exemplary bispecific anti- MUC16/anti-CD3 antibody that may be used in the methods of the present disclosure and comprises A-HCVR of SEQ ID NO: 1 , B-HCVR of SEQ ID NO: 3 and LCVR of SEQ ID NO: 2 is REGN4018 (ubamatamab).
  • bispecific anti-MUC16/anti-CD3 antibodies that can be used in the context of the methods of the present disclosure include, e.g., any of the antibodies as set forth in US Patent Publication No. 20180112001.
  • the methods of the present disclosure comprise administering to the subject an anti-MUC16/anti-CD3 bispecific antibody or antigen-binding fragment thereof in combination with an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the methods of the present disclosure comprise administering the antibodies (or fragments) for additive or synergistic activity to treat cancer, for example, an endometrial cancer.
  • the expression "in combination with” means that the anti- MUC16/anti-CD3 bispecific antibody or antigen-binding fragment thereof is administered before, after, or concurrent with the anti-PD-1 antibody or antigen-binding fragment thereof.
  • the term "in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof.
  • the anti-PD- 1 antibody or antigen-binding fragment thereof may be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof.
  • Administration "concurrent" with the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof means that the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the bispecific anti-MUC16/anti- CD3 antibody or antigen-binding fragment thereof, or administered to the subject as a single combined dosage formulation comprising both the anti-PD-1 antibody or antigen-binding fragment thereof and the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof.
  • the methods of the present disclosure comprise administration of a third therapeutic agent wherein the third therapeutic agent is an anti-cancer drug.
  • the methods of the present disclosure comprise administration of an additional therapy wherein the additional therapy is surgery.
  • the methods of the disclosure comprise administering an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-MUC16/anti-CD3 bispecific antibody or antigen-binding fragment thereof in combination with radiation therapy to generate long-term durable anti-tumor responses and/or enhance survival of patients with cancer.
  • the methods of the disclosure comprise administering radiation therapy prior to, concomitantly or after administering an anti-PD-1 antibody or antigen-binding fragment thereof and a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof to a cancer patient.
  • radiation therapy may be administered in one or more doses to tumor lesions after administration of one or more doses of the antibodies (or fragments).
  • radiation therapy may be administered locally to a tumor lesion to enhance the local immunogenicity of a patient's tumor (adjuvinating radiation) and/or to kill tumor cells (ablative radiation) after systemic administration of an anti-PD- 1 antibody or antigen-binding fragment thereof and/or a bispecific anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof.
  • the methods of the present disclosure may further comprise administration of a steroid (e.g., dexamethasone or an equivalent steroid), or an anti-IL-6 receptor antibody.
  • a steroid e.g., dexamethasone or an equivalent steroid
  • the anti-IL-6 receptor antibody is tocilizumab or sarilumab.
  • the steroid e.g., dexamethasone may be administered at a dose of from 1 mg to 20 mg (e.g., from 5 mg to 10 mg) IV or PO. In some cases, these agents may be administered as premedications prior to administration of the bispecific antibody.
  • the present disclosure includes methods which comprise administering a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD- 1 antibody or antigen-binding fragment thereof to a subject wherein the antibody or antibodies (or fragments) are contained within separate or a combined (single) pharmaceutical composition.
  • the pharmaceutical compositions of the disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like.
  • a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.
  • Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262: 4429-4432).
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • infusion or bolus injection by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • epithelial or mucocutaneous linings e.g., oral mucosa, rectal and intestinal mucosa, etc.
  • a pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe.
  • a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure.
  • Such a pen delivery device can be reusable or disposable.
  • a reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused.
  • a disposable pen delivery device there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
  • Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure.
  • Examples include, but are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and Co., Indianapolis, IN), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETTM, and OPTICLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few.
  • Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTARTM pen (sanofi-aventis), the FLEXPENTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly), the SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL), to name only a few.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • a pump may be used.
  • polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla.
  • a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.
  • the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil
  • oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • multiple doses of an antigen-binding molecule may be administered to a subject over a defined time course.
  • the methods according to this aspect of the disclosure comprise sequentially administering to a subject multiple doses of an antigen-binding molecule of the disclosure.
  • sequentially administering means that each dose of an antigen-binding molecule is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
  • the present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of an antigen-binding molecule, followed by one or more secondary doses of the antigen-binding molecule, and optionally followed by one or more tertiary doses of the antigen-binding molecule.
  • the terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the antigen-binding molecule (e.g., a bispecific anti-MUC16 x CD3 antibody or anti-PD-1 antibody) of the disclosure.
  • the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
  • the “secondary doses” are the doses which are administered after the initial dose;
  • the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses may all contain the same amount of the antigen-binding molecule, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of an antigen-binding molecule contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").
  • the initial dose (e.g., first weekly dose) may be split into two doses administered on separate days (e.g., consecutive days) no more than three days apart.
  • the first nominal dose i.e., the secondary dose
  • the dose may be split into two 3 mg doses administered on, e.g., consecutive days, or on separate days no more than three days apart.
  • the dose (e.g., the dose administered weekly, as a single dose or as two split fractions of the dose) is, or is at least, 1 mg, 2 mg, 3 mg, 4 mg, 5, mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 1 1 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg,
  • all doses are given as single doses e.g., single infusions), including the doses administered in weeks one and two of a dosing regimen.
  • an initial dose of from 1 mg to 5 mg may be administered as a single dose in week one
  • a secondary dose of from 3 mg to 400 mg may be administered as a single dose in week two
  • a tertiary dose of from 50 mg to 800 mg may be administered as a single dose in week three, and thereafter during a weekly dosing portion of a dosing regimen.
  • an initial dose of 5 mg may be administered as a single dose in week one
  • a secondary dose of 25 mg may be administered as a single dose in week two
  • a tertiary dose of from 50 mg to 800 mg may be administered as a single dose in week three, and thereafter during a weekly dosing portion of a dosing regimen.
  • the dosing schedule may thereafter (e.g., following 12 to 16 weeks) include administration every two weeks, every three weeks, once per month, or the like.
  • each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , 1 1 /2, 2, 2 1 /2, 3, 3 1 /2, 4, 4 1 /2, 5, 5 1 /2, 6, 6 1 /2, 7, 7 1 /2, 8, 8 1 / 2 , 9, 9 1 / 2 , 10, 10 1 / 2 , 1 1 , 1 1 1 / 2 , 12, 12 1 / 2 , 13, 13 1 /z, 14, 14 1 / 2 , 15, 15 1 / 2 , 16, 16 1 /z, 17, 17 1 / 2 , 18, 18 1 / 2 , 19, 19 1 / 2 , 20, 20 1 /2, 21 , 21 1 / 2 , 22, 22 1 / 2 , 23, 23 1 / 2 , 24, 24 1 / 2 , 25, 25 1 / 2 , 26, 26 1 / 2 , or more) weeks after the immediately preceding dose.
  • the phrase "the immediately preceding dose” as
  • the dose of antibody (or fragment thereof) administered to a patient may vary depending upon the age and the size of the patient, conditions, route of administration, and the like.
  • the preferred dose is typically calculated according to body weight or body surface area.
  • methods of treating can include intravenously administering the antibody of the present disclosure at a single dose of about 0.01 to about 100 mg/kg body weight, or more.
  • the dose is about 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, or more.
  • the concentration of the dose the frequency and/or the duration of the treatment can be adjusted.
  • Treatment methods can include 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses of a presently disclosed antibody administered weekly, biweekly, or triweekly over 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months
  • Scheduling for dosing can be modified, e.g., from weekly to biweekly, vice versa, or otherwise, as needed.
  • Effective dosages and schedules for administering antibodies may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly.
  • interspecies scaling of dosages can be performed using well-known methods in the art e.g., Mordenti etal., Pharmaceut Res 8:1351 (1991 )).
  • the methods according to this aspect of the disclosure may comprise administering to a patient any number of secondary and/or tertiary doses of an antigen-binding molecule (e.g., a bispecific anti-MUC16 x CD3 antibody, or an anti-PD-1 antibody).
  • an antigen-binding molecule e.g., a bispecific anti-MUC16 x CD3 antibody, or an anti-PD-1 antibody.
  • only a single secondary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
  • only a single tertiary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
  • each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose.
  • each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose.
  • the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
  • the present disclosure includes methods comprising administering to a subject a bispecific anti-MUC16 x CD3 antibody or antigen-binding fragment thereof and/or an anti-PD-1 antibody or antigen-binding fragment thereof at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved.
  • multiple doses of a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof alone, or in combination with an anti-PD-1 antibody or antigen-binding fragment thereof may be administered to a subject over a defined time course.
  • the methods according to this aspect of the disclosure comprise sequentially administering to a subject one or more doses of a bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof alone, or in combination with one or more doses of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • sequentially administering means that each dose of the antibody or antigen-binding fragment thereof is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
  • the present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of an antibody or antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, and optionally followed by one or more tertiary doses of the antibody or antigen-binding fragment thereof.
  • the amount of bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof, and optionally anti-PD-1 antibody or antigen-binding fragment thereof, administered to a subject according to the methods of the present disclosure is, generally, a therapeutically effective amount.
  • the phrase "therapeutically effective amount” means an amount of antibody or antigen-binding fragment thereof (anti-PD-1 antibody or bispecific anti- MUC16/anti-CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a cancer (e.g., endometrial cancer); (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth and development; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with cancer e.g., endometrial cancer); and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody (or fragment) as monotherapy.
  • conventional anti-cancer therapy e.g., reduced or
  • a therapeutically effective amount can be from about 0.1 milligrams (mg) to about 1000 mg, e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about
  • the dose is about 1 mg. In some cases, the dose is about 2 mg. In some cases, the dose is about 20 mg. In some cases, the dose is about 25 mg. In some cases, the dose is about 250 mg. In some cases, the dose is about 800 mg. Any of these doses may the initial dose, the intermediate or transitional dose, or the full dose.
  • the bispecific anti-MUC16/anti-CD3 antibody is administered to the subject at a dose of at least 1 mg weekly or every two weeks, at least 1 .5 mg weekly or every two weeks, at least 2.0 mg weekly or every two weeks, at least 2.5 mg weekly or every two weeks, at least 3.0 mg weekly or every two weeks, at least 3.5 mg weekly or every two weeks, at least 4 mg weekly or every two weeks, at least 5 mg weekly or every two weeks, at least 6 mg weekly or every two weeks, at least 7 mg weekly or every two weeks, at least 8 mg weekly or every two weeks, at least 9 mg weekly or every two weeks, at least 10 mg weekly or every two weeks, at least 15 mg weekly or every two weeks, at least 20 mg weekly or every two weeks, at least 25 mg weekly or every two weeks, at least 30 mg weekly or every two weeks, at least 35 mg weekly or every two weeks, at least 40 mg weekly or every two weeks, at least 45 mg weekly or every two weeks, at least 50 mg weekly or every two weeks, at least 55 mg weekly or every two
  • a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about
  • the anti-PD-1 antibody is administered to the subject at a dose of at least 1 mg weekly or every two weeks, at least 1 .5 mg weekly or every two weeks, at least 2.0 mg weekly or every two weeks, at least 2.5 mg weekly or every two weeks, at least 3.0 mg weekly or every two weeks, at least 3.5 mg weekly or every two weeks, at least 4 mg weekly or every two weeks, at least 5 mg weekly or every two weeks, at least 6 mg weekly or every two weeks, at least 7 mg weekly or every two weeks, at least 8 mg weekly or every two weeks, at least 9 mg weekly or every two weeks, at least 10 mg weekly or every two weeks, at least 15 mg weekly or every two weeks, at least 20 mg weekly or every two weeks, at least 25 mg weekly or every two weeks, at least 30 mg weekly or every two weeks, at least 35 mg weekly or every two weeks, at least 40 mg weekly or every two weeks, at least 45 mg weekly or every two weeks, at least 50 mg weekly or every two weeks, at least 55 mg weekly or every two weeks, at least 60 mg weekly or
  • the initial dose of the bispecific anti-MUC16/anti-CD3 antibody and/or the anti- PD- 1 antibody is from 1 mg to 5 mg.
  • the secondary dose is from 3 mg to 400 mg.
  • the tertiary dose is from 3 mg to 800 mg.
  • the initial dose is 5 mg
  • the secondary dose is 25 mg
  • the tertiary dose is from 50 mg to 800 mg.
  • the dosing regimen includes administration of the tertiary dose weekly for at least 12 weeks e.g., 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more) during a weekly dosing period of the dosing regimen.
  • the dosing regimen further includes administration of the tertiary dose once every two weeks during a biweekly dosing period of the dosing regimen that follows the weekly period of the dosing regimen.
  • the dosing regimen further includes administration of the tertiary dose one every three weeks, or once every four weeks.
  • the dose may be at least 1 mg weekly or every two weeks, at least 1 .5 mg weekly or every two weeks, at least 2.0 mg weekly or every two weeks, at least 2.5 mg weekly or every two weeks, at least 3.0 mg weekly or every two weeks, at least 3.5 mg weekly or every two weeks, at least 4 mg weekly or every two weeks, at least 5 mg weekly or every two weeks, at least 6 mg weekly or every two weeks, at least 7 mg weekly or every two weeks, at least 8 mg weekly or every two weeks, at least 9 mg weekly or every two weeks, at least 10 mg weekly or every two weeks, at least 15 mg weekly or every two weeks, at least 20 mg weekly or every two weeks, at least 25 mg weekly or every two weeks, at least 30 mg weekly or every two weeks, at least 35 mg weekly or every two weeks, at least 40 mg weekly or every two weeks, at least 45 mg weekly or every two weeks, at least 50 mg weekly or every two weeks, at least 55 mg weekly or every two weeks, at least 60 mg weekly or every two weeks, at least 65 mg weekly or every two weeks, at
  • the amount of bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof and optionally anti-PD-1 antibody or antigen-binding fragment thereof contained within the individual doses may be expressed in terms of milligrams of antibody or antigen-binding fragment thereof per kilogram of subject body weight (/.e., mg/kg).
  • the bispecific anti-MUC16/anti-CD3 antibody or antigen-binding fragment thereof, and optionally the anti-PD-1 antibody or antigen-binding fragment thereof, used in the methods of the present disclosure may be administered to a subject at a dose of about 0.0001 to about 100 mg/kg of subject body weight.
  • the bispecific anti-MUC16/anti-CD3 antibody or antigenbinding fragment thereof may be administered at a dose of about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, to about 20 mg/kg of a patient's body weight, and the optional anti-PD-1 antibody or antigen-binding fragment thereof may be administered at dose of about 0.1 mg/kg, about 0.3 mg
  • Example 1 Generation of Bispecific Antibodies that Bind MUC16 and CD3
  • the present disclosure provides methods of use comprising bispecific antigen-binding molecules that bind CD3 and MUC16; such bispecific antigen-binding molecules are also referred to herein as “anti-MUC16/anti-CD3 or anti-MUC16xCD3 bispecific molecules.”
  • the anti-MUC16 portion of the anti-MUC16/anti-CD3 bispecific molecule is useful for targeting tumor cells that express MUC16 (also known as CA-125), and the anti-CD3 portion of the bispecific molecule is useful for activating T-cells.
  • the bispecific antigen-binding molecules are bispecific antibodies.
  • the simultaneous binding of MUC16 on a tumor cell and CD3 on a T-cell facilitates directed killing (cell lysis) of the targeted tumor cell by the activated T-cell.
  • Bispecific antibodies comprising an anti-MUC16-specific binding domain and an anti- CD3-specific binding domain were constructed using standard methodologies, wherein the anti- MUC16 antigen binding domain and the anti-CD3 antigen binding domain each comprise different, distinct HCVRs paired with a common LCVR.
  • the molecules were constructed utilizing a heavy chain from an anti-CD3 antibody, a heavy chain from an anti-MUC16 antibody and a common light chain from the anti-MUC16 antibody.
  • the bispecific antibodies may be constructed utilizing a heavy chain from an anti-CD3 antibody, a heavy chain from an anti-MUC16 antibody and a light chain from an anti-CD3 antibody or an antibody light chain known to be promiscuous or pair effectively with a variety of heavy chain arms.
  • Exemplified bispecific antibodies were manufactured having an lgG1 Fc domain (BSMUC16/CD3-001 , -002, -003, and -004) or a modified (chimeric) lgG4 Fc domain (BSMUC16/CD3-005) as set forth in US Patent Application Publication No. US20140243504A1 , published on August 28, 2014.
  • An exemplary bispecific antibody comprising the VRs and CDRs of BSMUC16/CD3-001 is REGN4018 (ubamatamab).
  • REGN4018 comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 29, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 31 , and a common light chain comprising the amino acid sequence of SEQ ID NO: 30.
  • mice were administered therapeutically relevant doses of a 89 Zr-labelled BSMUC16/CD3-001 bispecific antibody, distribution to the spleen and lymph nodes was evident due to recognition of CD3 positive T cells in these lymphoid organs (data not shown).
  • Ex vivo biodistribution analyses in individual tissues confirmed localization to lymph nodes and spleen (data not shown). Uptake of 89 Zr-labelled BSMUC16/CD3-005 bispecific antibody in lymphoid tissues was greatly reduced relative to BSMUC16/CD3-001 due to its lower affinity for CD3.
  • BSMUC16/CD3-001 and BSMUC16/CD3-005 can accumulate in MUC16-expressing tumors.
  • 89 Zr-labelled BSMUC16/CD3-001 and 89 Zr-labelled BSMUC16/CD3-005 were administered to mice bearing ID8-VEGF-huMUC16A tumors. Tumor uptake between the bispecific antibodies was not significantly different despite the higher lymphoid uptake of BSMUC16/CD3-001 (data not shown).
  • mice were implanted subcutaneously with 10x10 6 ID8-VEGF-huMUC16A tumor cells.
  • Tumor bearing mice were dosed with 89 Zr radiolabeled antibodies 20 day post implantation when tumors averaged 150mm 3 .
  • a pre-calibrated Sofie Biosciences G8 PET/CT instrument (Sofie Biosciences (Culver city, CA) and Perkin Elmer) was used to acquire PET and CT images.
  • the energy window ranged from 150 to 650 keV with a reconstructed resolution of 1 .4 mm at the center of the field of view.
  • mice Under day 6 post dosing, mice underwent induction anesthesia using isoflurane and were kept under continuous flow of isoflurane during a 10-minute static PET acquisition.
  • CT images were acquired following PET acquisition. The PET image was subsequently reconstructed using pre-configured settings.
  • VivoQuant software inviCRO Imaging Services
  • 89 Zr-labeled BSMUC16/CD3-001 and 89 Zr-labeled BSMUC16/CD3-005 demonstrated specific localization to MUC16+ tumors and CD3+ lymphoid tissues, with lymphoid distribution correlating to relative CD3 affinity. Both MUC16xCD3 bispecifics demonstrated equivalent tumor localization in the presence of CD3+ tissues.
  • BSMUC16/CD3-001 cross-reacts with monkey MUC16 and CD3.
  • a multidose toxicity study was conducted in cynomolgus monkeys.
  • Six monkeys/sex/group received weekly administration of BSMUC16/CD3-001 for a total of five doses at 0.01 , 0.1 or 1 mg/kg.
  • 3 animals/sex/group were euthanized and tissues examined for microscopic finding, while the remaining three animals/sex/group underwent 12 weeks of treatment-free recovery to assess the reversibility or persistence of any BSMUC16/CD3-001 -related effects.
  • BSMUC16/CD3-001 There were no BSMUC16/CD3-001 -related clinical observations, nor any changes in urinalysis parameters, peripheral blood immunophenotyping, food consumption, or body weight during the dosing or recovery periods. Importantly, BSMUC16/CD3-001 administration did not result in any changes in respiratory, neurologic, or cardiovascular safety pharmacology evaluations, including no changes in ECG parameters. No BSMUC16/CD3-001 -related changes in organ weight were found, nor were any macroscopic changes noted at either terminal or recovery necropsy.
  • Cynomolgus monkeys (6 animals/sex/group) were administered control article (diluted placebo) or BSMUC16/CD3-001 (0.01 , 0.1 , or 1 mg/kg) once weekly via a 30-minute IV infusion.
  • the control article was 10mM histidine with 10% sucrose and 0.05% polysorbate 20, pH 6, diluted with 0.9% sodium chloride for injection, USP (sterile saline). Blood samples or tissues were collected at various time points for clinical pathology and histopathology.
  • BSMUC16/CD3- 001 concentration was determined by ELISA and toxicokinetic analysis was performed using WinNonLin software.
  • CRP was analyzed on a Roche Modular P 800 system.
  • Cytokines were measured by MSD (Meso Scale Diagnostics, Rockville, MD). T cells were quantitated using flow cytometry. Briefly, blood was collected in potassium EDTA tubes, lysed, stained for CD3, CD4 and CD8 (BD Biosciences) and relative values for each phenotype are determined using a FACS Canto II. These values are then multiplied by the absolute lymphocyte values (via hematology analysis) to enumerate absolute cell counts for each phenotype.
  • BSMUC16/CD3-001 -related microscopic changes evaluated by hematoxylin and eosin (H&E) histologic staining, included inflammation (infiltration of white blood cells) and increased mesothelial cell size and cellularity leading to non-adverse thickening of the serosal lining and/or submesothelial connective tissue of multiple thoracic and peritoneal organs.
  • H&E hematoxylin and eosin histologic staining
  • inflammation infiltration of white blood cells
  • mesothelial cell size and cellularity leading to non-adverse thickening of the serosal lining and/or submesothelial connective tissue of multiple thoracic and peritoneal organs.
  • These changes were generally focal or multi-focal in nature and were minimal to slight in severity and were considered to be on-target for BSMUC16/CD3-001 , resulting from engagement of MUC16 expressed on serosal epitheli
  • mice were genetically engineered to express human CD3 on T cells and a region of MUC16 covering the antibody binding region, both in the endogenous murine loci (knock-in mice).
  • MUC16 expression was examined by both RT-PCR and IHC. RNA expression was detected in the trachea as well as low levels in the lung, heart, ovary, pancreas and bladder (data not shown), similar to published data on murine MUC16 expression.
  • IHC was performed on selected tissues using an anti-human MUC16 antibody that recognizes a membrane-proximal region of MUC16.
  • MUC16 protein expression was confirmed in the surface epithelium of the ovary and stomach in these mice. MUC16 was also observed in the tracheal lining/epithelium as well as the submucosal glands, as has been described in humans (data not shown).
  • Tissue sections were incubated with the anti-MUC16 antibody (2pg/ml) for 8 hours at RT.
  • An isotype control antibody recognizing an irrelevant non-binding antibody was used as the negative control.
  • Primary antibody and negative control were applied manually.
  • Biotinylated Goat Anti-Human IgG Jackson ImmunoResearch
  • the chromogenic signal was developed using the Ventana DAB MAP Kit. Slides were manually counterstained with Hematoxylin (2 minutes), dehydrated and coverslipped.
  • T cells in these mice are polyclonal, as assessed by T cell receptor (TCR) VB usage, express human CD3, and are present in similar numbers to wildtype mice (data not shown).
  • TCR T cell receptor
  • BSMUC16/CD3-001 induced any T cell activation or effects on normal tissues in these animals.
  • non-tumor-bearing mice were injected with a high dose of BSMUC16/CD3-001 (10 mg/kg) and T cell numbers in blood, serum cytokines, and histopathology were then examined.
  • T cells can be activated by an anti-human CD3 antibody (OKT3) as measured by T cell margination from the blood and increased levels of serum cytokines (data not shown), BSMUC16/CD3-001 did not induce any such effects, suggesting limited accessibility of the MUC16 target (data not shown).
  • OKT3 anti-human CD3 antibody
  • MUC16 and CD3 humanized mice received two doses of BSMUC16/CD3-001 at 10 mg/kg on Day 0 and Day 3. On day 5, several MUC16-expressing tissues (trachea, stomach and ovary) were examined, and no cellular infiltration or necrosis was seen in these tissues following BSMUC16/CD3-001 administration (data not shown).
  • Histopathology examination revealed no inflammation or infiltration into MUC16-expressing tissues in mice after BSMUC16/CD3-001 administration at the time examined.
  • Example 5 Methods of Treating Endometrial Cancer with Anti-MUC16 x Anti-CD3 Bispecific Antibodies Alone or in Combination with Anti-PD-1 Antibody
  • a phase 1/2 study is being conducted to investigate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of REGN4018 (anti-MUC16 x anti-CD3 bispecific antibody; ubamatamab) alone or in combination with cemiplimab (anti-PD-1 antibody) in patients with advanced endometrial cancer after prior anti-PD1 and prior platinum-based therapy who have been selected based on demonstration of tumor MUC16 expression.
  • REGN4018 anti-MUC16 x anti-CD3 bispecific antibody; ubamatamab
  • cemiplimab anti-PD-1 antibody
  • the patients will include those with tumors that are likely to express MUC16.
  • Only patients with elevated (>2x ULN) serum CA-125 levels will be included, as this serum CA-125 level is likely to reflect the presence of MUCH 6 on the tumor cells.
  • the primary objective is to assess the preliminary efficacy of ubamatamab as a monotherapy, or in combination with cemiplimab, for treatment of endometrial cancer.
  • the primary objective is to assess the safety and pharmacokinetics (PK) in order to determine a maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of REGN4018 as monotherapy and in combination with cemiplimab.
  • the primary objective is to assess the preliminary efficacy of REGN4018 as determined by the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
  • the secondary objectives include (1 ) in the dose escalation phase, to assess the preliminary efficacy of REGN4018 as monotherapy and in combination with cemiplimab as determined by RECIST 1 .1 ; (2) in the dose expansion phase, to characterize the safety profile in each expansion cohort, to characterize the PK of REGN4018 as monotherapy and in combination with cemiplimab, and to assess the effect of REGN4018 as monotherapy and in combination with cemiplimab on patient-reported outcomes (PROs), including health-related quality of life (HRQoL), functioning, and symptoms; and (3) in both the dose escalation and dose expansion phases, to assess preliminary efficacy of REGN4018 as monotherapy and in combination with cemiplimab (separately by cohort) as measured by ORR based on immunebased therapy RECIST (iRESIST), best overall response (BOR), duration of response (DOR), disease control rate, CR rate, and progression-free survival (PFS) based
  • biomarkers that may correlate with mechanism of action, increased understanding of disease/target, observed toxicity, and potential anti-tumor activity including, but not limited, to:
  • an additional treatment arm may be opened to receive ubamatamab 250 mg IV Q3W + cemiplimab 250 mg or 350 mg IV Q3W, in parallel with the monotherapy cohort.
  • all arms will include weekly step-up dosing of ubamatamab prior to Q3W dosing.
  • Cohorts will use a Simon 2-stage study design, with an interim analysis after the first 20 patients. Any treatment arm with >3 objective responses will be expanded to 50 patients.
  • the primary endpoint will be the objective response rate for each arm (RECIST v1 .1 ). Secondary endpoints include evaluation of duration of response and progression-free survival, safety, PK, and change from baseline in quality of life and physical functioning. Exploratory endpoints include evaluation of baseline tumor MUC16 IHC expression and other biomarkers as predictors of response.
  • cycle 1 In the randomized phase 2 cohort, cycle 1 will be approximately 42-49 days in all arms, depending on when patients tolerate the full dose of REGN4018 without CRS. Subsequent cycles in all cohorts will be approximately 6 weeks (42 days). Treatment will continue until either disease progression, intolerable adverse events, withdrawal of consent, or other treatment withdrawal criterion is met. Post-treatment follow-up for patients who do not withdraw consent will be either approximately 90 days or 168 days, depending on the reason for treatment cessation. [0131] Study Population: Up to approximately 100 patients with advanced endometrial cancer will be enrolled. The initial cohort will evaluate REGN4018 250 mg IV every 3 weeks after initial step-up dosing. Treatment will be identical to Arm 1 of the randomized phase 2 cohort.
  • the cohort will hollow a Simon 2 stage design.
  • stage 1 20 patients will be enrolled.
  • the enrollment of an additional 30 patients in stage 2 will occur only if there are 3 or more with inconfirmed PR or better by RECIST 1 .1 in Simon stage 1 .
  • This study will enroll patients with recurrent or progressive endometrial cancer that has progressed or recurred after prior anti-PD- 1 therapy and platinum-based chemotherapy is added.
  • Expansion cohorts only: Must have progression on prior therapy documented radiographically and must have at least 1 measurable lesion (not previously irradiated) that can be accurately measured by Response Evaluation Criteria in Solid Tumors (RECIST).
  • Treatment-related immune-mediated AEs from immune-modulatory agents including but not limited to anti-PD- 1 /PD-L1 or anti-CTLA-4 monoclonal antibodies or PI3Kdelta inhibitors) that have not resolved to baseline at least 30 days prior to initiation of treatment with study therapy.
  • Endocrine immune-mediated AEs controlled with hormonal or other nonimmunosuppressive therapies (without resolution) or grade 1 imAEs affecting any organ system with resolution prior to enrollment are allowed.
  • Another malignancy that is progressing or requires active treatment with the exception of non-melanoma skin cancer that has undergone potentially curative therapy or in situ cervical carcinoma, or any other tumor that has been deemed to be effectively treated with definitive local control (with or without continued adjuvant hormonal therapy) for at least 2 years prior to enrollment.
  • the ECG can be repeated up to 2 times. If subsequent QTc interval is ⁇ 470 msec, the patient may be enrolled but only after review and approval by a cardiologist.
  • LVEF Left ventricular ejection fraction less than 50% as measured by echocardiogram at baseline. In cases of LVEF 45-50% in absence of clinical symptoms, after review and clearance by cardiologist, the patient may be enrolled. History of clinically significant cardiac disease including but not limited to the following, within 6 months prior to screening:
  • - Heart failure (NYHA class III and IV or ACC/AHA heart failure classification C or D) History of any clinically significant arrhythmia including paroxysmal atrial fibrillation requiring intervention at any time or implantation of a pacemaker or defibrillator. Any history of myocarditis. Signs or symptoms of active angina, arrhythmia or heart failure. Any moderate to severe valve abnormality (stenosis or regurgitation) and/or clinically significant valvular heart disease that has not already been managed surgically. Moderate to large pericardial effusion (e.g., > approximately 100 mL) as measured by echocardiogram at baseline. Patients requiring 2 or more therapeutic paracenteses in the month before screening. Baseline serum troponin above institutional upper limit of normal.
  • the patient may be enrolled.
  • the following are not exclusionary: vitiligo, childhood asthma that has resolved, hypothyroidism that required only hormone replacement, type 1 diabetes or psoriasis that does not require systemic treatment.
  • Known history of, or any evidence of interstitial lung disease, or active, non-infectious pneumonitis (past 5 years).
  • Moderate to large pleural effusion that may require thoracentesis within the next 4 weeks due to size or rate of enlargement.
  • Pre-existing chest tube is acceptable, if patient meets all other inclusion/exclusion criteria.
  • HepBsAg+ hepatitis B surface antigen positive
  • HBsAg negative but total HBV core antibody positive
  • HBc Ab+ HBV core antibody positive
  • Active infection requiring systemic therapy including: a. Infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of start of study therapy b. Known active tuberculosis or history of incompletely treated active or latent tuberculosis. Acceptable treatments for latent tuberculosis would be 9 months of isoniazid 300 mg by mouth daily or equivalent proven regimen per local guidelines. c.
  • MUC16 expression was evaluated by immunohistochemistry (IHC) using (Abnova Clone X325) in clinically annotated hysterectomy specimens from patients with endometrial cancer. Assessment included apical and a combination of membrane and cytoplasmic expression. MUC16 expression was quantified by total protein score (TPS, number of MUC16+ cancer cells) and H-score that incorporates staining intensity. Clinical annotation included available demographics, highest serum CA125, next generation sequencing (NGS), p53 IHC and histology. Clinical correlations used Kruskal-Wallis, Spearman, and Wilcoxon tests.
  • Heterogeneous MUC16 expression was observed in mixed histology cases, especially carcinosarcoma, where MUC16 generally stained the epithelial component. No difference in MUC16 H-score by p53 IHC status was observed.
  • 106 patients with available CA125 48% had elevation >70 u/mL; 25% had CA125 > 500 u/mL. In this study, CA125 did not correlate with MUC16 H-score.
  • MUC16 is broadly expressed in high-grade endometrial cancer.

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Abstract

La présente divulgation concerne des méthodes de traitement, de réduction de la gravité, ou d'inhibition de la croissance du cancer de l'endomètre. Les méthodes selon la présente divulgation consistent à administrer, à un patient qui en a besoin, une quantité thérapeutiquement efficace d'un anticorps bispécifique qui se lie spécifiquement au mucine 16 (MUC16) et au CD3, seul ou en association avec une quantité thérapeutiquement efficace d'un anticorps ou de son fragment de liaison à l'antigène qui se lie spécifiquement au récepteur de mort programmée 1 (PD-1).
PCT/US2024/059495 2023-12-12 2024-12-11 Méthodes de traitement du cancer de l'endomètre avec des anticorps anti-cd3 x anti-muc16 bispécifiques seuls ou en association avec des anticorps anti-pd-1 Pending WO2025128652A1 (fr)

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