Methods, therapies and uses for treating cancer

Abstract

To provide a pharmaceutical composition for treating BCMA-expressing cancer.SOLUTION: Provided is a medicament comprising a first therapeutic agent and a second therapeutic agent for use in treating cancer and / or a cancer-related disease in a subject. In some aspects, the first therapeutic agent is a B-cell maturation antigen (BCMA) - specific therapeutic agent. In some aspects, the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-Ll antibody, an immunomodulator, or a gamma secretase inhibitor (GSI).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to both single agent and combination therapies useful for treating cancer and / or cancer-related diseases. In particular, the present invention relates to single agent and combination therapies comprising BCMAxCD3 bispecific antibodies. [Background technology]

[0002] B-cell maturation antigen (BCMA, CD269, or TNFRSF17) is a member of the tumor necrosis factor receptor (TNFR) superfamily. BCMA was identified in aggressive human T-cell lymphomas containing the t(4;16) translocation. This gene is selectively expressed in the B-cell lineage, with highest expression in antibody-secreting plasmablasts and plasma cells. BCMA binds two ligands, B-cell-activating factor (BAFF) (also known as B-lymphocyte stimulator (BLyS) and APOL-related leukocyte-expressed ligand (TALL-1)), and proliferation-inducing ligand (APRIL), with affinities of 1 μM and 16 nM, respectively. Binding of APRIL or BAFF to BCMA promotes a signaling cascade involving NF-kappaB, Elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, resulting in signals for cell survival and proliferation. BCMA is also expressed in malignant B cells and several cancers involving B lymphocytes, including multiple myeloma, plasmacytoma, Hodgkin's lymphoma, and chronic lymphocytic leukemia. In autoimmune diseases involving plasmablasts, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, BCMA-expressing antibody-producing cells secrete autoantibodies that attack the self. BCMA is also found in a soluble form (i.e., soluble BCMA or sBCMA) in the peripheral blood of multiple myeloma patients, which can lead to the failure of BCMA-specific therapies. Although several BCMA-specific therapies are currently in development, multiple myeloma remains an intractable disease, with almost all patients developing resistance to these agents and ultimately relapsing.

[0003] The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively) play essential roles in immune regulation. PD-1, expressed on activated T cells, is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, initiating T cell death and local immunosuppression (Dong et al., Nat Med 1999;5:1365-69; Freeman et al., J Exp Med 2000;192:1027-34), potentially providing an immune-tolerant environment for tumor development and growth. Conversely, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity in nonclinical animal models (Iwai Y et al., Proc Natl Acad Sci USA 2002;99:12293-97). Several antibodies that block the interaction of PD-1 with one or both of its ligands, PD-L1 and PD-L2, are currently in development for the treatment of cancer.

[0004] The Notch pathway is a conserved signaling pathway that contributes to cell fate determination, proliferation, angiogenesis, and apoptosis. A unique feature of the Notch pathway is that both the ligands (Jagged-1, 2 and Delta-1, 3, 4) and receptors (Notch-1, 2, 3, 4) are type I membrane proteins. After direct cell-cell contact, the Notch receptor is cleaved by γ-secretase to release the intracellular domain (NICD), which translocates into the nucleus and modulates transcription. γ-secretase inhibitors (GSIs) have been developed for several diseases, such as Alzheimer's disease and cancer. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for improved therapies for the treatment of cancer and / or cancer-related diseases, such as multiple myeloma. Furthermore, there is a need for therapies that are more effective than existing therapies. Preferred combination therapies of the present invention exhibit greater efficacy than treatment with either therapeutic agent alone. [Means for solving the problem]

[0006] The present invention relates to a therapy, including a combination therapy, for the treatment of cancer and / or cancer-related diseases. A method for treating cancer and / or cancer-related diseases in a subject is provided herein. Also provided is a method for inhibiting tumor growth or progression in a subject having malignant cells. Also provided is a method for inhibiting metastasis of malignant cells in a subject. Also provided is a method for inducing tumor regression in a subject having malignant cells.

[0007] Disclosed herein is a method for treating cancer and / or cancer-related diseases in a subject, comprising administering a combination therapy comprising a first therapeutic agent and a second therapeutic agent to the subject.The present invention disclosed herein is further directed to a medicament comprising a first therapeutic agent and a second therapeutic agent for use in treating cancer and / or cancer-related diseases in a subject.The present invention is further directed to a first therapeutic agent for use in treating cancer and / or cancer-related diseases in a subject, wherein the first therapeutic agent is administered in combination with the second therapeutic agent.

[0008] In some embodiments, the first therapeutic agent is a B-cell maturation antigen (BCMA)-specific therapeutic agent. In some embodiments, the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulatory agent, or a gamma secretase inhibitor (GSI).

[0009] In some embodiments, the first therapeutic agent is a BCMA bispecific antibody. In some embodiments, the second therapeutic agent is an anti-PD-1 antibody. In other embodiments, the second therapeutic agent is an anti-PD-L1 antibody. In other embodiments, the second therapeutic agent is an immunomodulatory agent. In other embodiments, the second therapeutic agent is a GSI.

[0010] In some embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an anti-PD-1 antibody. In other embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an anti-PD-L1 antibody. In other embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an immunomodulatory agent. In other embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is a GSI.

[0011] In some embodiments, the combination therapy further comprises a third, fourth, or fifth therapeutic agent. In some embodiments, the combination therapy further comprises a chemotherapeutic agent. In some embodiments, the therapeutic agents are administered to the subject simultaneously, separately, or sequentially.

[0012] In some embodiments, the BCMA bispecific antibody is PF-06863135, the anti-PD-1 antibody is sasanlimab, the immunomodulatory agent is lenalidomide or pomalidomide, and / or the GSI is nirogacestat or a pharmaceutically acceptable salt thereof. In one embodiment, the BCMA bispecific antibody is PF-06863135. In one embodiment, the anti-PD-1 antibody is sasanlimab. In one embodiment, the immunomodulatory agent is lenalidomide. In another embodiment, the immunomodulatory agent is pomalidomide. In one embodiment, the GSI is nirogacestat or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, at least one of the therapeutic agents is administered to the subject in an intravenous (IV), subcutaneous (SC) or oral dose.

[0014] In some embodiments, at least one of the therapeutic agents is administered at a dose of about 0.01 μg / kg, 0.02 μg / kg, 0.03 μg / kg, 0.04 μg / kg, 0.05 μg / kg, 0.06 μg / kg, 0.07 μg / kg, 0.08 μg / kg, 0.09 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.3 μg / kg, 0.4 μg / kg, 0.5 μg / kg, 0.6 μg / kg, 0.7 μg / kg, 0.8 μg / kg, 0.9 μg / kg, 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, The subject is administered a dose of 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 110 μg / kg, 120 μg / kg, 130 μg / kg, 140 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1200 μg / kg, or 1400 μg / kg or higher.

[0015] In some embodiments, at least one of the therapeutic agents is administered to a subject at a dose of about 1 mg / kg to about 1000 mg / kg, about 2 mg / kg to about 900 mg / kg, about 3 mg / kg to about 800 mg / kg, about 4 mg / kg to about 700 mg / kg, about 5 mg / kg to about 600 mg / kg, about 6 mg / kg to about 550 mg / kg, about 7 mg / kg to about 500 mg / kg, about 8 mg / kg to about 450 mg / kg, about 9 mg / kg to about 400 mg / kg, about 5 mg / kg to about 200 mg / kg, about 2 mg / kg to about 150 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 60 mg / kg.

[0016] In some embodiments, at least one of the therapeutic agents is administered at a dose of about 0.05 μg, 0.2 μg, 0.5 μg, 1 μg, 10 μg, 100 μg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, The subject is administered a fixed dose of 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 350 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, or 1500 mg or higher.

[0017] In some embodiments, at least one of the therapeutic agents is administered to a subject at least once daily, once daily, twice daily, three times daily, four times daily, once every two days, once every three days, once weekly, once every two weeks, once every three weeks, once every four weeks, once every 30 days, once every five weeks, once every six weeks, once monthly, once every two months, once every three months, or once every four months.

[0018] In some embodiments, the cancer and / or cancer-related disease is a B-cell-associated cancer and / or cancer-related disease. In some embodiments, the B-cell-associated cancer and / or cancer-related disease is multiple myeloma, malignant plasma cell neoplasms, lymphoma, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Kahler's disease and myelomatosis, plasma cell leukemia, bone and extramedullary plasmacytoma associated with multiple myeloma, solid bone and extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis, osteosclerotic myeloma, B-cell prolymphocytic leukemia, and leukemia. Hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenström's macroglobulienemia, diffuse large B-cell lymphoma, mucosal lymphoma Lymphoid tissue lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell / histiocytocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (lower limb type), EBV-positive diffuse large cell lymphoma in the elderly The cancer is selected from B-cell lymphoma, inflammation-associated diffuse large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma resulting in HHV8-associated multicentric Castleman disease, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell-related lymphomas. In some embodiments, the B-cell-related cancer is multiple myeloma. In some embodiments, the multiple myeloma is relapsed / refractory multiple myeloma.

[0019] Also provided herein are methods of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a B-cell maturation antigen (BCMA) bispecific antibody, and the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulatory agent, or a gamma secretase inhibitor (GSI). Also provided herein are first therapeutic agents for use in methods of treating multiple myeloma in a subject, wherein the first therapeutic agent is a B-cell maturation antigen (BCMA) bispecific antibody and is administered in combination with a second therapeutic agent selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulatory agent, or a gamma secretase inhibitor (GSI). In some embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an anti-PD-1 antibody. In other embodiments, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an anti-PD-L1 antibody. In another embodiment, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is an immunomodulatory agent. In another embodiment, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is a GSI.

[0020] Also provided is a method of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is sasanlimab.

[0021] Also provided is a method of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is lenalidomide.

[0022] Also provided is a method of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is pomalidomide.

[0023] Also provided is a method of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is nirogacestat.

[0024] Also provided is a method of treating cancer in a subject, comprising administering PF-06863135 to the subject according to a dosing regimen.

[0025] In some embodiments, the dosing regimen is as follows: (a) 0.1, 0.3, 1, 3, 10, 30, 50, or 100 μg / kg weekly (Q1W) intravenously (IV); (b) 0.1, 0.3, 1, 3, 10, 30, 50, or 100 μg / kg IV once every 2 weeks (Q2W); (c) approximately 0.5 to 10 mg Q1W IV or Q2W IV; (d) about 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5, or 8 mg Q1W IV or Q2W IV; (e) a treatment dosing of about 0.5, 1, 2, 3, 4, 5, 6, 7.5, or 8 mg Q1W IV for one week followed by a first treatment dosing of about 6, 7, 7.5, 8, 9, or 10 mg Q1W IV or Q2W IV, wherein the priming dose is less than a single dose during the treatment dosing; or (f) Treatment dosing of about 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5, or 8 mg Q1W single priming dose for 1 week, followed by a first treatment dose of about 6, 7, 7.5, 8, 9, or 10 mg Q1W IV for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 6, 7, 7.5, 8, 9, or 10 mg Q2W IV, wherein the priming dose is less than a single dose during the first treatment dose.

[0026] In another embodiment of the invention, the dosing regimen is as follows: (a) 80, 130, 215, 360, 600, or 1000 μg / kg Q1W subcutaneously (SC); (b) 80, 130, 215, 360, 600, or 1000 μg / kg Q2W SC; (c) approximately 16 to 80 mg Q1W SC or Q2W SC; (d) approximately 16-20, 40-44, or 76-80 mg Q1W SC; (e) approximately 16-20, 40-44, or 76-80 mg Q2W SC; (f) approximately 40 mg Q1W SC or Q2W SC; (g) approximately 44 mg of Q1W SC or Q2W SC, (h) approximately 76 mg Q1W SC or Q2W SC; (i) approximately 80 mg Q1W SC or Q2W SC, (j) a priming dose of about 44 mg Q1W SC for 1 to 4 weeks, or a priming dose of about 32 mg Q1W SC for 1 to 4 weeks, followed by a first treatment dose of about 76 mg Q1W SC or Q2W SC; (k) a priming dose of about 40 mg Q1W SC for 1 to 4 weeks, followed by a first treatment dose of about 80 mg Q1W SC or Q2W SC; (l) a priming dose of about 44 mg Q1W SC for 1 to 4 weeks, or a priming dose of about 32 mg Q1W SC for 1 to 4 weeks, followed by a first treatment dose of about 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 76 mg Q2W SC; (m) a priming dose of about 40 mg Q1W SC for 1 to 4 weeks, followed by a first treatment dose of about 80 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 80 mg Q2W SC; (n) a priming dose of about 44 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC or Q2W SC; (o) a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC or Q2W SC; (p) a priming dose of about 40 mg Q1W SC for 1 week, followed by a first treatment dose of about 80 mg Q1W SC or Q2W SC; (q) a priming dose of about 44 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 76 mg Q2W SC; (r) a priming dose of about 44 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC for 23 weeks, followed by a second treatment dose of about 76 mg Q2W SC; (s) a priming dose of about 44 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC for 24 weeks, followed by a second treatment dose of about 76 mg Q2W SC (t) a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 76 mg Q2W SC; (u) a priming dose of about 40 mg Q1W SC for 1 week, followed by a first treatment dose of about 80 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, followed by a second treatment dose of about 80 mg Q2W SC; or (v) A priming dose of about 40 mg Q1W SC for 1 week, followed by a first treatment dose of about 80 mg Q1W SC for 23 or 24 weeks, followed by a second treatment dose of about 80 mg Q2W SC.

[0027] In some embodiments, the priming dosage is a single priming dose of 44 mg Q1W SC, 40 mg Q1W SC, or 32 mg Q1W SC administered for one week.

[0028] Also provided are methods of treating cancer in a subject comprising administering to the subject (a) a single priming dose of about 32 mg SC or about 44 mg SC in week 1, or both a first priming dose of about 12 mg SC and a second priming dose of about 32 mg SC in week 1, and (b) a first treatment dose of about 76 mg Q1W SC starting in week 2, wherein week 1, week 2, and any subsequent weeks refer to the first, second, and any subsequent weeks of administering PF06863135 to the subject, and wherein PF6863135 is administered to the subject as a pharmaceutical product comprising PF06863135.

[0029] In some embodiments, subjects are administered a single priming dose of about 44 mg SC of PF06863135 in week 1. In some embodiments, subjects are administered a first priming dose of about 12 mg SC on day 1 of week 1, and a second priming dose of about 32 mg SC on day 4 of week 1.

[0030] In some embodiments, the method further comprises administering to the subject PF06863135 at a second treatment dose of about 76 mg Q2W SC starting at week 25 or week 1 of cycle 7, wherein PF06863135 at the first treatment dose is administered until the end of week 24 or the end of cycle 6, wherein a cycle is 28 days, and cycle 1, cycle 2, and subsequent cycle numbers refer to the first, second, and subsequent cycle numbers in which the subject is administered PF06863135.

[0031] In some embodiments, a subject is administered PF06863135 at a first treatment dose of about 76 mg Q1W SC, and after receiving such first treatment dose for at least 23 weeks, the subject is administered PF06863135 at a second treatment dose of 76 mg Q2W, or continues to receive PF06863135 at the first treatment dose. In some embodiments, after receiving the first treatment dose for at least 23 weeks, the subject is administered PF06863135 at the second treatment dose, according to the drug product's respective regulatory labeling or according to the subject's response. In some embodiments, the subject continues to receive PF06863135 in the first treatment dose after receiving the first treatment dose for at least 23 weeks, each cycle being 28 days, and the first cycle beginning on the day the subject receives the single priming dose or first priming dose of PF06863135, unless the subject demonstrates an IMWG response of partial response or better after receiving at least six cycles of treatment and the response is sustained for at least 1 month, at least 2 months, at least 3 months, at least 1 cycle, at least 2 cycles, or at least 3 cycles.

[0032] Also provided are methods of treating cancer in a subject, comprising administering to a subject a dosing regimen of: (a) a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q1W SC; (b) a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q2W SC; (c) a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, and a second treatment dose of about 44 mg Q2W SC; or (d) A priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q1W SC for 23 or 24 weeks, and a second treatment dose of about 44 mg Q2W SC. Also provided are methods comprising administering PF-06863135 to a subject according to

[0033] In some embodiments, the subject is administered PF-06863135 with a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q1W SC. In some embodiments, the subject is administered PF-06863135 with a priming dose of about 32 mg Q1W SC for 1 week, followed by a first treatment dose of about 44 mg Q1W SC for 23 or 24 weeks, followed by a second treatment dose of about 44 mg Q2W SC.

[0034] Also provided is a method of treating cancer in a subject, comprising administering PF-06863135 subcutaneously to the subject a first treatment dose for 23, 24, or 25 weeks, followed by a second treatment dose.

[0035] In some embodiments, the first treatment dose is about 4 mg Q1W and the second treatment dose is about 4 mg Q1W or about 4 mg Q2W. In some embodiments, the first treatment dose is about 12 mg Q1W and the second treatment dose is about 12 mg Q1W or about 12 mg Q2W. In some embodiments, the first treatment dose is about 24 mg Q1W and the second treatment dose is about 24 mg Q1W or about 24 mg Q2W. In some embodiments, the first treatment dose is about 32 mg Q1W and the second treatment dose is about 32 mg Q1W or about 32 mg Q2W. In some embodiments, the first treatment dose is about 44 mg Q1W and the second treatment dose is about 44 mg Q1W or about 44 mg Q2W. In some embodiments, the first treatment dose is about 76 mg Q1W and the second treatment dose is about 76 mg Q1W or about 76 mg Q2W. In some embodiments, the first treatment dose is about 4 mg Q1W and the second treatment dose is about 4 mg Q2W. In some embodiments, the first treatment dose is about 12 mg Q1W and the second treatment dose is about 12 mg Q2W. In some embodiments, the first treatment dose is about 24 mg Q1W and the second treatment dose is about 24 mg Q2W. In some embodiments, the first treatment dose is about 32 mg Q1W and the second treatment dose is about 32 mg Q2W. In some embodiments, the first treatment dose is about 44 mg Q1W and the second treatment dose is about 44 mg Q2W. In some embodiments, the first treatment dose is about 76 mg Q1W and the second treatment dose is about 76 mg Q2W.

[0036] In some embodiments, when the dose of the first treatment dosage is 32 mg or more, the method further comprises administering PF06863135 to the subject in a priming dosage, administering the priming dosage for one week, and administering the first dose of the first treatment dosage in the week immediately following the week in which the priming dosage is administered. In some embodiments, the priming dosage is a single priming dose, and the single priming dose is about 24 mg. In some embodiments, the priming dosage comprises a first priming dose of about 4 mg and a second priming dose of about 20 mg, wherein the two priming doses are administered on two different days, and the first priming dose is administered before the second priming dose. In some embodiments, the priming dosage comprises a first priming dose of about 8 mg and a second priming dose of about 16 mg, wherein the two priming doses are administered on two different days, and the first priming dose is administered before the second priming dose. In some embodiments, the priming dose comprises a first priming dose of about 12 mg and a second priming dose of about 12 mg, the two priming doses being administered on two different days, with the first priming dose being administered before the second priming dose. In some embodiments, the priming dose comprises a first priming dose of about 8 mg and a second priming dose of about 24 mg, the two priming doses being administered on two different days, with the first priming dose being administered before the second priming dose. In some embodiments, the priming dose comprises a first priming dose of about 4 mg and a second priming dose of about 28 mg, the two priming doses being administered on two different days, with the first priming dose being administered before the second priming dose.

[0037] In some embodiments, a subject is administered a second treatment dose of PF06863135 for 6 to 18 cycles, each cycle lasting 21 or 28 days, after which the subject is subcutaneously administered a third treatment dose of PF06863135. In some embodiments, the third treatment dose is about 4 mg Q2W or about 4 mg Q4W. In some embodiments, the third treatment dose is about 12 mg Q2W or about 12 mg Q4W. In some embodiments, the third treatment dose is about 24 mg Q2W or about 24 mg Q4W. In some embodiments, the third treatment dose is about 32 mg Q2W or about 32 mg Q4W. In some embodiments, the third treatment dose is about 44 mg Q2W or about 44 mg Q4W. In some embodiments, the third treatment dose is about 76 mg Q2W or about 76 mg Q4W.

[0038] In some embodiments, the first treatment dose is about 4 mg Q1W, the second treatment dose is about 4 mg Q2W, and the third treatment dose is about 4 mg Q4W. In some embodiments, the first treatment dose is about 12 mg Q1W, the second treatment dose is about 12 mg Q2W, and the third treatment dose is about 12 mg Q4W. In some embodiments, the first treatment dose is about 24 mg Q1W, the second treatment dose is about 24 mg Q2W, and the third treatment dose is about 32 mg Q4W. In some embodiments, the first treatment dose is about 32 mg Q1W, the second treatment dose is about 32 mg Q2W, and the third treatment dose is about 24 mg Q4W. In some embodiments, the first treatment dose is about 44 mg Q1W, the second treatment dose is about 44 mg Q2W, and the third treatment dose is about 44 mg Q4W. In some embodiments, the first treatment dose is about 76 mg Q1W, the second treatment dose is about 76 mg Q2W, and the third treatment dose is about 76 mg Q4W.

[0039] Also provided are methods of treating cancer in a subject, comprising: (a) a first treatment dose of about 32 mg to about 76 mg Q1W SC starting at week 1; or (b) a priming dose during week 1 and a first treatment dose beginning in week 2, the priming doses being (i) a first priming dose of about 4 mg SC to about 32 mg SC and a second priming dose of about 12 mg SC to about 44 mg SC, the first and second priming doses being administered consecutively in week 1, or (ii) a single priming dose of about 24 mg to about 44 mg SC, the first treatment dose being about 32 mg to about 76 mg Q1W SC or about 32 mg to about 152 mg Q2W SC beginning in week 2, the dose of the first treatment dose being higher than each of the single priming dose, the first priming dose, and the second priming dose. administering PF-06863135 to a subject, Also provided are methods wherein week 1, week 2, and any subsequent weeks refer respectively to the first, second, and any subsequent weeks during which PF06863135 is administered to the subject, and wherein PF06863135 is administered to the subject as a pharmaceutical product comprising PF06863135.

[0040] In some embodiments, a subject is administered a single priming dose of about 24 mg SC, about 32 mg SC, or about 44 mg SC in week 1. In some embodiments, a subject is administered a first priming dose of about 12 mg SC and a second priming dose of about 32 mg SC in week 1. In some embodiments, a subject is administered a single priming dose of about 4 mg, about 8 mg, about 12 mg, or about 24 mg during week 1. In some embodiments, a subject is administered a first priming dose and a second priming dose. In some embodiments, the first priming dose is about 4 mg and the second priming dose is about 20 mg. In some embodiments, the first priming dose is about 8 mg and the second priming dose is about 16 mg. In some embodiments, the first priming dose is about 12 mg and the second priming dose is about 12 mg. In some embodiments, the first priming dose is about 8 mg and the second priming dose is about 24 mg.

[0041] In some embodiments, the first treatment dose is about 32 mg Q1W SC or about 32 mg Q2W SC. In some embodiments, the first treatment dose is about 44 mg Q1W SC or about 44 mg Q2W SC. In some embodiments, the subject is administered the first treatment dose until at least the end of cycle 1 or at least the end of cycle 6, where a cycle is 21 days or 28 days, where cycle 1 begins on week 1, day 1 of week 2, or day 1 of week 3, and cycle 1, cycle 2, and subsequent cycles refer to the first, second, and subsequent cycles, respectively, in which the subject is administered PF06863135.

[0042] In some embodiments, the method further includes administering to the subject a second treatment dosage of PF06863135 of about 32 mg to about 152 mg Q2W SC, about 32 mg to about 152 mg Q3W SC, or about 32 mg to about 152 mg Q4W SC after the subject has already received the first treatment dosage, wherein the second treatment dosage is of a dosing frequency that is less frequent than the respective first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage. In some embodiments, after the first treatment dosage has been administered to the subject through at least the end of cycle 6, a second treatment dosage of PF06863135 may be administered to the subject in place of the first treatment dosage, or the subject may continue to be administered the first treatment dosage, wherein the second treatment dosage is about 32 mg to about 152 mg Q2W SC, about 32 mg to about 152 mg Q3W SC, or about 32 mg to about 152 mg Q4W SC, and wherein the second treatment dosage is of an administration frequency that is less frequent than the first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage. In some embodiments, (i) the first treatment dose is about 32 mg Q1W SC and the second treatment dose is about 32 mg Q2W SC, 32 mg Q3W SC, 32 mg Q4W SC, 44 mg Q2W SC, 44 mg Q3W SC, 44 mg Q4W SC, 76 mg Q3W SC, 76 mg Q4W SC, 116 mg Q4W SC, or 152 mg Q4W SC, or (ii) the first treatment dose is about 32 mg Q2W SC and the second treatment dose is about 32 mg Q3W SC, 32 mg Q4W SC, 44 mg Q3W SC, 44 mg Q4W SC, 76 mg Q3W SC, 76 mg Q4W SC, 116 mg Q4W SC, or 152 mg Q4W SC.In some embodiments, (i) the first treatment dose is about 44 mg Q1W SC and the second treatment dose is about 44 mg Q2W SC, 44 mg Q3W SC, 44 mg Q4W SC, 76 mg Q2W SC, 76 mg Q3W SC, 76 mg Q4W SC, 116 mg Q4W SC, or about 152 mg Q4W SC, or (ii) the first treatment dose is about 44 mg Q2W SC and the second treatment dose is about 32 mg Q2W SC, 44 mg Q3W SC, 76 mg Q3W SC, 116 mg Q3W SC, 152 mg Q3W SC, 32 mg Q4W SC, 44 mg Q4W SC, 76 mg Q4W SC, 116 mg Q4W SC, or about 152 mg Q4W SC. In some embodiments, the second treatment medication is administered to the subject according to the regulatory label of each drug.In some embodiments, the second treatment medication is administered to the subject according to the subject's response to the first treatment medication.In some embodiments, the first treatment medication is continued to be administered to the subject unless the subject demonstrates an IMWG response of at least partial response during the time the subject is receiving the first treatment medication, and the response is sustained for at least 1 month, at least 2 months, at least 3 months, at least 1 cycle, at least 2 cycles, or at least 3 cycles.

[0043] In some embodiments, the first treatment dose is (i) about 76 mg SC Q1W, (ii) about 76 mg SC Q2W, or (iii) about 76 mg SC Q1W for 3 weeks followed by about 116 mg SC Q1W, or (iv) about 76 mg SC Q1W for 3 weeks followed by about 152 mg SC Q1W. In some embodiments, the subject is administered the first treatment dose until at least the end of cycle 1, at least the end of cycle 3, or at least the end of cycle 6, where a cycle is 21 days or 28 days, and cycle 1 begins on week 1, week 2, day 1, or week 3, day 1, and cycle 1, cycle 2, and subsequent cycles refer to the first, second, and subsequent cycles, respectively, in which the subject is administered PF06863135. In some embodiments, the method further includes administering to the subject a second treatment dosage of about 44 mg to about 152 mg Q2W SC, about 44 mg to about 152 mg Q3W SC, or about 44 mg to about 152 mg Q4W SC after the subject has already received the first treatment dosage, wherein the second treatment dosage is of a dosing frequency that is less frequent than the first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage. In some embodiments, after a first treatment dosage has been administered to a subject through at least the end of cycle 6, a second treatment dosage of about 44 mg to about 152 mg Q2W SC, about 44 mg to about 152 mg Q3W SC, or about 44 mg to about 152 mg Q4W SC is administered to the subject in place of the first treatment dosage, or the subject may continue to be administered the first treatment dosage, wherein the second treatment dosage is of an administration frequency that is less frequent than the respective first treatment dosage, or the second treatment dosage has a lower dose than that of the first treatment dosage. In some embodiments, the first treatment dose is about 76 mg Q1W SC and the second treatment dose is about 44 mg Q2W SC, about 76 mg Q2W SC, about 116 mg Q2W SC, about 152 mg Q2W SC, about 44 mg Q3W SC, about 76 mg Q3W SC, about 116 mg Q3W SC, about 152 mg Q3W SC, about 44 mg Q4W SC, about 76 mg Q4W SC, about 116 mg Q4W SC or about 152 mg Q4W SC.In some embodiments, the first treatment dose is about 76 mg Q2W SC, and the second treatment dose is about 44 mg Q2W SC, about 44 mg Q3W SC, about 76 mg Q3W SC, about 116 mg Q3W SC, about 152 mg Q3W SC, about 44 mg Q4W SC, about 76 mg Q4W SC, about 116 mg Q4W SC, or about 152 mg Q4W SC. In some embodiments, the first treatment dose is about 76 mg Q1W, and the second treatment dose is about 76 mg Q2W. In some embodiments, the first treatment dose is about 76 mg Q2W, and the second treatment dose is about 76 mg Q4W. In some embodiments, the second treatment dose is administered to the subject in accordance with the regulatory labeling of the respective pharmaceutical product. In some embodiments, the second treatment dose is administered to the subject according to the subject's response to the first treatment dose. In some embodiments, if, while the subject is receiving the first treatment dose, the subject demonstrates an IMWG response of at least partial response, and the response is sustained for at least 1 month, at least 2 months, at least 3 months, at least 1 cycle, at least 2 cycles, or at least 3 cycles, then the subject is administered a second treatment dose.

[0044] In some embodiments, a subject is administered PF06863135 at a first treatment dose until the end of cycle 1, followed by a second treatment dose, where a cycle is 21 days or 28 days, and cycle 1 begins on week 1, day 1, week 2, or day 1, or week 3, and cycle 1, cycle 2, and subsequent cycle numbers refer to the first, second, and subsequent cycles that the subject is administered PF06863135, respectively. In some embodiments, the second treatment dose is administered until at least the end of cycle 6, after which a third treatment dose of about 76 mg to about 152 mg Q3W SC or about 76 mg to about 152 mg Q4W SC is administered to the subject in place of the second treatment dose, or the subject continues to be administered the second treatment dose. In some embodiments, the second treatment dosage is administered until at least the end of cycle 6, followed by a third treatment dosage of about 76 mg to about 152 mg Q3W SC or about 76 mg to about 152 mg Q4W SC. In some embodiments, the second treatment dosage is administered until the end of cycle 6, and the first dose of the third treatment dosage begins in cycle 7, with the third treatment dosage being 116 mg Q4W SC or 152 mg Q4W SC. In some embodiments, after receiving the second treatment dosage through at least cycle 6, the subject is administered PF06863135 in the third treatment dosage, according to the drug's respective regulatory labeling or according to the subject's response. In some embodiments, the subject continues to receive PF06863135 in the second treatment dose through at least cycle 6, unless, while the subject is receiving the second treatment dose, the subject demonstrates an IMWG response of at least partial response and the response is sustained for at least 1 month, at least 2 months, at least 3 months, at least 1 cycle, at least 2 cycles, or at least 3 cycles. In some embodiments, the first treatment dose is about 76 mg SC Q1W, the second treatment dose is about 116 mg SC Q2W, and the third treatment dose is about 116 mg SC Q4W. In some embodiments, the first treatment dose is about 76 mg SC Q1W, the second treatment dose is about 152 mg SC Q2W, and the third treatment dose is about 152 mg SC Q4W.

[0045] In some embodiments, the method comprises administering to the subject a first treatment dosage of about 32 mg Q1W for 23, 24, or 25 weeks, followed by a second treatment dosage of about 32 mg Q1W or about 32 mg Q2W for 6 to 18 cycles, followed by a third treatment dosage of about 32 mg Q2W or about 32 mg Q4W, wherein one cycle is 21 or 28 days. In some embodiments, the second treatment dosage is about 32 mg Q2W and the third treatment dosage is about 32 mg Q4W.

[0046] In some embodiments, the method comprises administering to the subject a first treatment dosage of about 44 mg Q1W for 23, 24, or 25 weeks, followed by a second treatment dosage of about 44 mg Q1W or about 44 mg Q2W for 6 to 18 cycles, followed by a third treatment dosage of about 44 mg Q2W or about 44 mg Q4W, wherein one cycle is 21 or 28 days. In some embodiments, the second treatment dosage is about 44 mg Q2W and the third treatment dosage is about 44 mg Q4W.

[0047] In some embodiments, the method comprises administering to the subject a first treatment dosage of about 76 mg Q1W for 23, 24, or 25 weeks, followed by a second treatment dosage of about 76 mg Q1W or about 76 mg Q2W for 6 to 18 cycles, followed by a third treatment dosage of about 76 mg Q2W or about 76 mg Q4W, wherein one cycle is 21 or 28 days. In some embodiments, the second treatment dosage is about 76 mg Q2W and the third treatment dosage is about 76 mg Q4W.

[0048] In some embodiments, the method comprises administering to the subject a first treatment dosage of about 116 mg Q1W for 23, 24, or 25 weeks, followed by a second treatment dosage of about 116 mg Q1W or about 116 mg Q2W for 6 to 18 cycles, followed by a third treatment dosage of about 116 mg Q2W or about 116 mg Q4W, wherein one cycle is 21 or 28 days. In some embodiments, the second treatment dosage is about 116 mg Q2W and the third treatment dosage is about 116 mg Q4W.

[0049] In some embodiments, the method comprises administering to the subject a first treatment dosage of about 152 mg Q1W for 23, 24, or 25 weeks, followed by a second treatment dosage of about 152 mg Q1W or about 152 mg Q2W for 6 to 18 cycles, followed by a third treatment dosage of about 152 mg Q2W or about 152 mg Q4W, wherein one cycle is 21 or 28 days. In some embodiments, the second treatment dosage is about 152 mg Q2W and the third treatment dosage is about 152 mg Q4W.

[0050] In some embodiments, a cycle is 21 days if the subject is receiving PF06863135 at a Q1W or Q3W dosing frequency, and 28 days if the subject is receiving PF06863135 at a Q2W or Q4W dosing frequency. In some embodiments, a cycle is 28 days unless the patient is receiving PF06863135 at a Q3W dosing frequency. In some embodiments, a cycle is 21 days from cycle 1 through the end of the last cycle in which the subject is receiving their first treatment medication.

[0051] Also provided is a method of treating cancer, comprising administering erlanatamab (PF06863135) to a subject according to the dosing schedule set forth below, where the dosing schedule is described by the number of weeks, the dose, and the frequency of administration corresponding to each week. (a)

[0052] [Table 1]

[0053] , (b)

[0054] [Table 2]

[0055] , (c)

[0056] [Table 3]

[0057] , (d)

[0058] [Table 4]

[0059] , (e)

[0060] [Table 5]

[0061] or (f)

[0062] [Table 6]

[0063] In the table, if the dose is 12mg+32mg during week 1, a 12mg dose is administered on one day followed by a 32mg dose on another day, A+B is 4(A)+20(B), 8(A)+16(B), 12(A)+12(B), or 8(A)+24(B), and if the dose is Amg+Bmg during week 1, a Amg dose is administered on one day followed by a Bmg dose on another day.

[0064] In some embodiments, a subject is administered erlanatamab (PF06863135) according to the dosing schedule set forth below.

[0065] (a)

[0066] [Table 7]

[0067] , (b)

[0068] [Table 8]

[0069] , (c)

[0070] [Table 9]

[0071] , (d)

[0072] [Table 10]

[0073] , (e)

[0074] [Table 11]

[0075] or (f)

[0076] [Table 12]

[0077] In some embodiments, the subject is administered PF06863135 according to dosing schedule (a), (b), or (c), wherein the dosing frequency for dosing schedules (a), (b), and (c), from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) weekly, (ii) every 2 weeks, (iii) every 3 weeks, (iv) every 4 weeks, (v) every or every 2 weeks, (vi) every or every 3 weeks, or (vii) every or every 4 weeks. In some embodiments, the subject is administered PF06863135 according to dosing schedule (d), (e), or (f), wherein the dosing frequency for dosing schedules (d), (e), and (f), from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) every 2 weeks, (ii) every 3 weeks, (iii) every 4 weeks, (iv) every 2 or every 3 weeks, or (v) every 2 or every 4 weeks.

[0078] In some embodiments, a subject is administered erlanatamab (PF06863135) according to the dosing schedule set forth below.

[0079] (a)

[0080] [Table 13]

[0081] , (b)

[0082] [Table 14]

[0083] , (c)

[0084] [Table 15]

[0085] , (d)

[0086] [Table 16]

[0087] , (e)

[0088] [Table 17]

[0089] or (f)

[0090] [Table 18]

[0091] In some embodiments, the subject is administered 12 mg of erlanatamab on day 1 of week 1, followed by 32 mg of erlanatamab on day 4 of week 1. In some embodiments, the subject is administered PF06863135 according to dosing schedule (a), (b), or (c), wherein the dosing frequency for dosing schedules (a), (b), and (c), respectively, from week 25 onwards, week 26 onwards, and week 27 onwards, is (i) weekly, (ii) every 2 weeks, (iii) every 3 weeks, (iv) every 4 weeks, (v) every week or every 2 weeks, (vi) every week or every 3 weeks, or (vii) every week or every 4 weeks. In some embodiments, the subject is administered PF06863135 according to dosing schedule (d), (e), or (f), wherein the dosing frequency for dosing schedules (d), (e), and (f) from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) every 2 weeks, (ii) every 3 weeks, (iii) every 4 weeks, (iv) every 2 weeks or every 3 weeks, or (v) every 2 weeks or every 4 weeks.

[0092] In some embodiments, a subject is administered erlanatamab (PF06863135) according to the dosing schedule set forth below.

[0093] (a)

[0094] [Table 19]

[0095] , (b)

[0096] [Table 20]

[0097] , (c)

[0098] [Table 21]

[0099] , (d)

[0100] [Table 22]

[0101] , (e)

[0102] [Table 23]

[0103] or (f)

[0104] [Table 24]

[0105] In some embodiments, the subject is administered a single dose of 32 mg of erlanatamab during week 1. In some embodiments, the subject is administered 12 mg of erlanatamab on day 1 of week 1, followed by 32 mg of erlanatamab on day 4 of week 1. In some embodiments, the subject is administered PF06863135 according to dosing schedule (a), (b), or (c), wherein the dosing frequency for dosing schedules (a), (b), and (c), respectively, from week 25 onwards, week 26 onwards, and week 27 onwards is (i) weekly, (ii) every 2 weeks, (iii) every 3 weeks, (iv) every 4 weeks, (v) every week or every 2 weeks, (vi) every week or every 3 weeks, or (vii) every week or every 4 weeks. In some embodiments, the subject is administered PF06863135 according to dosing schedule (d), (e), or (f), wherein the dosing frequency for dosing schedules (d), (e), and (f) from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) every 2 weeks, (ii) every 3 weeks, (iii) every 4 weeks, (iv) every 2 weeks or every 3 weeks, or (v) every 2 weeks or every 4 weeks.

[0106] In some embodiments, the dose and administration frequency during week 1 are collectively referred to as the priming dose; if a subject is administered only one dose of erlanatamab in the priming dose, such one dose is referred to as the single priming dose; if a subject is administered two doses of erlanatamab sequentially during week 1, the two doses are referred to as the first priming dose and the second priming dose, respectively; the dose and administration frequency during weeks 2-24, weeks 2-25, and weeks 2-26, respectively, in each of dosing schedules (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as the first treatment dose, and the dose and administration frequency during and after week 25, after week 26, and after week 27 in each of dosing schedules (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as the second treatment dose, respectively.

[0107] In some embodiments, the subject is administered a second treatment dose of PF06863135 for 6 to 18 cycles, after which the subject is administered a third treatment dose of PF06863135 subcutaneously, where the third treatment dose is 32 mg Q2W, 32 mg Q4W, 44 mg Q2W, 44 mg Q4W, 76 mg Q2W, 76 mg Q4W, 116 mg Q2W, 116 mg Q4W, 152 mg Q2W, or 152 mg Q4W, wherein one cycle is 21 days or 28 days, and cycle 1 starts on week 1 day 1, week 2 day 1, or week 3 day 1.

[0108] In some embodiments, the first treatment dose is 32 mg Q1W, the second treatment dose is 32 mg Q1W or 32 mg Q2W, and the third treatment dose is 32 mg Q2W or 32 mg Q4W. In some embodiments, the first treatment dose is 32 mg Q1W, the second treatment dose is 32 mg Q2W, and the third treatment dose is 32 mg Q4W. In some embodiments, the first treatment dose is 44 mg Q1W, the second treatment dose is 44 mg Q1W or 44 mg Q2W, and the third treatment dose is 44 mg Q2W or 44 mg Q4W. In some embodiments, the first treatment dose is 44 mg Q1W, the second treatment dose is 44 mg Q2W, and the third treatment dose is 44 mg Q4W. In some embodiments, the first treatment dose is 76 mg Q1W, the second treatment dose is 76 mg Q1W or 76 mg Q2W, and the third treatment dose is 76 mg Q2W or 76 mg Q4W. In some embodiments, the first treatment dose is 76 mg Q1W, the second treatment dose is 76 mg Q2W, and the third treatment dose is 76 mg Q4W. In some embodiments, the first treatment dose is 116 mg Q1W, the second treatment dose is 116 mg Q1W or 116 mg Q2W, and the third treatment dose is 116 mg Q2W or 116 mg Q4W. In some embodiments, the first treatment dose is 116 mg Q1W, the second treatment dose is 116 mg Q2W, and the third treatment dose is 116 mg Q4W. In some embodiments, the first treatment dose is 152 mg Q1W, the second treatment dose is 152 mg Q1W or 32 mg Q2W, and the third treatment dose is 152 mg Q2W or 152 mg Q4W.

[0109] Also provided is a method of treating cancer, comprising administering erlanatamab (PF06863135) to a subject according to the dosing schedule set forth below, where the dosing schedule is described by the number of weeks, the dose, and the frequency of administration corresponding to each week.

[0110] [Table 25]

[0111] In the table, if the dose is 12mg+32mg during week 1, a 12mg dose is administered on one day followed by a 32mg dose on another day, and A+B is 4(A)+20(B), 8(A)+16(B), 12(A)+12(B), or 8(A)+24(B), where an Amg dose is administered on one day followed by a Bmg dose on another day.

[0112] In some embodiments, a subject receives 12 mg of erlanatamab on day 1 of week 1, followed by 32 mg of erlanatamab on day 4 of week 1.

[0113] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0114] [Table 26]

[0115] In some embodiments, for dosing frequency during week 25 and thereafter, the dosing frequency is every 4 weeks.

[0116] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0117] [Table 27]

[0118] In some embodiments, the dosing frequency is every 4 weeks through week 25 onwards.

[0119] In some embodiments, the dose and administration frequency during week 1 are collectively referred to as the priming dose; if a subject is administered only one dose of erlanatamab in the priming dose, such one dose is referred to as a single priming dose; if a subject is administered two doses of erlanatamab sequentially during week 1, the two doses are referred to as the first priming dose and the second priming dose, respectively; the dose and administration frequency during weeks 2-4 are collectively referred to as the first treatment dose; the dose and administration frequency during weeks 5-24 are collectively referred to as the second treatment dose; and the dose and administration frequency during week 25 and thereafter are collectively referred to as the third treatment dose.

[0120] Also provided is a method of treating cancer, comprising administering erlanatamab (PF06863135) to a subject according to the dosing schedule set forth below, where the dosing schedule is described by the number of weeks, the dose, and the frequency of administration corresponding to each week.

[0121] [Table 28]

[0122] In the table, where the dose is 12 mg + 32 mg during week 1, a 12 mg dose is administered on one day, followed by a 32 mg dose on another day, and A + B is 4(A) + 20(B), 8(A) + 16(B), 12(A) + 12(B), or 8(A) + 24(B), where an A mg dose is administered on one day, followed by a B mg dose on another day. In some embodiments, a subject receives 12 mg of erlanatamab on day 1 of week 1, followed by 32 mg of erlanatamab on day 4 of week 1.

[0123] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0124] [Table 29]

[0125] In some embodiments, the dosing frequency is every two weeks during weeks 13 through 24. In some embodiments, the dosing frequency is every four weeks during week 25 and thereafter.

[0126] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0127] [Table 30]

[0128] In some embodiments, the dosing frequency is every two weeks during weeks 13 through 24. In some embodiments, the dosing frequency is every four weeks during week 25 and thereafter.

[0129] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0130] [Table 31]

[0131] In some embodiments, the dosing frequency is every two weeks during weeks 13-24. In some embodiments, the dosing frequency is every four weeks during week 25 and thereafter. In some embodiments, the dosing frequency is every two weeks during weeks 13-24, and every two weeks or every four weeks during week 25 and thereafter.

[0132] In some embodiments, a subject is administered erlanatamab according to the following dosing schedule:

[0133] [Table 32]

[0134] In some embodiments, the dosing frequency is every two weeks during weeks 13 through 24. In some embodiments, the dosing frequency is every four weeks during week 25 and thereafter.

[0135] In some embodiments, the dose and administration frequency during week 1 are collectively referred to as the priming dose; if a subject is administered only one dose of erlanatamab in the priming dose, such one dose is referred to as a single priming dose; if a subject is administered two doses of erlanatamab sequentially during week 1, the two doses are referred to as the first priming dose and the second priming dose, respectively; the dose and administration frequency during weeks 2-4 and the dose and administration frequency during weeks 5-12 are all collectively referred to as the first treatment dose; the dose and administration frequency during weeks 13-24 are collectively referred to as the second treatment dose; and the dose and administration frequency during weeks 25 and beyond are collectively referred to as the third treatment dose.

[0136] The present invention is further directed to erlanatamab (PF-06853135) for use in a method of treating cancer using the dosing regimen defined herein.

[0137] In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is progressive multiple myeloma. In some embodiments, the cancer is relapsed or refractory multiple myeloma.

[0138] In some embodiments, the cancer is triple-class refractory multiple myeloma. In some embodiments, the subject's multiple myeloma is refractory to all three of the following multiple myeloma treatments: (1) a prior multiple myeloma treatment comprising a proteasome inhibitor, (2) a prior multiple myeloma treatment comprising an immunomodulatory agent, and (3) a prior multiple myeloma treatment comprising an anti-CD38 antibody.

[0139] In some embodiments, the cancer is double-class refractory multiple myeloma. In some embodiments, the subject's multiple myeloma is refractory to at least two of the following three types of multiple myeloma treatments: (1) a prior multiple myeloma treatment comprising a proteasome inhibitor, (2) a prior multiple myeloma treatment comprising an immunomodulatory agent, and (3) a prior multiple myeloma treatment comprising an anti-CD38 antibody.

[0140] In some embodiments, the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma and the subject has undergone a stem cell transplant. In some embodiments, the subject has undergone an autologous stem cell transplant. In some embodiments, the subject has undergone an autologous or allogeneic stem cell transplant. In some embodiments, the subject is minimal residual disease positive after a stem cell transplant.

[0141] In some embodiments, the cancer is multiple myeloma, and in some embodiments, the subject is progressive or intolerant to established multiple myeloma therapy. In some embodiments, the established multiple myeloma therapy comprises at least one drug selected from the group consisting of a proteasome inhibitor, an IMid drug, and an anti-CD38 antibody.

[0142] In some embodiments, the cancer is multiple myeloma, the subject has received at least four prior therapies, the subject's multiple myeloma has been refractory or relapsed to (1) a prior multiple myeloma treatment comprising a proteasome inhibitor, (2) a prior multiple myeloma treatment comprising an immunomodulatory agent, and (3) a prior multiple myeloma treatment comprising an anti-CD38 monoclonal antibody, and the subject has demonstrated disease progression on the last treatment. In one aspect of these embodiments, the subject has received prior treatment with a BCMA-targeted ADC or a BCMA-targeted CAR-T. In another aspect of these embodiments, the subject has not received any prior treatment with a BCMA-targeted ADC or a BCMA-targeted CAR-T.

[0143] In some embodiments, the cancer is multiple myeloma, and the subject has received at least one, at least two, at least three, or at least four prior multiple myeloma treatments, wherein the subject's multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma treatment comprising a proteasome inhibitor, (2) a prior multiple myeloma treatment comprising an immunomodulatory agent, and (3) a prior multiple myeloma treatment comprising an anti-CD38 antibody, and the subject has documented disease progression on the last multiple myeloma treatment. In one aspect of this embodiment, the subject has received at least three prior multiple myeloma treatments. In another aspect of this embodiment, the subject has received at least four prior multiple myeloma treatments.

[0144] In some embodiments, the subject's prior multiple myeloma therapy includes a BCMA-directed ADC therapy or a BCMA-directed CAR-T cell therapy. In some embodiments, the subject's prior multiple myeloma therapy includes a BCMA-directed therapy.

[0145] In some embodiments, the subject's prior multiple myeloma therapy does not include a BCMA-directed ADC therapy or a BCMA-directed CAR-T cell therapy. In some embodiments, the subject's prior multiple myeloma therapy does not include a BCMA-directed therapy.

[0146] In some embodiments, the cancer is multiple myeloma, the subject has received at least one or at least two prior multiple myeloma treatments, and the subject's multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma treatment that includes a proteasome inhibitor and (2) a prior multiple myeloma treatment that includes an immunomodulatory agent. In some embodiments, the subject has demonstrated disease progression on their last multiple myeloma treatment.

[0147] In some embodiments, the cancer is multiple myeloma and the subject has not received any prior multiple myeloma treatment. In some embodiments, the subject has not received any prior multiple myeloma treatment after diagnosis of multiple myeloma. In some embodiments, the subject is stem cell transplant ineligible. In some embodiments, the cancer is multiple myeloma and the subject is stem cell transplant ineligible. In some embodiments, the subject is autologous stem cell transplant ineligible. In some embodiments, the subject is allogeneic stem cell transplant ineligible. In some embodiments, the subject is both autologous stem cell transplant ineligible and allogeneic stem cell transplant ineligible.

[0148] In some embodiments, (i) a cycle is 21 days if the subject is receiving PF06863135 at a weekly or every 3 weeks dosing frequency, and a cycle is 28 days if the subject is receiving PF06863135 at a biweekly or every 4 weeks dosing frequency, or (ii) a cycle is 28 days unless the patient is receiving PF06863135 at a every 3 weeks dosing frequency.

[0149] In some embodiments, the method further comprises administering sasanlimab to the subject.

[0150] In some embodiments, both PF-06863135 and sasanlimab are administered in 4-week treatment cycles for at least the first treatment cycle, and if a priming dose of PF-06863135 is administered, the first treatment cycle begins on day 7 after administration of the single priming dose or the final dose of the priming dose, and sasanlimab is administered at a dose of 300 mg Q4W SC.

[0151] In some embodiments, the first dose of sasanlimab is administered on day 1 of the first treatment cycle. In some embodiments, the first dose of PF-06863135 in a treatment cycle is administered on day 1 of the treatment cycle.

[0152] In some embodiments, Week 1 and Cycle 1 begin on the day the subject is administered a single priming dose or first priming dose, or if the subject does not receive a priming dose or doses of PF06863135, Week 1 and Cycle 1 begin on the day the subject is administered a first dose of the first treatment dose of PF06863135, a cycle lasts 28 days, and sasanlimab is administered at a dose of 300 mg Q4W SC. In some embodiments, the subject receives at least one priming dose of PF6863135, and sasanlimab is administered to the subject on day 8 of each cycle.

[0153] In some embodiments, the method further comprises administering lenalidomide to the subject.

[0154] In some embodiments, both PF-06863135 and lenalidomide are administered in 4-week treatment cycles for at least the first treatment cycle, where if a priming dose of PF-06863135 is administered, the first treatment cycle begins on day 7 after administration of the single priming dose or the final dose of the priming dose, and lenalidomide is administered at a daily oral dose of 25 mg on days 1-21 of each treatment cycle.

[0155] In some embodiments, lenalidomide is administered at a dose of 25 mg orally daily on days 1-21 of each treatment cycle without dexamethasone.

[0156] In some embodiments, the first dose of PF-06863135 in a treatment cycle is administered on day 1 of the treatment cycle.

[0157] In some embodiments, a priming dose of PF6863135 is administered, one cycle is 28 days, and lenalidomide is administered at a daily oral dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 25 mg on days 8-28 or 15-28 of the first cycle and days 1-28 of the second and third cycles, and then, starting in the fourth cycle, lenalidomide is administered on days 1-28 of each cycle at a daily oral dose about 5-10 mg higher than that administered during the third cycle, or continues to be administered at the same daily oral dose as in the third cycle.

[0158] In some embodiments, a priming dose of PF06863135 is administered and lenalidomide is administered at a daily oral dose of about 10 mg, or about 15 mg, for at least 10 consecutive days in each cycle, starting on day 8 of cycle 1.

[0159] In some embodiments, no priming dose of PF06863135 is administered and lenalidomide is administered at a daily oral dose of about 10 mg, about 15 mg, about 20 mg, or about 25 mg for at least 10, at least 14, or at least 21 consecutive days in each cycle.

[0160] In some embodiments, the subject is administered PF06863135 in an induction phase followed by a maintenance phase, wherein the induction phase begins on the day the first dose of a priming dose of PF06863135 is administered, or if a priming dose of PF06863135 is not administered, the induction phase begins on the day the first dose of a first treatment dose of PF06863135 is administered, and if the subject is receiving a first treatment dose, the induction phase ends on the last day of the last week or the last day of the last cycle, whichever is later; During the induction phase, lenalidomide is administered at a daily oral dose of about 5 mg to about 25 mg for at least 10 consecutive days during each cycle of the induction phase, and during the maintenance phase, PF06863135 is administered at the second treatment dose and lenalidomide is administered at a daily oral dose of about 5 mg to about 25 mg for at least 10 consecutive days during one cycle, each cycle being 21 or 28 days, and the induction phase lasting 1 to 10 cycles. In some embodiments, the method further includes administering dexamethasone to the subject during the induction phase at a daily oral dose of about 10 mg to about 40 mg for at least days 1 and 8 of the first cycle of the induction phase.

[0161] In some embodiments, each cycle in the induction phase is 21 or 28 days long, with cycle 1 starting on day 1 of week 3, and lenalidomide induction phase dosing is about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 25 mg administered orally daily on days 1-14 or days 1-21 of each cycle in the induction phase; dexamethasone, if administered, is administered at a daily dose of about 20 mg on days 1, 8, and 15 of cycles 1 and 2 of the induction phase; each cycle in the maintenance phase is 28 days long, and maintenance lenalidomide dosing is about 5 mg, about 10 mg, or about 15 mg administered orally daily on days 1-28 of each cycle in the maintenance phase. In some embodiments, the induction phase ends after 24-26 weeks. In some embodiments, the induction phase ends after 12-14 weeks.

[0162] In some embodiments, the method further includes administering pomalidomide to the subject. In some embodiments, both PF06863135 and pomalidomide are administered in a 4-week treatment cycle, for at least the first treatment cycle, wherein a priming dose of PF-06863135 is administered, the first treatment cycle beginning 7 days after the administration of the single priming dose or the final dose of the priming dose, and pomalidomide is administered at a dose of 4 mg daily orally on days 1-21 of each treatment cycle. In some embodiments, pomalidomide is administered at a dose of 4 mg daily, 3 mg daily, 2 mg daily, or 1 mg daily orally on days 1-21 of each treatment cycle, without dexamethasone. In some embodiments, the first dose of PF-06863135 in a treatment cycle is administered on day 1 of the treatment cycle.

[0163] In some embodiments, the method further includes administering daratumumab to the subject. In some embodiments, the daratumumab is administered subcutaneously weekly, every two weeks, every three weeks, or every four weeks at a daratumumab dosing of about 1800 mg. In some embodiments, the daratumumab dosing begins with about 1800 mg weekly for about eight doses during cycle 1, followed by about 1800 mg every two weeks for about eight to about ten doses, and then about 1800 mg every four weeks thereafter.

[0164] In some embodiments, the method further includes administering isatuximab to the subject. In some embodiments, the isatuximab is administered Q1W IV, Q2W IV, Q3W IV, or Q4W IV at an isatuximab dose of about 5 mg to about 10 mg / kg. In some embodiments, the isatuximab dose administered to the subject can be the same or different while the subject is receiving a priming dose, a first treatment dose, a second treatment dose, or a third treatment dose of PF06863135.

[0165] In some embodiments, the method further includes administering at least one premedication dose to the subject on the day the single priming dose, first priming dose, second priming dose, or first treatment dose of PF06863135 is administered to the subject, where the premedication is acetaminophen, diphenhydramine, or dexamethasone. In some embodiments, the dexamethasone is administered orally or intravenously daily at a dose of about 10 mg to about 40 mg of dexamethasone. In some embodiments, the dexamethasone is administered orally or intravenously daily at a dose of about 10 mg to about 40 mg of dexamethasone on the day the subject is administered at least the first treatment dose of PF06863135. In some embodiments, the dexamethasone dose administered to the subject as a premedication can be the same or different while the subject is receiving the priming dose, the first treatment dose, the second treatment dose, or the third treatment dose of PF06863135.

[0166] In some embodiments, the method further comprises administering a second therapeutic agent to the subject. In some embodiments, the second therapeutic agent is an anticancer agent. In some embodiments, the second therapeutic agent is a GSI. In some embodiments, the second therapeutic agent is nirogacestat or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the method further comprises administering radiation therapy to the subject.

[0168] In aspects and / or embodiments which refer to a method of treatment described herein, such aspects and / or embodiments are also further aspects and / or embodiments which relate to the use of the defined therapeutic agent or agents for use in the manufacture of a therapeutic agent or agents for use in the method of treatment, or a medicament or medicaments for use in the treatment. [Brief explanation of the drawings]

[0169] [Figure 1]FIG. 1 depicts the induction of PD-1 expression on CD8+ T cells following treatment with BCMAxCD3 bispecific antibody. [Figure 2] Figures 2A and 2B depict the therapeutic activity of BCMAxCD3 bispecific antibodies in combination with anti-PD1 antibodies in A) the orthotopic MM.1S-Luc-PDL1 multiple myeloma model and B) the subcutaneous MM.1S-PD-L1 multiple myeloma model. [Figure 3-1] [Figure 3-2] Figures 3A-3E depict the upregulation of BCMA expression on the cell surface of multiple myeloma cells following treatment with GSI. [Figure 4-1] [Figure 4-2] Figures 4A-4E depict the upregulation of BCMA expression on the cell surface of multiple myeloma cells in a time-dependent manner following treatment with GSI. [Figure 5-1] [Figure 5-2] Figures 5A-5E depict the reduced release of soluble BCMA (sBCMA) in multiple myeloma cell lines following treatment with GSI. [Figure 6-1] [Figure 6-2] 6A-6E depict that treatment with GSI improves BCMAxCD3 bispecific antibody-mediated cell killing in multiple myeloma cell lines. [Figure 7] 7A-7B depict A) upregulation of BCMA expression on the cell surface of Raji lymphoma cells following treatment with GSI and B) the upregulation is in a time-dependent manner. [Figure 8] FIG. 8 depicts that treatment with GSI improves BCMAxCD3 bispecific antibody-mediated cell killing in lymphoma cell lines. DETAILED DESCRIPTION OF THE INVENTION

[0170] This application relates to the treatment of cancer and / or cancer-related diseases. Certain embodiments relate to the treatment of an individual with cancer or a cancer-related disease by administering to the individual a combination therapy of a first therapeutic agent that is a BCMAxCD3 bispecific antibody and a second therapeutic agent that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or a gamma-secretase inhibitor (GSI), or a pharmaceutically acceptable salt thereof.

[0171] I. Definition In order that the present invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0172] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0173] "About," when used to modify a parameter defined as a number (e.g., the dose of a BCMAxCD3 bispecific antibody or the length of treatment time with a combination therapy described herein), means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg.

[0174] An "antibody" is an immunoglobulin molecule capable of specifically binding to a target, e.g., a carbohydrate, polynucleotide, lipid, polypeptide, etc., via at least one antigen recognition site located within the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), single-chain (ScFv) and domain antibodies (including, e.g., shark and camelid antibodies), and fusion proteins comprising antibodies, as well as any other modified configuration of an immunoglobulin molecule containing an antigen recognition site. Antibodies include any class of antibody, e.g., IgG, IgA, or IgM (or subclass thereof), and antibodies need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, several of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[0175] As used herein, the term "antigen-binding fragment" or "antigen-binding portion" of an antibody refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen. The antigen-binding function of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab; Fab'; F(ab')2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single-domain antibody (dAb) fragment (Ward et al., Nature 341:544-546, 1989), and isolated complementarity-determining regions (CDRs).

[0176] A "bispecific antibody" or "diabody" is a hybrid antibody having two different antigen-binding sites that bind to two different epitopes, which may be present on the same or different protein targets.

[0177] A "B cell maturation antigen bispecific antibody" or "BCMA bispecific antibody" is a bispecific antibody that specifically binds to BCMA and another antigen.

[0178] A "heterodimer," "heterodimeric protein," "heterodimeric complex," or "heteromultimeric polypeptide" is a molecule comprising a first polypeptide and a second polypeptide, where the second polypeptide differs in amino acid sequence from the first polypeptide by at least one amino acid residue.

[0179] An antibody, bispecific antibody, or polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to a target (e.g., a BCMA protein) is a term well understood in the art, and methods for determining such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a particular cell or substance more frequently, rapidly, for a longer duration, and / or with greater affinity than it reacts or associates with alternative cells or substances. An antibody or bispecific antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, more readily, and / or with a longer duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a BCMA epitope is an antibody that binds to this epitope with greater affinity, avidity, more readily, and / or with a longer duration than it binds to other BCMA epitopes or BCMA epitopes. For example, it is understood by reading this definition that an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

[0180] The "variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. As known in the art, the variable regions of heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs, and CDRs from other chains contribute to the formation of the antigen-binding site of antibodies. There are at least two techniques for determining CDRs: (1) methods based on interspecies sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed., 1991, National Institutes of Health, Bethesda, MD)); and (2) methods based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948). As used herein, CDRs may refer to CDRs defined by either method or a combination of both methods.

[0181] The "CDRs" of a variable domain are the amino acid residues within the variable region identified according to the Kabat, Chothia, both Kabat and Chothia pool, AbM, contact, and / or conformation definitions, or any method of CDR determination known in the art. Antibody CDRs can be identified as hypervariable regions as originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington, DC. CDR locations can also be identified as structural loop structures originally described by Chothia et al. See, e.g., Chothia et al., Nature 342:877-883, 1989. Other approaches to CDR identification include the "AbM definition," a compromise between Kabat and Chothia, derived using Oxford Molecular's AbM antibody modeling software (now Accelrys®), or the "contact definition" of CDRs based on observed antigen contacts, as described in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to herein as the "conformational definition" of CDRs, CDR positions can be identified as residues that make an enthalpic contribution to antigen binding. See, e.g., Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still other CDR boundary definitions do not strictly follow one of the above methods, but nevertheless, they may be shortened or lengthened in light of predictions or experimental findings that certain residues or groups of residues, or even the entire CDR, do not significantly affect antigen binding, but will overlap with at least a portion of Kabat CDR.As used herein, CDR may refer to CDRs defined by any method known in the art, including a combination of methods.The method used herein can utilize CDRs defined according to any of these methods.For any given embodiment containing more than one CDR, the CDRs may be defined according to any of the Kabat, Chothia, extended, AbM, contact, and / or conformation definitions.

[0182] "Isolated antibody" and "isolated antibody fragment" refer to a purified state, and in such context, mean that the named molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials, such as cellular debris and growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such materials or the absence of water, buffers, or salts, unless they are present in amounts that would substantially interfere with experimental or therapeutic uses of the binding compounds described herein.

[0183] As used herein, "monoclonal antibody" or "mAb" or "Mab" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for any naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a large number of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0184] "Chimeric antibody" refers to antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as the fragment exhibits the desired biological activity.

[0185] A "human antibody" refers to an antibody that contains only human immunoglobulin protein sequences. A human antibody may contain mouse carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only mouse or rat immunoglobulin sequences, respectively.

[0186] "Humanized antibody" refers to forms of antibodies that contain sequences derived from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulins. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are from human immunoglobulin sequences. A humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefixes "hum," "hu," or "h" are optionally added to antibody clone names to distinguish humanized antibodies from the parent rodent antibody. Humanized forms of rodent antibodies generally contain the same CDR sequences as the parent rodent antibody but can contain certain amino acid substitutions to increase affinity, increase the stability of the humanized antibody, or for other reasons.

[0187] The terms "cancer," "cancerous," or "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. "Cancer" or "cancerous tissue" may include tumors. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, myeloma, blastoma, and sarcoma. Cancers include, but are not limited to, multiple myeloma, malignant plasma cell neoplasms, lymphoma, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Kahler's disease and myelomatosis, plasma cell leukemia, bone and extramedullary plasmacytoma with multiple myeloma, solid bone and extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light-chain amyloidosis, osteosclerosing myeloma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenström's macroglobulinemia, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, small cell lymphocytic lymphoma , primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell / histiocytocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma with inflammation, ALK-positive large B-cell lymphoma The cancers and / or cancer-related diseases may include B-cell-related cancers and / or cancer-related diseases, including B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease, unclassified B-cell lymphoma intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell-related lymphomas.Examples of cancer and cancer-related diseases are further described herein.

[0188] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer and / or cancer-related diseases. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogesterone agents, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth. Chemotherapeutic agents are further described herein.

[0189] As used herein, "chemotherapy" refers to a chemotherapeutic agent as defined above, or a combination of two, three, or four chemotherapeutic agents for the treatment of cancer and / or cancer-related diseases. When chemotherapy consists of more than one chemotherapeutic agent, the chemotherapeutic agents can be administered to a patient on the same day or on different days during the same treatment cycle.

[0190] As used throughout this specification and claims, the terms "consists essentially of" and variations such as "consist essentially of" or "consisting essentially of" refer to the inclusion of any recited element or elements, and the optional inclusion of other elements of a similar or different nature other than the recited elements, that do not materially alter the basic or novel characteristics of a particular dosage regimen, method, or composition.

[0191] "Multiple myeloma therapy" refers to a drug, or a combination of two or more drugs, that (1) has been approved by the United States Food and Drug Administration (USFDA) or the European Medicines Agency for the treatment of multiple myeloma, or (2) is or has been in clinical trials in the United States or Europe for the treatment of multiple myeloma.

[0192] "Established multiple myeloma therapy" refers to a multiple myeloma therapy approved by the USFDA or the European Medicines Agency, which may be a single drug, a combination therapy of two or more drugs.

[0193] As used herein, "IMiD drug," "imid drug," or "immunomodulatory agent" interchangeably refer to drugs understood by physicians treating multiple myeloma as IMiD drugs or immunomodulatory agents in the context of the treatment of multiple myeloma. Examples of IMiD drugs or immunomodulatory agents include, but are not limited to, thalidomide, lenalidomide, and pomalidomide.

[0194] "BCMA-directed ADC therapy" refers to a multiple myeloma therapy that includes an antibody-drug conjugate in which the antibody binds to the B-cell maturation antigen (BCMA). Examples of BCMA-directed ADCs include, but are not limited to, belantamab mafodotin-blmf, which has been approved by the USFDA and marketed under the trade name BLENREP.

[0195] As used herein, "BCMA-directed CAR-T cell therapy" or "anti-BCMA CAR-T cells" interchangeably refer to multiple myeloma therapy comprising chimeric antigen receptor T cells, in which the chimeric antigen receptor recognizes B-cell maturation antigen (BCMA). Examples of "BCMA-targeted CAR-T therapy" or "anti-BCMA CAR T cell therapy" include, but are not limited to, idecabutadiene bicelucel (ide-cel; or bb2121) and JNJ-4528, also known as LCAR-B38M.

[0196] "BCMA-directed therapy" refers to a multiple myeloma therapy whose active ingredient comprises a component that binds to a B-cell maturation antigen. BCMA-directed therapies include BCMA-directed ADC therapy, BCMA-directed CAR-T therapy, and multiple myeloma therapy comprising a BCMA bispecific antibody.

[0197] "Newly diagnosed multiple myeloma" refers to multiple myeloma in which the patient (subject) has not yet undergone any treatment for the diagnosis of multiple myeloma.

[0198] " Homology " refers to the sequence similarity between two polypeptide sequences when they are optimally aligned. If a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, for example, if a position in the light chain CDR of two different Abs is occupied by alanine, the two Abs are homologous at that position. The percentage of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 out of 10 positions in two sequences are identical or homologous when the sequences are optimally aligned, the two sequences are 80% homologous. Generally, the comparison is performed when the two sequences are aligned to obtain the maximum homology percentage. For example, the comparison can be performed by the BLAST algorithm, where the parameters of the algorithm are selected to obtain the maximum match between each sequence over the entire length of each reference sequence.

[0199] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410; Gish, W. et al. (1993) Nature Genet. 3:266-272; Madden, T. L. et al. (1996) Meth. Enzymol. 266:131-141; Altschul, S. F. et al. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al. (1997) Genome Res. 7:649-656; Wootton, J. C. et al. (1993) Comput. Chem. 17:149-163; Hancock, J. M. et al. (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO et al., "A model of evolutionary change in proteins." Atlas of Protein Sequence and Structure (1978) vol. 5, suppl. 3. MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM et al., "Matrices for detecting distant relationships.", Atlas of Protein Sequence and Structure Structure (1978) vol.5, suppl.3.MODayhoff (ed.), pp.353~358, Natl.Biomed.Res.Found., Washington, DC;Altschul,SF (1991)J.Mol.Biol.219:555~565;States, DJ et al. (1991)Methods 3:66~70;Henikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA 89:10915~10919;Altschul, SF et al. (1993) J.Mol.Evol.36:290~300;ALIGNMENT STATISTICS:Karlin, S. et al. (1990)Proc.Natl.Acad.Sci.USA 87:2264~2268; Karlin, S. et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873~5877; Dembo, A. et al. (1994) Ann. Prob. 22:2022~2039; and. Altschul, SF, "Evaluating the statistical significance of multiple distinct local alignments." Theoretical and Computational Methods in Genome Research (S. Suhai, ed.) (1997) pp. 1-14, Plenum, New York.

[0200] A "patient," "subject," or "individual" refers to any organism suffering from or prone to a condition that can be prevented or treated by administration of a therapeutic agent or composition or combination provided herein, such as cancer and / or a cancer-related disease, and includes both humans and animals. The terms "patient," "subject," and "individual" include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), preferably humans.

[0201] "Durable response" refers to a sustained therapeutic effect after cessation of treatment with a therapeutic agent or combination therapy described herein. In some embodiments, the durable response has a duration at least equal to the treatment period, or at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period.

[0202] As used herein, "administration" refers to the delivery of a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary administration routes include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, for example, by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than intestinal and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. Therapeutic agents can be administered parenterally or orally. Other parenteral routes include topical, epidermal, or mucosal administration routes, for example, intranasal, intravaginal, rectal, sublingual, or topical. Administration can be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0203] As used herein, "treating" or "treating" cancer and / or cancer-related diseases means administering a combination therapy according to the present invention to a subject, patient, or individual having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, a reduction in cancer cell count, a reduction in tumor size, a reduction in the rate of cancer cell invasion into peripheral organs, or a reduction in the rate of tumor metastasis or tumor growth, or reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition to which such term applies, or one or more symptoms of such a disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of treatment as "treating," as defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reduction (or destruction) of neoplastic or cancerous cell proliferation; inhibition of metastasis or neoplastic cells; reduction or decrease in tumor size; remission of cancer; reduction of symptoms resulting from cancer; increase in the quality of life of cancer sufferers; reduction in the dose of other drugs required to treat cancer; delay in cancer progression; cure of cancer; overcoming one or more resistance mechanisms of cancer; and / or prolongation of cancer patient survival.Positive therapeutic effects in cancer can be measured in several ways (see, for example, WA Weber, J.Nucl.Med.50:1S-10S(2009)).In some embodiments, the treatment achieved by the combination of the present invention is any of partial response (PR), complete response (CR), overall response (OR), objective response rate (ORR), progression-free survival (PFS), radiological PFS, disease-free survival (DFS) and overall survival (OS). PFS, also referred to as "time to tumor progression," refers to the length of time during and after treatment that cancer does not grow, including the amount of time that a patient experiences CR or PR, and the amount of time that a patient experiences stable disease (SD).DFS refers to the length of time that a patient remains disease-free during and after treatment.OS refers to the extension of life expectancy compared to naive or untreated subjects or patients.In some embodiments, the response to the combination of the present invention is any of PR, CR, PFS, DFS, ORR, OR, or OS, as assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response criteria (Eisenhauer et al., EA et al., Eur. J Cancer 45:228-247 (2009)). In some embodiments, anti-myeloma activity can be assessed by overall response rate (ORR), time to response (TTR), complete response rate (CRR), duration of response (DOR), duration of complete response (DoCR), duration of stable disease (DOSD), progression-free survival (PFS), and overall survival (OS), using the International Myeloma Working Group (IMWG) criteria. Treatment regimens for the combination therapies provided herein that are effective in treating cancer patients may vary depending on factors such as the patient's disease state, age, and weight, as well as the ability of the therapy to elicit an anti-cancer response in the subject. Any of the embodiments of the present invention may not be effective in achieving a positive treatment effect in all subjects, as determined by a number of tests, including but not limited to, Cox's log-rank test, Cochran-Mantel-Haenszel's log-rank test, Student's t-test, chi-square test, Mann and Whitney U test, Kruskal-Wallis test (H test), Jonckheere-Terpstrat test, and Wilcon's test. It should do so in a statistically significant number of subjects as determined by any statistical test known in the art, such as the .OMEGA. on test. The term "treatment" also encompasses in vitro and ex vivo treatments, e.g., of a cell, with a reagent, diagnostic compound, binding compound, or by another cell.

[0204] As used herein, "drug product" refers to a formulation that contains an active pharmaceutical ingredient and is regulated by the US FDA, EMA, or other corresponding regulatory authority in other markets. A drug product may be an investigational new drug or a formulation already approved by a regulatory authority.

[0205] The terms "treatment regimen," "dosing protocol," and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0206] As used herein, an "effective dosage" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to produce any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk of, reducing the severity of, or delaying the onset of, a disease, including the biochemical, histological, and / or behavioral manifestations of the disease, its complications, and intermediate pathological phenotypes present during the disease's development. For therapeutic use, beneficial or desired results include clinical results such as reducing or ameliorating the occurrence of one or more symptoms of various diseases or conditions (e.g., cancer), reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, and / or delaying the progression of the disease. An effective dosage can be administered in one or more administrations. For purposes of the present invention, an effective dosage of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0207] As used herein, "dosing" refers to both the "dosage" (e.g., 1 mg, 20 mg) and the "dosing frequency" (e.g., once daily (QD), once weekly (Q1W or QW), every two weeks (Q2W), every three weeks (Q3W), and every four weeks (Q4W). Dosing may also include the route of administration of the drug, e.g., subcutaneous (SC), intravenous (IV), oral (PO), etc., if so specified. Similarly, a "priming dose," a "first treatment dose," a "second treatment dose," etc., each refer to both the dosage and the dosing frequency of such a dose, including, where appropriate, the route of administration, if so specified. In some embodiments, there is one dose and one dosing frequency in a dosing. In some embodiments, there is more than one dose and / or more than one dosing frequency in a dosing.

[0208] As used herein, unless otherwise specified, a "dose level," when used to describe the administration of erlanatamab (also known as PF06863135), refers to one of the following doses: 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 44 mg, 76 mg, 116 mg, and 152 mg, respectively, where 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 44 mg, 76 mg, 116 mg, and 152 mg are each one dose level higher than 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 44 mg, 76 mg, and 116 mg, respectively.

[0209] As used herein, "a drug product's respective regulatory labeling" refers to a drug product's unexpired United States Package Insert (USPI) from the U.S. Food and Drug Administration (FDA), a drug product's unexpired Product Name Compendium (SMPC) from the European Medicines Agency (EMA), or similar labeling of a drug product from other regulatory authorities in other markets. In some embodiments, "a drug product's respective regulatory labeling" in a U.S. patent or patent application refers to a drug product's unexpired USPI, and in a patent or patent application in a European country that adopts an EMA manufacturing authorization for a drug product refers to a drug product's unexpired SMPC, and similarly in other jurisdictions.

[0210] As used herein, "subject response" refers to the clinical response of a subject treated with a pharmaceutical product containing erlanatamab (PF006863135), either as monotherapy or in combination with a second therapeutic product, to the underlying treatment. "Subject response" includes one or more aspects of clinical efficacy, such as complete response, partial response, and duration of response. "Subject response" may also include additional aspects, such as toxicity and adverse events.

[0211] As used herein, "IMWG response" refers to the clinical response of a patient (subject) to a pharmaceutical agent for treating multiple myeloma, where the response, such as a complete response or partial response, is defined according to the most recent definition from the International Myeloma Working Group.

[0212] As used herein, "cycle" and "week" refer to a duration when used in the context of describing a method for treating cancer, including its use, dosing, or dosing schedule. Unless otherwise specified, a cycle is 21 or 28 days when a subject is treated with a therapeutic agent, such as erlanatamab (PF06863135), or a drug thereof as monotherapy or in combination with a second therapeutic agent. Week 1 refers to the first week when a subject is treated under a method, or under either a drug or dosing schedule, unless otherwise specified. Week 2 begins immediately after the end of week 1, week 3 begins immediately after the end of week 2, etc. Unless otherwise specified, cycle 1 begins on the first day of week 1, week 2, or week 3. Unless otherwise stated, cycle 2 begins immediately after the end of cycle 1, cycle 3 begins immediately after the end of cycle 2, etc.

[0213] As used herein, "stem cell transplant ineligible" refers to a patient diagnosed with multiple myeloma who is ineligible for stem cell transplant as a treatment for multiple myeloma.

[0214] "Tumor," as applied to a subject diagnosed with or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, including primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the cell type that forms them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms). Multiple myeloma is a cancer of plasma cells.

[0215] "Tumor burden," also referred to as "tumor mass," refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells in the body, including lymph nodes and bone marrow, or the total size of the tumor. For example, tumor burden can be determined by various methods known in the art, such as by using calipers to measure the size of the tumor at the time of removal from the subject, or while in the body, using imaging techniques such as ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scan.

[0216] The term " tumor size " refers to the total size of tumor, which can be measured as the length and width of tumor.Tumor size can be determined by various methods known in the art, for example, by using calipers to measure the size of tumor when removed from subject, or while in the body, by using imaging techniques, such as bone scan, ultrasound, CT or MRI scan.

[0217] The term "immunotherapy" refers to the treatment of a subject by methods that involve inducing, enhancing, suppressing, or otherwise modifying the immune response.

[0218] As used herein, the term "immune effector cell" or "effector cell" refers to a cell within the natural repertoire of cells in the human immune system that can be activated to affect the viability of a target cell. Target cell viability may include the cell's ability to survive, proliferate, and / or interact with other cells.

[0219] A "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an ingredient that can be included in the compositions described herein and that does not cause significant adverse toxicological effects to a subject.

[0220] The terms "protein," "polypeptide," and "peptide" are used interchangeably herein to refer to any peptide-linked chain of amino acids, regardless of length, of co-translational or post-translational modifications.

[0221] As used herein, "substantially" or "essentially" means nearly all or completely, eg, 95% or more of a given amount.

[0222] The term "substantially homologous" or "substantially identical" means that a particular subject sequence, e.g., a mutant sequence, varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which is not to cause adverse functional dissimilarity between the reference sequence and the subject sequence. For purposes herein, sequences having greater than 95 percent homology (identity) to a given sequence, equivalent biological activity (not necessarily equivalent strength of biological activity), and equivalent expression characteristics are considered to be substantially homologous (identical). For purposes of determining homology, truncation of the mature sequence should be disregarded.

[0223] The term "synergy" or "synergistic" is used to mean that the result of the combination of two or more compounds, components, or targeted agents is greater than the sum of the individual agents. The term "synergy" or "synergistic" also means that the use of two or more compounds, components, or targeted agents results in an improvement in the disease state or disorder being treated compared to the use of each compound, component, or targeted agent individually. This improvement in the disease state or disorder being treated is a "synergistic effect." A "synergistic amount," as "synergistic" is defined herein, is the amount of a combination of two compounds, components, or targeted agents that results in a synergistic effect. The determination of the synergistic interaction between one or two components, the optimal range for that effect, and the absolute dosage range of each component for that effect can be clearly determined by administering the components to a patient in need of treatment over a range of w / w (weight per weight) ratios and doses. However, observations of synergy in in vitro or in vivo models can be predictive of effects in humans and other species, and in vitro or in vivo models exist for measuring synergy, as described herein, and the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and absolute doses and plasma concentrations required in humans and other species by application of pharmacokinetic / pharmacodynamic methods.

[0224] As used herein, PF-06863135 is interchangeably used with erlanatamab. PF06863135 is a BCMAxCD3 bispecific antibody. PF-06863135 is described, for example, in U.S. Patent No. 9,969,809. Selected sequences of PF-06863135 are shown in Table 15.

[0225] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include the plural, and plural terms shall include the singular.

[0226] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0227] II. METHODS, USES AND MEDICINES Provided herein are methods and compositions for treating cancer and / or cancer-related diseases in a subject, comprising combination therapy comprising at least a first therapeutic agent and a second therapeutic agent.

[0228] BCMA-specific therapeutic agents In some embodiments, the therapeutic agent may be a BCMA-specific therapeutic agent. In other embodiments, the BCMA-specific therapeutic agent may be a BCMA multispecific antibody (e.g., bispecific or trispecific), a BCMA antibody-drug conjugate, or a BCMA chimeric antigen receptor (CAR)-modified T cell therapy. B cell maturation antigen (BCMA, also known as TNFRSF17 and CD269) is a candidate for bispecific antibody-based immunotherapy. BCMA expression is upregulated during B cell maturation into plasmablasts and plasma cells, but it is not expressed on naive B cells, hematopoietic stem cells, or normal tissues such as the heart, lung, kidney, or tonsils. In multiple myeloma, BCMA expression has been identified at various disease stages and in patients with different cytogenetic risks. Furthermore, BCMA expression was not affected by autologous stem cell transplantation (ASCT) or chemotherapy treatment. In vivo, bispecific antibodies against BCMA have been shown to induce T cell activation, reduce tumor burden, and prolong survival.

[0229] Examples of BCMA multispecific antibodies that may be useful in the combination therapies of the invention include, but are not limited to, AMG420 (BCMAxCD3 bispecific T cell engager, BiTE®, Amgen), AMG701 (BCMAxCD3 BiTE®, Amgen), CC-93269 (BCMAxCD3 bispecific antibody, Celgene), JNJ-64007957 (Janseen), PF-06863135 (BCMAxCD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio / AbbVie), REGN5458 (BCMAxCD3 bispecific antibody, Regeneron), AFM26 (BCMAxCD16 tetravalent bispecific antibody, Affimed GmbH), HPN217 (BCMAxALBxCD3 trispecific, Harpoon Therapeutics).

[0230] In some embodiments, the BCMA-specific therapeutic agent is a BCMA bispecific antibody molecule. A BCMA bispecific antibody is a monoclonal antibody that has binding specificities for at least two different antigens (e.g., BCMA and CD3).

[0231] In some aspects, the BCMA bispecific antibody comprises a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain specifically binds CD3 and the second antibody variable domain specifically binds BCMA.

[0232] In some embodiments, the therapeutic agent in the combination therapy of the invention is a BCMA bispecific antibody. In some embodiments, the BCMA bispecific antibody may have any of the characteristics or properties of any of the BCMA bispecific antibodies provided in WO2016166629, which is incorporated herein by reference for all purposes.

[0233] In some embodiments, the first antibody variable domain specifically binds to CD3. Information regarding CD3 is provided, for example, via UniProtKB #P07766. In some embodiments, the first antibody variable domain comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1, and / or three CDRs of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the VH comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 2, 3, or 4, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 5 or 6, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 7, and / or the VL comprises a VL CDR1 comprising the sequence set forth in SEQ ID NO: 10, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 11, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 12. In some embodiments, the VH comprises the sequence set forth in SEQ ID NO: 1, and / or the VL comprises the sequence set forth in SEQ ID NO: 9. In some embodiments, for example, the first antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:8 and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:13.

[0234] In some embodiments, the second antibody variable domain specifically binds to BCMA. Information regarding BCMA is provided, for example, via UniProtKB ID#Q02223. In some embodiments, the second antibody variable domain comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 14, and / or three CDRs of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the VH comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 15, 16, or 17, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 18 or 19, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 20, and / or the VL comprises a VL CDR1 comprising the sequence set forth in SEQ ID NO: 23, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 24, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 25. In some embodiments, the VH comprises the sequence set forth in SEQ ID NO: 14, and / or the VL comprises the sequence set forth in SEQ ID NO: 22. In some embodiments, the second antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:21 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:26.

[0235] In some embodiments, the BCMA bispecific antibody is PF-06863135, also known as erlanatamab. The BCMA bispecific antibody used in the examples disclosed herein was PF-06863135 unless otherwise indicated. PF-06863135 is a heterodimeric humanized full-length bispecific antibody containing one B-cell maturation antigen (BCMA)-binding arm and one cluster of differentiation (CD3)-binding arm paired by hinge mutation technology. It utilizes an engineered human IgG2Δa fragment crystallizable (Fc) region. PF-06863135 is described, for example, in U.S. Patent No. 9,969,809, which is incorporated herein for all purposes. The sequence of PF-06863135 is shown in Table 19.

[0236] An effective amount of a BCMA-specific therapeutic agent can be administered according to the dosages described herein.

[0237] Anti-PD-1 and PD-L1 antibody therapeutics In some embodiments, a therapeutic agent for use in the combination therapy of the present invention may be an anti-PD-1 or anti-PD-L1 antibody. The programmed cell death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively) play an integral role in immune regulation. PD-1, expressed on activated T cells, is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, initiating T cell death and localized immune suppression (Dong et al., Nat Med 1999;5:1365-69; Freeman et al., J Exp Med 2000;192:1027-34), potentially providing an immune-permissive environment for tumor development and growth. Conversely, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity in non-clinical animal models (Iwai Y et al., Proc Natl Acad Sci USA 2002;99:12293-97).

[0238] Examples of anti-PD-1 and anti-PD-L1 antibodies that may be useful in the combination therapy of the present invention include, but are not limited to, atezolizumab (TECENTRIQ®, MPDL3280A, Roche Holding AG), durvalumab (IMFINZI®, AstraZeneca PLC), nivolumab (OPDIVO®, ONO-4538, BMS-936558, MDX1106, Bristol-Myers Squibb Company), pembrolizumab (KEYTRUDA®, MK-3475, lambrolizumab, Merck & Co., Inc.), BCD-100 (BIOCAD Biopharmaceutical Company), tislelizumab (BGB-A317, BeiGene Ltd. / Celgene Corporation), genolizumab (CBT-501, CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), GLS-010 (Harbin Gloria Pharmaceuticals Co., Ltd.), Sintilimab (IBI308, Innovent Biologics, Inc.), WBP3155 (CStone Pharmaceuticals Co., Ltd.), AMP-224 (GlaxoSmithKline plc), BI754091 (Boehringer Ingelheim) GmbH), BMS-936559 (Bristol-Myers Squibb Company), CA-170 (Aurigene Discovery Technologies), FAZ053 (Novartis AG), Spartalizumab (PDR001, Novartis AG), LY3300054 (Eli Lilly & Company), MEDI0680 (AstraZeneca PLC), PDR001 (Novartis AG), sasanlimab (PF-06801591, Pfizer Inc.), cemiplimab (LIBTAYO®, REGN2810, Regeneron Pharmaceuticals, Inc.), camrelizumab (SHR-1210, Incyte Corporation), TSR-042 (Tesaro, Inc.), AGEN2034 (Agenus Inc.), CX-072 (CytomX Therapeutics, Inc.), JNJ-63723283 (Johnson & Johnson), MGD013 (MacroGenics, Inc.), AN-2005 (Adlai Nortye), ANA011(AnaptysBio,Inc.), ANB011(AnaptysBio,Inc.), AUNP-12(Pierre Fabre Medicament SA), BBI-801(Sumitomo Dainippon Pharma Co.,Ltd), BION-004(Aduro Biotech), CA-327(Aurigene Discovery Technologies), CK-301(Fortress Biotech, Inc.), ENUM244C8 (Enumeral Biomedical Holdings, Inc.), FPT155 (Five Prime Therapeutics, Inc.), FS118 (F-star Alpha Ltd.), hAb21 (Stainwei Biotech, Inc.), J43 (Transgene SA), JTX-4014 (Jounce Therapeutics, Inc.), KD033 (Kadmon Holdings, Inc.), KY-1003 (Kymab Ltd.), MCLA-134 (Merus BV), MCLA-145 (Merus BV), PRS-332 (Pieris AG), SHR-1316 (Atridia Pty Ltd.), STI-A1010 (Sorrento Therapeutics, Inc.), STI-A1014 (Sorrento Therapeutics, Inc.), STI-A1110 (Les Laboratoires Servier), and XmAb20717 (Xencor, Inc.).

[0239] In some embodiments, the therapeutic agent in the combination therapy of the invention is an anti-PD-1 antibody, which may have any of the characteristics or properties of any of the antibodies provided in WO2016 / 092419, which is incorporated herein by reference for all purposes.

[0240] In some embodiments, the anti-PD-1 antibody comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 27, and / or three CDRs of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the VH comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 28, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 29, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 30, and / or the VL comprises a VL CDR1 comprising the sequence set forth in SEQ ID NO: 32, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 33, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 34. In some embodiments, the VH comprises the sequence set forth in SEQ ID NO: 27, and / or the VL comprises the sequence set forth in SEQ ID NO: 31.

[0241] In some embodiments, the anti-PD-1 antibody is sasanlimab (PF-06801591). Sasanlimab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that binds to the PD-1 receptor. Blocking its interaction with PD-L1 and PD-L2 releases PD-1 pathway-mediated inhibition of the immune response, resulting in an anti-tumor immune response. Clinical anti-tumor activity for sasanlimab has been observed in a panel of anti-PD1-sensitive solid tumor types, including non-small cell lung cancer and urothelial carcinoma. Sasanlimab is described, for example, in U.S. Patent No. 10,155,037, which is incorporated herein for all purposes. The anti-PD-1 antibody used in the examples disclosed herein was a therapeutic humanized anti-human PD-1 antibody (hIgG2a-D265A) prepared in-house, unless otherwise noted.

[0242] An effective amount of the anti-PD-1 antibody or anti-PD-L1 antibody can be administered according to the dosages described herein.

[0243] Gamma secretase inhibitor therapeutic agent The therapeutic agent for use in the combination therapy of the present invention may be a gamma secretase inhibitor (GSI). The terms "gamma secretase inhibitor," "γ-secretase inhibitor," and "GSI" are used interchangeably herein and refer to compounds (including pharmaceutically acceptable salts, solvates, and prodrugs thereof) or other agents that inhibit or reduce the biological activity of gamma secretase. Membrane-bound BCMA can be actively cleaved by the protease activity of gamma secretase from the surface of tumor cells and undergo gamma secretase-mediated release. This can reduce the target density of BCMA-specific therapeutic agents on tumor cells and release soluble BCMA (sBCMA) fragments that can inhibit BCMA-specific therapeutic agents. By inhibiting gamma secretase, membrane-bound BCMA is preserved, allowing increased target density while reducing the levels of sBCMA. Thus, administration of a GSI can enhance the activity of BCMA-specific therapeutic agents.

[0244] Examples of small molecule GSIs that may be useful in the combination therapy of the present invention include, but are not limited to, dipeptide-class GSIs, sulfonamide-class GSIs, transition-state mimetic-class GSIs, benzocaprolactam-class GSIs, and other GSIs known in the art. For example, the GSI can be selected from MK-0752 (Merck & Co., Inc.), MRK-003 (Merck & Co., Inc.), nirogacestat (PF-03084014, SpringWorks Therapeutics), RO4929097 (Roche), semagacestat (LY450139, Eli Lilly & Company), BMS-906024 (Bristol-Myers Squibb Company), and DAPT, or pharmaceutically acceptable salts thereof. Further examples of GSIs include 1-(S)-endo-N-(1,3,3)-trimethylbicyclo[2.2.1]hept-2-yl)-4-fluorophenylsulfonamide, WPE-III-31C, (S)-3-[N'-(3,5-difluorophenyl-alpha-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, and (N)-[(S)-2-hydroxy-3-methyl-butyryl]-1-(L-alaninyl)-(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one. See De Kloe & De Strooper (2014), Small Molecules That Inhibit Notch Signaling, in Bellen & Yamamoto (eds.), Notch Signaling: Methods and Protocols, Methods in Mol. Biol., vol. 1, 187 (pp. 311-322), New York, NY: Springer-Science+Business Media.

[0245] In some embodiments, the therapeutic agent in the combination therapy of the present invention is a GSI.In some embodiments, the GSI may have any of the characteristics or properties of any of the GSIs provided in WO2005 / 092864, which is incorporated herein by reference for all purposes.In some embodiments, the GSI is nirogacestat (PF-03084014, SpringWorks Therapeutics), or a pharmaceutically acceptable salt thereof.Nirogacestat has the structural formula:

[0246] [ka] It is an oral, selective, small molecule GSI with

[0247] Nirogacestat is described, for example, in U.S. Patent Nos. 7,342,118, 7,795,447, and 7,951,958, which are incorporated herein for all purposes. The GSI used in the examples disclosed herein was nirogacestat, unless otherwise indicated.

[0248] An effective amount of GSI can be administered according to the dosage described herein.In some embodiments, GSI is administered at a dosage sufficient to upregulate the surface expression of BCMA on tumor cells.In some embodiments, GSI is administered at a dosage sufficient to reduce the release of BCMA on tumor cells.In some embodiments, GSI is administered at a dosage sufficient to reduce the level of sBCMA.In some embodiments, GSI is administered at a dosage sufficient to improve the activity of BCMA-specific therapeutic agents.

[0249] therapeutic agent In some embodiments, therapeutic agents for use in the combination therapies of the invention may include one or more of biotherapeutics, chemotherapeutics, immunomodulatory agents (e.g., thalidomide, lenalidomide, pomalidomide, iveldmide, and apremilast), proteasome inhibitors (e.g., bortezomib, carfilzomib, and ixazomib), corticosteroids (e.g., dexamethasone and prednisone), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), and nuclear export inhibitors (e.g., selinexol). Additional therapeutic agents for use in the combination therapies of the invention include cancer vaccines, immune cell therapies (e.g., CAR-T cell-based therapies), radiation therapy, vaccines, cytokine therapies (e.g., immunostimulatory cytokines, including various signaling proteins that stimulate immune responses, such as interferons, interleukins, and hematopoietic growth factors), targeted cytokines, inhibitors of other immunosuppressive pathways, inhibitors of angiogenesis, T cell activators, inhibitors of metabolic pathways, mTOR (mechanistic target of rapamycin) inhibitors (e.g., rapamycin, rapamycin derivatives, sirolimus, temsic, rolimus, everolimus, and deforolimus), inhibitors of the adenosine pathway, gamma secretase inhibitors (e.g., nirogacestat), tyrosine kinase inhibitors including, but not limited to, INLYTA®, ALK (anaplastic lymphoma kinase) inhibitors (e.g., crizotinib, ceritinib, alectinib, and sunitinib), BRAF inhibitors (e.g., vemurafenib and dabrafenib), PI3K inhibitors, HPK1 inhibitors, epigenetic modifiers, inhibitors or depletors of Treg cells and / or myeloid-derived suppressor cells, JAK (JanusKinase inhibitors (e.g., ruxolitinib and tofacitinib, baricitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, and upadacitinib), STAT (signal transducer and activator of transcription) inhibitors (e.g., STAT1, STAT3, and STAT5 inhibitors, e.g., fludarabine), cyclin-dependent kinase (CDK) or other cell cycle inhibitors, immunogenic agents (e.g., attenuated cancerous cells, tumor antigens, tumor-derived antigens, or antigen-presenting cells such as dendritic cells pulsed with nucleic acids), MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, and selumetinib), GLS1 inhibitors, PARP inhibitors (e.g., talazoparib, olaparib, rucaparib, niraparib), oncolytic viruses, gene therapies including DNA, RNA delivered directly or by adeno-associated virus (AAV) or nanoparticles, innate immune response modulators (e.g., TLR, KIR, NKG2A), IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitors, PRR (pattern recognition receptor) agonists, and cells transfected with genes encoding immune stimulating cytokines such as, but not limited to, GM-CSF.

[0250] In some aspects, therapeutic agents for use in the combination therapies of the invention include, but are not limited to, anti-CTLA-4 antibodies, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD8 antibodies, anti-4-1BB antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti-TIGIT antibodies, anti-OX40 antibodies, anti-IL-7R alpha (CD127) antibodies, anti-IL-8 antibodies, anti-IL-15 antibodies, anti-HVEM antibodies, anti-BTLA antibodies, anti-CD38 antibodies, anti-CD40 antibodies, anti-CD40L antibodies, anti-CD47 antibodies, anti-CSF1R antibodies, anti-CSF1 antibodies, anti-IL-7R antibodies, anti-MARCO antibodies, anti-CXCR4 antibodies, anti-VEGF antibodies, anti-VEGFR1 antibodies, Anti-VEGFR2 antibody, anti-TNFR1 antibody, anti-TNFR2 antibody, anti-CD3 bispecific antibody, anti-CD19 antibody, anti-CD20 antibody, anti-Her2 antibody, anti-EGFR antibody, anti-ICOS antibody, anti-CD22 antibody, anti-CD52 antibody, anti-CCR4 antibody, anti-CCR8 antibody, anti-CD200R antibody, anti-VISG4 antibody, anti-CCR2 antibody, anti-L Antibodies may include ILRb2 antibodies, anti-CXCR4 antibodies, anti-CD206 antibodies, anti-CD163 antibodies, anti-KLRG1 antibodies, anti-FLT3 antibodies, anti-B7-H4 antibodies, anti-B7-H3 antibodies, KLRG1 antibodies, BTN1A1 antibodies, BCMA antibodies, anti-SLAMF7 antibodies, anti-avb8 antibodies, anti-CD80 antibodies, or anti-GITR antibodies.

[0251] In some embodiments, other examples of therapeutic agents for use in the combination therapies of the invention include 5T4; A33; alpha folate receptor 1 (e.g., mirvetuximab soravtansine); Alk-1; BCMA (see, e.g., WO2016166629 and others disclosed herein); BTN1A1 (see, e.g., WO2018222689); CA19-9; CA-125 (e.g., abagovomab); carboanhydrase IX; CCR2; CCR4 (e.g., mogamulizumab); CCR5 (e.g., leronlimab); CCR8; CD3 [e.g., blinatumomab (CD3 / CD19 bispecific), PF-06671008 (CD3 / P-cadherin bispecific), PF-06863135 (CD3 / BCMA bispecific)]; CD19 (e.g., blinatumomab, MOR208); CD20 (e.g., ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumab ozogamicin, moxetumomab pasudotox); CD25; CD28; CD30 (e.g., brentuximab vedotin); CD33 (e.g., gemtuzumab ozogamicin); CD38 (e.g., daratumumab, daratumumab and hyaluronidase, and isatuximab), CD40; CD-40L; CD44v6; CD47 (e.g., Hu5F9-G4, CC-90002, SRF231, B6H12); CD52 (e.g., alemtuzumab); CD56; CD63; CD79 (e.g., polatuzumab vedotin); CD80; CD86; CD123; CD276 / B7-H3 (e.g., omburtamab); CDH17; C EA; ClhCG; CTLA-4 (e.g., ipilimumab, tremelimumab), CXCR4; desmoglein 4; DLL3 (e.g., rovalpituzumab tesirin); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g., cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvIII; endosialin; EpCAM (e.g., oportuzumab monatox); FAP; fetal acetylcholine receptor; FLT3 (see, e.g., WO2018 / 220584);4-1BB (CD137) [e.g., utomilumab / PF-05082566 (see WO2012 / 032433) or urelumab / BMS-663513], GD2 (e.g., dinutuximab, 3F8); GD3; GITR (e.g., TRX518); GloboH; GM1; GM2; HER2 / neu [e.g., margetuximab, pertuzumab, trastuzumab; ado-trastuzumab emtansine, trastuzumab duocarmazine, PF-06804103 (see US8828401)]; HER3; HER4; ICOS; IL-10; ITG-Av86; LAG-3 (e.g., leratolimab, IMP701); Lewis-Y; LG; Ly-6; M-CSF [see, e.g., PD-0360324 (US7326414)]; (membrane-bound) IgE; MCSP; mesothelin; MIS receptor type II; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notch1; Notch3; Nectin-4 (e.g., enfortumab vedotin); OX40 [see, e.g., PD-04518600 (US7960515)] see references)]; P-cadherin [e.g., PF-06671008 (see WO2016 / 001810)]; PCDHB2; PD-1 [e.g., BCD-100, camrelizumab, pembrolizumab, sasanlimab (PF-06801591, see WO2016 / 092419), sintilimab, spartalizumab, STI-A1110, tislelizumab, TSR-042, and others disclosed herein]; PD-L1 (e.g., atezolizumab, durvalumab, BMS-936559 (MDX-1105), L Y3300054, and others disclosed herein); PDGFRA (e.g., olaratumab); plasma cell antigen; polySA; PSCA; PSMA; PTK7 [e.g., PF-06647020 (US9409995)]; Ror1; SAS; SLAMF7 (e.g., elotuzumab); SHH; SIRPa (e.g., ED9, Effi-DEM); STEAP; sTn; TGF-beta; TIGHT; TIM-3; TMPRSS3; TNF-alpha precursor; TROP-2 (e.g., sacituzumab govitecan); TSPAN8;They may be directed against or target VEGF (e.g., bevacizumab, brolucizumab); VEGFR1 (e.g., ranibizumab); VEGFR2 (e.g., ramucirumab, ranibizumab); and Wue-1.

[0252] In some embodiments, the therapeutic agent for use in the combination therapy of the present invention may be a therapeutic antibody having any suitable format. For example, the therapeutic antibody may have any format described elsewhere herein. In some embodiments, the therapeutic antibody may be a naked antibody. In some embodiments, the therapeutic antibody may be linked to a drug / agent (also known as an "antibody-drug conjugate" (ADC)). Drugs or agents that can be linked to antibodies in ADC format may include, for example, cytotoxic agents, immunomodulatory agents, imaging agents, therapeutic proteins, biopolymers, or oligonucleotides. Exemplary cytotoxic agents that can be incorporated into ADCs include anthracyclines, auristatins, dolastatins, combretastatins, duocarmycins, pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, enediynes, geldanamycin, maytansine, puromycin, taxanes, vinca alkaloids, camptothecins, tubulysins, hemiasterlins, spliceostatins, pladienolides, and stereoisomers, isosteres, analogs, or derivatives thereof.

[0253] In some embodiments, therapeutic antibodies against specific antigens can be incorporated into multispecific antibodies (e.g., bispecific or trispecific antibodies). Bispecific antibodies are monoclonal antibodies with binding specificities for at least two different antigens. In some embodiments, the bispecific antibody comprises a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain can recruit the activity of human immune effector cells by specifically binding to an effector antigen located on the human immune effector cells, and the second antibody variable domain can specifically bind to a target antigen as provided herein. In some embodiments, the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the antibody comprises an immunologically inert Fc region. In some embodiments, the antibody is a human antibody or a humanized antibody.

[0254] The human immune effector cells may be any of a variety of immune effector cells known in the art. For example, the immune effector cells may be members of the human lymphocyte lineage, including, but not limited to, T cells (e.g., cytotoxic T cells), B cells, and natural killer (NK) cells. The immune effector cells may also be members of the human myeloid lineage, including, but not limited to, monocytes, neutrophilic granulocytes, and dendritic cells. Such immune effector cells may have a cytotoxic or apoptotic effect on target cells or other desired effect upon activation by binding of an effector antigen.

[0255] The effector antigen is an antigen (e.g., a protein or polypeptide) expressed on human immune effector cells. Examples of effector antigens that can be bound by heterodimeric proteins (e.g., heterodimeric antibodies or bispecific antibodies) include, but are not limited to, human CD3 (or CD3 (cluster of differentiation) complex), CD16, NKG2D, NKp46, CD2, CD28, CD25, CD64, and CD89. The target antigen is typically expressed on target cells in a disease state (e.g., cancer cells). Examples of target antigens for use in bispecific antibodies are disclosed herein.

[0256] In some embodiments, the bispecific antibodies provided herein bind to two different target antigens on the same target cell (e.g., two different antigens on the same tumor cell). Such antibodies can be advantageous, for example, because they have increased specificity for a target cell of interest (e.g., a tumor cell expressing two particular tumor-associated antigens of interest). For example, in some embodiments, the bispecific antibodies provided herein comprise a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain is capable of specifically binding to a first target antigen provided herein and the second antibody variable domain is capable of specifically binding to a second target antigen provided herein.

[0257] In some embodiments, therapeutic agents for use in the combination therapy of the present invention may include immunomodulatory agents, such as thalidomide, lenalidomide, pomalidomide, iveldomide, and apremilast, which can stimulate an immune response in a subject. Additional immunomodulatory agents include pattern recognition receptor (PRR) agonists, immune stimulating cytokines, immune cell therapy, and cancer vaccines.

[0258] Pattern recognition receptors (PRRs) are receptors expressed by cells of the immune system that recognize various molecules associated with pathogens and / or cell damage or cell death. PRRs are involved in both innate and adaptive immune responses. PRR agonists can be used to stimulate immune responses in subjects. There are several classes of PRR molecules, including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and stimulator of interferon genes (STING) proteins.

[0259] Exemplary TLR agonists provided herein include agonists of TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9.Examples of RLR agonists that are useful in the treatment methods, medicaments, and uses of the present invention include, for example, short double-stranded RNA with uncapped 5' triphosphate (RIG-I agonist); poly I:C (MDA-5 agonist), and BO-112 (MDA-A agonist).Examples of NLR agonists that are useful in the treatment methods, medicaments, and uses of the present invention include, for example, liposomal muramyl tripeptide / mifamurtide (NOD2 agonist). Examples of CLR agonists useful in the treatment methods, medicaments, and uses of the present invention include, for example, MD fraction (a purified soluble beta-glucan extract from Grifola frondosa) and Imprime PGG (yeast-derived beta-1,3 / 1,6-glucan PAMP). Examples of STING agonists useful in the treatment methods, medicaments, and uses of the present invention include various immunostimulatory nucleic acids, such as synthetic double-stranded DNA, cyclic di-GMP, cyclic GMP-AMP (cGAMP), synthetic cyclic dinucleotides (CDNs), such as MK-1454 and ADU-S100 (MIW815), and small molecules such as P0-424. Other PRRs include, for example, DNA-dependent activator of IFN regulatory factors (DAI) and Absent in Melanoma 2 (AIM2).

[0260] Immunostimulatory cytokines include various signaling proteins that stimulate immune responses, such as, but not limited to, interferons, interleukins, and hematopoietic growth factors. In some embodiments, exemplary immunostimulatory cytokines include, but are not limited to, GM-CSF, G-CSF, IFNγ, IFNα, IL-2 (e.g., denileukin diphytox), IL-6, IL-7, IL-10, IL-11, IL-12, IL-15, IL-18, IL-21, and TNFα. Immunostimulatory cytokines may have any suitable format. In some embodiments, immunostimulatory cytokines may be recombinant versions of wild-type cytokines. In some embodiments, immunostimulatory cytokines may be mutant proteins having one or more amino acid changes compared to the corresponding wild-type cytokine. In some embodiments, immunostimulatory cytokines may be incorporated into chimeric proteins containing the cytokine and at least one other functional protein (e.g., an antibody). In some embodiments, the immune stimulatory cytokine can be covalently linked to a drug / agent (e.g., any of the drugs / agents described elsewhere herein as possible ADC components). In some embodiments, the cytokine is PEGylated.

[0261] Immune cell therapy involves treating patients with immune cells that can target cancer cells, such as tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor T cells (CAR-T cells).

[0262] Cancer vaccines include various compositions that contain tumor-associated antigens (or can be used to generate tumor-associated antigens in a subject) and thus can be used to induce an immune response in a subject directed toward tumor cells containing tumor-associated antigens. Exemplary materials that can be contained in cancer vaccines include attenuated cancerous cells, tumor antigens, antigen-presenting cells, such as dendritic cells pulsed with a nucleic acid encoding a tumor-derived antigen or a tumor-associated antigen. In some embodiments, cancer vaccines can be prepared using a patient's own cancer cells. In some embodiments, cancer vaccines can be prepared using biological materials not derived from a patient's own cancer cells. Examples of cancer vaccines include sipuleucel-T and talimogene laherparepvec (T-VEC).

[0263] The combination therapy provided herein may include one or more chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuledopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (synthetic analogs, KW-2189 and and CBI-TMI); eloterobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard, and the like; nitrosoureas reas), such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, and the like; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma 1I and calicheamicin phi 1I, see e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin) anti-inflammatory drugs, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate, thromycin, thromycin, thromycin C ... oxalates, etc.; purine analogs, for example, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; pyrimidine analogs, for example, ancitabine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.; androgens, for example, calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.; anti-adrenal agents, for example, aminoglutethimide, mitotane, trilostane, etc.; furoic acid, etc. Folic acid supplements; FOLFOX containing folinic acid, 5-FU, and oxaliplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine;Pentostatin; Fenameth; Pirarubicin; Losoxantrone; Podophyllic acid; 2-ethylhydrazide; Procarbazine; Razoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2"-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, e.g., paclitaxel and doxetaxel; Chlorophenone; Examples of anti-inflammatory drugs include lorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, the topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0264] In some embodiments, the combination therapy of the present invention may use antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (Fareston); aromatase inhibitors that inhibit the aromatase enzyme, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole.

[0265] In some embodiments, the therapeutic agents for use in the combination therapies of the present invention include antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, fluridil, apalutamide, enzalutamide, cimetidine, and goserelin; KRAS inhibitors; MCT4 inhibitors; MAT2a inhibitors; tyrosine kinase / vascular endothelial growth factor (VEGF) receptor inhibitors, such as sunitinib, axitinib, sorafenib, tivozanib, and the like; alk / c-Met / ROS inhibitors, such as crizotinib, mTOR inhibitors, such as temsirolimus and gedatricisib; src / abl inhibitors, such as bosutinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, PF-06873600, abemaciclib, and ribociclib; erb inhibitors, such as dacomitinib; PARP inhibitors, such as talazoparib, olaparib, rucaparib, and niraparib; SMO inhibitors, such as glasdegib and PF-5274857; EGFR T790M inhibitors, such as PF-06747775; EZH2 inhibitors or other epigenetic modifiers, such as PF-06821497; PRMT5 inhibitors, such as PF-06939999; TGFRβr1 inhibitors, such as PF-06952229; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0266] treatment Each therapeutic agent in the combination therapy of the invention can be administered in accordance with standard pharmaceutical practice, either alone or in a medicament comprising the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents (also referred to herein as a pharmaceutical composition).

[0267] Each therapeutic agent in the combination therapy of the present invention can be administered simultaneously (i.e., in the same medicament), concomitantly (i.e., in separate medicaments administered immediately after the other in any order), or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and the other agent is a sterile liquid) and / or are administered on different dosing schedules, e.g., a chemotherapeutic agent is administered at least daily and a therapeutic agent is administered less frequently, e.g., once a week, once every two weeks, or once every three weeks.

[0268] In some embodiments, the therapeutic agents in the combination therapy can be administered using the same dosage regimen (dose, frequency and treatment duration) as would typically be used when the agent is used as a monotherapy to treat the same cancer.In other embodiments, the patient may receive a lower total amount of at least one therapeutic agent in the combination therapy than when the agent is used as a monotherapy, for example, at a lower dose, less frequent dose, and / or shorter treatment duration.

[0269] The therapeutic agent in the combination therapy of the present invention can be administered by any suitable enteral or parenteral route. The term "enteral route" of administration refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal routes, or intragastric routes. The term "parenteral route" of administration refers to an administration route other than the enteral route. Examples of parenteral administration routes include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intratracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous, or topical administration. The therapeutic agent of the present disclosure can be administered using any suitable method, such as oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. The preferred route and method of administration may vary depending on several factors, such as the particular therapeutic agent used, the desired rate of absorption, the particular formulation or dosage form used, the type or severity of the disorder being treated, the particular site of action, and the condition of the patient, etc. Examples of parenteral administration routes also include intraosseous and intrapleural.

[0270] Oral administration of solid dosage forms of therapeutic agents can be provided in individual units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one therapeutic agent. In another embodiment, oral administration can be in the form of powder or granules. In another embodiment, oral dosage forms are sublingual, such as lozenges. In such solid dosage forms, therapeutic agents are usually combined with one or more adjuvants. Such capsules or tablets can contain controlled-release formulations. In the case of capsules, tablets, and pills, dosage forms can include buffering agents or can be prepared with enteric coatings.

[0271] In another embodiment, the oral administration of the therapeutic agent may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatic agents.

[0272] In some embodiments, the therapeutic agent is administered in a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants, wetting agents, and / or suspending agents, and include depot preparations.

[0273] In some embodiments, the therapeutic agent is administered in a topical dosage form. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain a compound to enhance absorption or penetration of the active ingredient through the skin or other affected area. When the therapeutic agent is administered via a transdermal device, administration may be achieved using a patch, either of the reservoir and porous membrane type or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated, see, for example, Finnin and Morgan, J. Pharm. Sci., 88(10), 955-958 (1999).

[0274] Other carrier materials and modes of administration known in the pharmaceutical industry can also be used with the therapeutic agents. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. Drug formulations are described in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and discussed in Kibbe et al. (eds.), Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0275] The selection of a dosage regimen (also referred to herein as an administration regimen) for the combination therapy of the present invention may depend on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of target cells, tissues, or organs in the subject being treated. Preferably, the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with an acceptable level of side effects. Thus, the dosage and frequency of each therapeutic or chemotherapeutic agent in the combination will depend in part on the specific therapeutic agent, the severity of the cancer being treated, and patient characteristics. Guidance on selecting appropriate doses of antibodies, cytokines, and small molecules is available. See, for example, Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz et al. (2000) New See Engl. J. Med. 342:613-619; Ghosh et al. (2003) New Engl. J. Med. 348:24-32; Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602; Physicians' Desk Reference 2003 (Physicians' Desk Reference, 57th ed.); Medical Economics Company; ISBN: 1563634457; 57th ed. (November 2002).Determination of an appropriate dosage regimen can be made by a physician using, for example, parameters or factors known or suspected in the art to affect or predicted to affect treatment, and will depend, for example, on the patient's medical history (e.g., prior therapy), the type and stage of the cancer being treated, and biomarkers of response to one or more therapeutic agents in the combination therapy.

[0276] In some embodiments, the therapeutic agents in the combination therapies of the invention are administered in a dose range of about 0.01 μg / kg, 0.02 μg / kg, 0.03 μg / kg, 0.04 μg / kg, 0.05 μg / kg, 0.06 μg / kg, 0.07 μg / kg, 0.08 μg / kg, 0.09 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.3 μg / kg, 0.4 μg / kg, 0.5 μg / kg, 0.6 μg / kg, 0.7 μg / kg, 0.8 μg / kg, 0.9 μg / kg, 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg , 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 110 μg / kg, 120 μg / kg, 130 μg / kg, 140 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1200 μg / kg, or 1400 μg / kg or more.

[0277] In some embodiments, the therapeutic agents in the combination therapies of the present invention can be administered to a subject at a dose of about 1 mg / kg to about 1000 mg / kg, about 2 mg / kg to about 900 mg / kg, about 3 mg / kg to about 800 mg / kg, about 4 mg / kg to about 700 mg / kg, about 5 mg / kg to about 600 mg / kg, about 6 mg / kg to about 550 mg / kg, about 7 mg / kg to about 500 mg / kg, about 8 mg / kg to about 450 mg / kg, about 9 mg / kg to about 400 mg / kg, about 5 mg / kg to about 200 mg / kg, about 2 mg / kg to about 150 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 60 mg / kg.

[0278] In some embodiments, the therapeutic agents in the combination therapies of the invention can be administered to a subject at a dose of at least 0.05 μg / kg, 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.2 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med. 349:427-434; Herold et al. (2002) New Engl. J. Med. 346:1692-1698; Liu et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji et al. (2003) Cancer Immunol. Immunother. 52:133-144.

[0279] In some embodiments, the amount of hydroxybenzoates is about or at least about 0.05 μg, 0.2 μg, 0.5 μg, 1 μg, 10 μg, 100 μg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg A fixed dose of 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 350 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, or 1500 mg or more of a therapeutic agent can be administered to a patient. The fixed dose can be administered, for example, daily, every other day, three times a week, or at intervals such as weekly, biweekly, triweekly, monthly, bimonthly, trimonthly, or quadruply.

[0280] For oral administration, a therapeutic agent (eg, typically a small molecule chemotherapeutic agent) can be provided in tablet form at a dose of the therapeutic agent described herein.

[0281] In some embodiments, the therapeutic agents in the combination therapies of the invention can be administered orally, IV, or SC in a dose at least once daily, once daily, twice daily, three times daily, four times daily, once every two days, once every three days, once weekly, once every two weeks, once every three weeks, once every four weeks, once every 30 days, once every five weeks, once every six weeks, once monthly, once every two months, once every three months, or once every four months.

[0282] The treatment method described herein can be continued as long as the physician supervising the patient's care deems the treatment method effective. Non-limiting parameters that indicate the effectiveness of the treatment method include any one or more of the following: tumor shrinkage (measured by weight and / or volume); reduction in the number of individual tumor colonies; tumor elimination; and progression-free survival. Changes in tumor size can be determined by any suitable method, such as imaging. Various diagnostic imaging modalities known in the art can be used, such as computed tomography (CT scan), dual-energy CDT, positron emission tomography, ultrasound, CAT scan, and MRI. In some embodiments, the combination therapy of the present invention is used to treat tumors that are large enough to be detected by palpation or by imaging techniques known in the art, such as MRI, ultrasound, or CAT scan.

[0283] Exemplary lengths of time associated with a course of therapy include about 1 week; about 2 weeks; about 3 weeks; about 4 weeks; about 5 weeks; about 6 weeks; about 7 weeks; about 8 weeks; about 9 weeks; about 10 weeks; about 11 weeks; about 12 weeks; about 13 weeks; about 14 weeks; about 15 weeks; about 16 weeks; about 17 weeks; about 18 weeks; about 19 weeks; about 20 weeks; about 21 weeks; about 22 weeks; about 23 weeks; about 24 weeks; about 7 months; about 8 months; about 9 months; about 10 months; about 11 months; about 12 months; about 13 months; about 14 months; about 15 months; about 16 months; about 17 months; about 18 months; about 19 months; about 20 months; about 21 months; about 22 months; about 23 months; about 24 months; about 30 months; about 3 years; about 4 years, and about 5 years.

[0284] The combinations and methods described herein can be used to treat patients suffering from any condition that can be treated or prevented by the methods provided herein, such as cancer and / or cancer-related diseases.

[0285] In some embodiments, the condition is cancer, including but not limited to carcinoma, lymphoma, leukemia, myeloma, blastoma, and sarcoma. In some embodiments, the cancer is, but not limited to, multiple myeloma, malignant plasma cell neoplasm, lymphoma, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Kahler's disease and myelomatosis, plasma cell leukemia, plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis, osteosclerosing myeloma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymic) large cell lymphoma Follicular B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell / histiocytic large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma with inflammation, ALK-positive large B-cell lymphoma , plasmablastic lymphoma, large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease, unclassified B-cell lymphoma intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell-associated lymphomas.

[0286] In some embodiments, the cancer is gastric cancer, small intestine cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), thymic cancer, epithelial cancer, salivary gland cancer, liver cancer, bile duct cancer, neuroendocrine tumor, stomach cancer, thyroid cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), mesothelioma, ovarian cancer, breast cancer, prostate cancer, kidney cancer, esophageal cancer, pancreatic cancer, glioma, kidney cancer (e.g., renal cell carcinoma), bladder cancer, cervical cancer, uterine cancer, vulvar cancer, endometrial cancer, penile cancer, testicular cancer, anal cancer, choriocarcinoma, colon cancer, colorectal cancer, oral cancer, skin cancer, Merkel cell carcinoma, glioblastoma, brain tumor, bone cancer, eye cancer, melanoma, or microsatellite instability-high (MSI-H) cancer.

[0287] The combination therapy of the present invention can be used before or after surgery to remove the tumor, and can be used before, during, or after radiation therapy.

[0288] In some embodiments, the combination therapy of the present invention is administered to patients who have not been previously treated with a therapeutic or chemotherapeutic agent, i.e., are treatment-naive. In other embodiments, the combination therapy is administered to patients who have failed to achieve a durable response before or after therapy with a therapeutic or chemotherapeutic agent, i.e., are treatment-experienced. In some embodiments, the subject has received prior therapy to treat the tumor, and the tumor has recurred or is refractory.

[0289] The present invention provides a combination therapy that has additive efficacy or additive therapeutic effects while reducing or avoiding undesirable or harmful effects.The present invention also encompasses synergistic combinations in which the therapeutic efficacy is greater than additive while reducing or avoiding undesirable or harmful effects.In certain embodiments, the methods and compositions provided herein enable the treatment or prevention of diseases and disorders, and the treatment is improved by using lower and / or less frequent doses of at least one of the therapeutic agents in the combination therapy to enhance anti-tumor response, for at least one of the following reasons: i) to reduce the occurrence of undesirable or harmful effects caused by separate administration of the therapeutic agents while at least maintaining the effectiveness of the treatment; ii) to increase patient compliance; and iii) to improve the effectiveness of anti-tumor treatment.

[0290] kit The therapeutic agents of the combination therapy of the present invention can be conveniently combined in the form of a kit suitable for simultaneous administration of the compositions.

[0291] In one embodiment, the kit includes at least a first container, a second container, and a package insert. The first container contains at least one dose of a first therapeutic agent of a combination therapy, and the second container contains at least one dose of a second therapeutic agent. The package insert / label includes instructions for using the therapeutic agent to treat a patient for cancer and / or cancer-related diseases. The first and second containers may be the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit may further include other materials that may be useful for administering the therapeutic agent, such as diluents, filters, IV bags and lines, needles, and syringes.

[0292] Clinical trials A Phase 1, open-label, multi-dose, multi-center, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic study of PF-06863135 is ongoing in adult patients with advanced multiple myeloma who have relapsed from or are refractory to standard therapy (NCT03269136). This is a two-part study to evaluate the safety and tolerability of increasing dose levels of PF-06863135 in Part 1 and to establish a recommended Phase 2 dose (RP2D) in Part 2. This Phase 1 study is described in Example 10. Two additional clinical trials of PF06863135 (erlanatamab) monotherapy are described in Examples 11 and 12.

[0293] Further clinical evaluation of PF-06863135 in combination with any of the therapeutic agents disclosed herein can be performed, including PF-06863135 in combination with anti-PD-1 / PD-L1 antibodies (e.g., sasanlimab / PF-06801591), PF-06863135 in combination with immunomodulatory agents (e.g., thalidomide, lenalidomide, pomalidomide, iveldomide, and apremilast), PF-06863135 in combination with gamma secretase inhibitors (e.g., nirogacestat), other treatments, e.g., biotherapeutics (e.g., CD38 antibodies daratumumab, daratumumab, and hives). PF-06863135 in combination with anti-cancer drugs (e.g., erlanatamab, isatuximab, and the SLAMF7 antibody elotuzumab), chemotherapy agents (e.g., melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin, and dendamustine), proteasome inhibitors (e.g., bortezomib, carfilzomib, and ixazomib), corticosteroids (e.g., dexamethasone and prednisone), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), and nuclear export inhibitors (e.g., selinexol). Examples 12-16 describe several planned combination therapy clinical trials of PF-06863135 (erlanatamab).

[0294] General method Standard methods in molecular biology are described in Sambrook, Fritsch, and Maniatis (1982 & 1989, 2nd ed., 2001, 3rd ed.) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA. Standard methods can also be found in Ausbel et al. (2001) Current Protocols in Molecular Biology, Vol. 1-4, John Wiley and Sons, Inc. New York, NY, which describe cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0295] Methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, have been described (Coligan et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation are described (see, e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., New York, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391). The production, purification, and fragmentation of polyclonal and monoclonal antibodies have been described (Coligan et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0296] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford University Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring, NY). Harbor, NY, pp. 139-243; Carpenter et al. (2000) J. Immunol. 165:6205; He et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; see U.S. Patent No. 6,329,511).

[0297] An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

[0298] Purification of the antigen is not essential for antibody production. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animal and fused with a myeloma cell line to produce hybridomas (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithana et al. (1999) J. Immunol. 163:5157-5164).

[0299] Antibody can be conjugated with, for example, low molecular weight drug molecule, enzyme, liposome, polyethylene glycol (PEG).Antibody is useful for treatment, diagnosis, kit or other purposes, for example, the antibody that is conjugated with dye, radioisotope, enzyme or metal, for example, colloidal gold (see, for example, Le Doussal et al. (1991) J.Immunol.146:169-175; Gibellini et al. (1998) J.Immunol.160:3891-3898; Hsing and Bishop (1999) J.Immunol.162:2804-2811; Everts et al. (2002) J.Immunol.168:883-889).

[0300] Methods for flow cytometry, including fluorescence-activated cell sorting (FACS), are available (see, for example, Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd Edition; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). For example, fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use as diagnostic reagents are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0301] Standard methods for immune system histology have been described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, PA; Louis et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0302] For example, software packages and databases for determining antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments are available (e.g., GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne et al. (2000) Bioinformatics 16:741-742; Menne et al. (2000) Bioinformatics Applications Note 16:741-742; Wren et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res.14:4683-4690). [Example]

[0303] Example 1 In vitro study of PD-1 induction on CD8+ T cells co-cultured with MM.1S multiple myeloma cells treated with BCMAxCD3 bispecific antibody This example demonstrates that treatment with BCMAxCD3 bispecific antibodies enhances CD8 + 1 shows that it induces PD-1 expression on T cells.

[0304] PBMC-derived CD3+ T cells (Stem Cell Technologies) were negatively selected using the EasySep Human T Cell Enrichment Kit (Stem Cell Technologies). 10,000 luciferase-expressing target multiple myeloma MM.1S cells (MM.1S-luc) were plated onto 50,000 CD3+ T cells in a clear 96-well V-bottom plate. + Pan T cells were seeded together. Cells were treated with 1 nM BCMAxCD3 bispecific antibody, and PD-1 expression was analyzed 3, 24, 48, and 72 hours after the addition of BCMAxCD3 bispecific antibody. At the specified time points, cells were collected from the wells, washed with PBS + 2% FBS, and stained with ZombieNIR Viability dye (Biolegend) in PBS for 20 minutes at room temperature, followed by staining with antibodies against human CD8 and PD-1 (Biolegend). Samples were analyzed using FlowJo flow cytometry analysis software. Dead cells were excluded from the analysis by gating on the ZombieNIR-negative population. Samples were analyzed for CD8 + Further gating was performed on the positive population. + The percentage of cells was determined as CD8 + The results, summarized in Figure 1 and Table 1, show that treatment of BCMA-expressing MM.1S multiple myeloma cells with the BCMAxCD3 bispecific antibody induces PD-1 expression on CD8+ T cells.

[0305] [Table 33]

[0306] Example 2 In vivo testing of BCMAxCD3 bispecific antibodies in combination with anti-PD-1 antibodies in the MM.1S-PDL1 orthotopic and subcutaneous mouse model This example shows the combined efficacy of a BCMAxCD3 bispecific antibody in combination with an anti-PD-1 antibody in (A) orthotopic MM.1S-Luc-PD-L1 and (B) MM.1S-PD-L1 multiple myeloma models compared to BCMAxCD3 bispecific or anti-PD-1 antibody alone.

[0307] A. Orthotopic Mouse Model MM.1S-Luc multiple myeloma cells were genetically engineered to express PD-L1 and are designated MM.1S-Luc-PD-L1. MM.1S-Luc-PD-L1 cells were cultured at 5x10 for intravenous (IV) inoculation into NSG mice. 6 The cells were prepared as a single cell suspension.

[0308] Tumor growth was monitored by luminescence imaging via intraperitoneal (IP) injection of luciferin solution in DPBS and imaged using a Perkin Elmer IVIS Spectrum camera system. 19 days after tumor cell inoculation, 2x10 7 Animals were administered IV with expanded human T cells. Two days after T cell administration, a single dose of BCMAxCD3 bispecific antibody (10 μg / kg) was administered as a bolus IV injection. Anti-PD-1 antibody was administered twice weekly as a bolus IP injection at 5 mg / kg for a total of six injections.

[0309] Tumor growth was monitored by imaging measurements collected twice weekly. Mice were imaged using a Perkin Elmer IVIS Spectrum camera system with automated parameter determination and a maximum imaging time of 3 minutes. Data were collected using Living Image software. Regions of interest (ROIs) were drawn around the entire body of the mouse, excluding as much of the tail as possible. Background flux measured on the anesthesia manifold was subtracted from each ROI. Tumor measurements are expressed as total flux in photons / sec (p / s). The study was terminated 40 days after tumor inoculation. The results, summarized in Figure 2A and Table 2, demonstrate that treatment with the BCMAxCD3 bispecific antibody and anti-PD-1 antibody was more effective than treatment with the bispecific antibody or antibody treatment alone.

[0310] [Table 34]

[0311] B. Subcutaneous Mouse Model MM.1S multiple myeloma cells were engineered to express PD-L1 and are designated MM.1S-PD-L1. On day 19 after subcutaneous (SC) inoculation of MM.1S-PD-L1 tumor cells, preactivated and expanded T cells (20x10 6 100 animals were administered at 0.3 or 1 mg / kg. BCMAxCD3 bispecific antibody (0.3 or 1 mg / kg) or negative bispecific antibody (1 mg / kg) was administered IV on day 21 and dosed Q7Dx3. Anti-PD-1 mAb was administered intraperitoneally (IP) at 5 mg / kg twice weekly starting on day 21. Tumor measurements were recorded 2–3 times weekly using digital calipers. N (at study initiation) was 5–12 animals per group. The results, summarized in Figure 2B and Table 3, demonstrate that treatment with BCMAxCD3 bispecific antibody and anti-PD-1 antibody was more effective than treatment with bispecific antibody or antibody treatment alone.

[0312] [Table 35]

[0313] Example 3 An in vitro assay to detect cell surface BCMA expression in multiple myeloma cell lines treated with gamma secretase inhibitors (GSIs) This example demonstrates the upregulation of cell surface BCMA in multiple myeloma cell lines treated with GSI.

[0314] Multiple myeloma cells (MM.1S, OPM2, H929, Molp8, RPMI8226) were seeded at 40,000 cells / well in 96-well U-bottom plates. Cells were incubated for 24 hours in the presence of GSI diluted in RPMI (0.1% DMSO). The following concentrations of GSI were tested: 1000 nM, 500 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, 2.5 nM, 1 nM, 0.1 nM, and 0.01 nM. After 24 hours, cells were harvested, washed with PBS + 2% FBS, and stained with ZombieNIR Viability Dye (Biolegend) diluted 1 / 500 in PBS for 20 minutes at room temperature. Cells were then washed with PBS + 2% FBS and stained with anti-BCMA PE-labeled antibody (Biolegend) diluted in PBS + 2% FBS for 30 minutes at 4°C. Cells were acquired on a BD Flow Cytometer and analyzed using FlowJo flow cytometry analysis software. Dead cells were excluded from the analysis by gating on the ZombieNIR-negative population. BCMA mean fluorescence intensity (MFI) was plotted against GSI concentration to establish the EC50.

[0315] The results summarized in Figures 3A-3E and Table 4 show that GSI treatment upregulates BCMA expression on the cell surface of multiple myeloma cell lines MM.1S, OPM2, H929, Molp8, and RPMI8226, respectively.

[0316] [Table 36]

[0317] Example 4 An in vitro assay to detect cell surface BCMA expression in a time-dependent manner in multiple myeloma cell lines treated with GSI This example shows that treatment of multiple myeloma cell lines with GSI increases BCMA cell surface expression in a time-dependent manner, and that after GSI is removed from the culture, BCMA surface levels return to baseline.

[0318] Multiple myeloma cells (MM.1S, OPM2, H929, Molp8, and RPMI8226) were seeded in 6-well plates at 800,000 cells / 2 ml / well with GSI diluted to 1 μM in RPMI medium (containing 0.1% DMSO). Cells were harvested to assess cell surface BCMA expression at baseline and then 3, 6, and 24 hours after the addition of GSI. After 24 hours of incubation with GSI, cells were washed twice in PBS and replated into fresh 6-well plates. After washing away GSI, cells were further harvested for staining at 3, 6, and 24 hours. At the indicated time points, samples were stained with ZombieNIR Viability dye (Biolegend) diluted 1 / 500 in PBS for 20 minutes at room temperature, washed with PBS + 2% FBS, and further stained with anti-BCMA PE-labeled antibody diluted in PBS + 2% FBS for 30 minutes at 4°C. Samples were acquired on a BD Flow Cytometer and analyzed using FlowJo software. Dead cells were excluded from the analysis by gating on the ZombieNIR-negative population. BCMA MFI was plotted as a histogram.

[0319] The results summarized in Figures 4A-4E and Table 5 show that GSI up-regulates cell surface BCMA expression on MM.1S, OPM2, H929, Molp8, and RPMI8226 cells, respectively, in a time-dependent manner, and that the up-regulated surface BCMA expression does not persist after GSI is removed from the culture.

[0320] [Table 37]

[0321] Example 5 An in vitro assay to detect soluble BCMA (sBCMA) levels in multiple myeloma cell lines treated with GSI This example demonstrates the reduced release of sBCMA in multiple myeloma cell lines treated with GSI.

[0322] Multiple myeloma cells (MM.1S, OPM2, H929, Molp8, RPMI8226) were seeded at 40,000 cells / well in 96-well U-bottom plates. Cells were incubated for 24 hours in the presence of GSI diluted in RPMI medium (0.1% DMSO). The following concentrations of GSI were tested: 1000 nM, 500 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, 2.5 nM, 1 nM, 0.1 nM, and 0.01 nM. After 24 hours, cell culture medium was collected, and the concentration of sBCMA in the supernatant was measured using the Human BCMA / TNFRSF DuoSet ELISA Kit (R&D Systems) according to the manufacturer's instructions.

[0323] The results summarized in Figures 5A-5E and Table 6 show that GSI treatment blocks the release of sBCMA in multiple myeloma cell lines MM.1S, OPM2, H929, Molp8, and RPMI8226, respectively.

[0324] [Table 38]

[0325] Example 6 BCMAxCD3 bispecific antibody combined with GSI in multiple myeloma This example shows that treatment with a BCMAxCD3 bispecific antibody in combination with a GSI shows enhanced cell killing in multiple myeloma cells cultured with human T cells compared to the BCMAxCD3 bispecific antibody alone.

[0326] PBMC-derived CD3 + T cells (Stem Cell Technologies) were negatively selected using the EasySep Human T Cell Enrichment Kit (Stem Cell Technologies). Luciferase-expressing multiple myeloma cells (MM.1S-luc, OPM2-luc, H929-luc, Molp8-luc, RPMI8226-luc) were treated with 1 μM GSI 10,000. After 24 hours, the cells were cultured in a clear 96-well V-bottom plate at 50,000 CD3 + Pan T cells were seeded together. Cells were further treated with a range of concentrations of BCMAxCD3 bispecific antibody with or without 1 μM GSI. Sixty hours after treatment, luciferase activity in the treated cells was analyzed using a NeoLite reagent kit (Perkin Elmer) and acquired on a VictorX multimode plate reader (Perkin Elmer). Cell viability was calculated by dividing the luciferase activity of the treated cells by the luciferase activity of the untreated control (no BCMAxCD3 bispecific antibody added).

[0327] The results summarized in Figures 6A-6E and Tables 7-8 show that treatment with GSI enhances BCMAxCD3 bispecific antibody ("BCMAxCD3" in Tables 7 and 8)-mediated cell killing in multiple myeloma cell lines (MM.1S (21x), OPM2 (21x), H929, Molp8, RPMI8226 (24x), respectively) when cultured with human T cells.

[0328] [Table 39]

[0329] [Table 40]

[0330] Example 7 In vitro assay to detect cell surface BCMA expression in lymphoma cell lines treated with GSI This example demonstrates the upregulation of cell surface BCMA expression in lymphoma cells treated with GSI.

[0331] Lymphoma cells (Raji cell line) were seeded at 40,000 cells / well in 96-well U-bottom plates. Cells were incubated for 24 hours in the presence of GSI diluted in RPMI medium (0.1% DMSO). The following concentrations of GSI were tested: 1000 nM, 500 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, 2.5 nM, 1 nM, 0.1 nM, and 0.01 nM. After 24 hours, cells were harvested, washed with PBS + 2% FBS, and then stained with ZombieNIR Viability Dye (Biolegend) diluted 1 / 500 in PBS for 20 minutes at room temperature. Next, cells were washed with PBS + 2% FBS and stained with anti-BCMA PE-labeled antibody (Biolegend) diluted in PBS + 2% FBS for 30 minutes at 4°C. Cells were acquired on a BD Flow Cytometer and analyzed using FlowJo flow cytometry analysis software. Dead cells were excluded from the analysis by gating on the ZombieNIR-negative population. BCMA MFI was plotted against GSI concentration to establish the EC50.

[0332] The results summarized in Figure 7 and Table 9 show that GSI treatment upregulates BCMA expression on the cell surface of Raji lymphoma cells.

[0333] [Table 41]

[0334] Example 8 An in vitro assay to detect cell surface BCMA expression in a time-dependent manner in lymphoma cell lines treated with GSI This example shows that treatment of lymphoma cell lines with GSI increases BCMA cell surface expression in a time-dependent manner, and that after GSI is removed from the culture, BCMA surface levels return to baseline.

[0335] Lymphoma cells (Raji) were seeded in 6-well plates at 800,000 cells / 2 ml / well with GSI diluted to 1 μM in RPMI medium (containing 0.1% DMSO). Cells were harvested to assess cell surface BCMA expression at baseline and then 3, 6, and 24 hours after GSI addition. After 24 hours of incubation with GSI, cells were washed twice in PBS and replated into fresh 6-well plates. After washing away GSI, cells were further harvested for staining at 3, 6, and 24 hours. At the indicated time points, samples were stained with ZombieNIR Viability dye (Biolegend) diluted 1 / 500 in PBS for 20 minutes at room temperature, washed with PBS + 2% FBS, and further stained with anti-BCMA PE-labeled antibody diluted in PBS + 2% FBS for 30 minutes at 4°C. Samples were acquired on a BD Flow Cytometer and analyzed using FlowJo software. Dead cells were removed from the analysis by gating on the ZombieNIR-negative population. BCMA mean fluorescence intensity (MFI) was plotted as a histogram.

[0336] The results summarized in Figure 7B and Table 10 show that GSI upregulates cell surface BCMA expression on Raji cells in a time-dependent manner, and that the upregulated surface BCMA expression does not persist after GSI is removed from the culture.

[0337] [Table 42]

[0338] Example 9A BCMAxCD3 bispecific antibody combined with GSI in lymphoma cells This example shows that treatment with a BCMAxCD3 bispecific antibody in combination with a GSI shows enhanced cell killing in low BCMA-expressing lymphoma cells cultured with human T cells compared to the BCMAxCD3 bispecific antibody alone.

[0339] PBMC-derived CD3 + T cells (Stem Cell Technologies) were negatively selected using the EasySep Human T Cell Enrichment Kit (Stem Cell Technologies). 10,000 luciferase-expressing target lymphoma cells (Raji-luc) were treated with 1 μM GSI. After 24 hours, the cells were transfected with 50,000 CD3 T cells in a clear 96-well V-bottom plate. + Pan T cells were seeded together. Cells were further treated with a range of concentrations of BCMAxCD3 bispecific antibody with or without 1 μM GSI. Sixty hours after treatment, luciferase activity in the treated cells was analyzed using a NeoLite reagent kit (Perkin Elmer) and acquired on a VictorX multimode plate reader (Perkin Elmer). Cell viability was calculated by dividing the luciferase activity of the treated cells by the luciferase activity of the untreated control (no BCMAxCD3 bispecific antibody added).

[0340] The results summarized in Figure 8 and Table 11A show that treatment with GSI enhances BCMAxCD3 bispecific antibody-mediated cell killing in a lymphoma cell line (Raji) when cultured with human T cells.

[0341] [Table 43]

[0342] Example 9B Gamma secretase inhibitor activity enhances the in vitro cytotoxic effect of the BCMAxCD3 bispecific antibody PF06863135 against multiple myeloma cells in a co-culture assay This example demonstrates the combination benefit of treating multiple myeloma cells with GSI and the BCMAxCD3 bispecific antibody PF06863135 (erlanatamab) compared to BCMAxCD3 antibody alone in cytotoxic T lymphocytes (CTLs) in an in vitro co-culture assay.

[0343] Luciferase-expressing multiple myeloma cell lines (H929-Luc, Molp8-Luc, OPM2-Luc, and RPMI8226-Luc) were cultured with 1 mM GSI at 37°C and 5% CO2 for 24 h or left untreated. Myeloma cells were then harvested and isolated from 50,000 CD3 T cells enriched from human PBMCs using a negative selection Pan T cell isolation kit (Miltenyi Biotec). + T cells were plated onto 96-well U-bottom plates at 10,000 cells / well. Media containing serial dilutions of the BCMAxCD3 bispecific antibody PF06863135, with or without 1 mM GSI, was further added to the wells, and the plates were then incubated at 37°C and 5% CO2 for 72 h. At the end of the incubation period, Bright-Glo substrate (Promega) was added to the wells, and luminescence was measured on a SpectraMax plate reader. Percent cell viability was calculated by taking the luminescence signal value for each test well, dividing by the average signal from untreated control wells, and multiplying by 100. EC was calculated by generating a four-parameter dose-response curve fit of the cell viability data versus antibody dose concentration using GraphPad Prism. 50 Values ​​were further calculated. Table 11B shows that treatment with GSI improves BCMAxCD3 antibody-mediated killing of multiple myeloma cells (H929, Molp8, OPM2, and RPMI8226) treated in co-culture with human T cells.

[0344] [Table 44]

[0345] Example 10 First-in-human Phase 1 clinical trial of the BCMAxCD3 bispecific antibody erlanatamab (PF-06863135) This example describes an ongoing Phase 1, open-label, multicenter clinical trial of PF-06863135 (a BCMAxCD3 bispecific antibody) as monotherapy and in combination with sasanlimab, lenalidomide, or pomalidomide in adult patients with advanced multiple myeloma that has relapsed from or is refractory to standard therapy. The trial is registered on ClinicalTrials.gov with identifier NCT03269136 and was first listed in August 2017. Study results for Part 1 of the trial and additional treatment arms of the study are described in this example.

[0346] The study arms and initial dosing design are briefly described in Table 12. For each study arm, drug treatment will continue until disease progression, patient refusal (withdrawal of consent), or unacceptable toxicity.

[0347] [Table 45]

[0348] The RP2D dose was then determined based on the clinical outcomes in Part 1 and selected to be a maintenance dose of 76 mg Q1W SC with a single priming dose of 44 mg SC administered 1 week before the first maintenance dose.

[0349] In Part 1, a combination dose discovery study, subjects received a fixed dose of PF06863135 with a maintenance dose beginning one week after the priming dose. The starting dose was determined to be one level below the single-agent RP2D and either escalated to the RP2D dose or tapered to the RP2D-2 level. Table 12A lists potential fixed dose levels for the PF06863135 and second-agent combination study. For Part 1C, the starting dose of lenalidomide was modified to 15 mg QD orally on days 1-21 of a 28-day cycle, beginning 7 days after the PF06863135 priming dose.

[0350] [Table 46]

[0351] Part 1 of the study is a single-agent dose-escalation arm of PF-06863135 at dose levels of 0.1, 0.3, 1, 3, 10, 30, and 50 μg / kg Q1W via intravenous (IV) administration and 80, 130, 215, 360, 600, and 1000 μg / kg Q1W via subcutaneous (SC) administration. Upon reaching the maximum tolerated dose (MTD) / maximum administered dose (MAD), patients will be treated with dose levels selected from those described in this paragraph, and at dose levels below the MTD / MAD for Q2W administration, both IV and SC, to further support the determination of the recommended phase 2 dose (RP2D). For the study, the dose-limiting toxicity observation period will be 21 days for Q1W dosing and 28 days for Q2W dosing. The treatment cycle, also known as cycle, will be 3 weeks for Q1W dosing and 4 weeks for Q2W dosing.

[0352] Clinical outcomes for Part 1 of the study. As of April 15, 2020, a total of 23 patients were enrolled in Part 1 of the study and treated with PF-06863135 administered intravenously (IV) at 0.1 (N = 2), 0.3 (N = 3), 1 (N = 2), 3 (N = 3), 10 (N = 2), 30 (N = 5), and 50 (N = 6) μg / kg. As of August 21, 2020, a total of 30 patients were enrolled in Part 1 of the study and treated with PF-06863135 administered subcutaneously (SC) at 80 (N = 3), 130 (N = 4), 215 (N = 4), 360 (N = 4), 600 (N = 6), and 1000 (N = 6) μg / kg. Safety and efficacy data were available in 23 IV and 30 SC treated patients according to IMWG (International Myeloma Working Group) criteria.

[0353] Among patients in the IV cohort, two patients (one patient in the 30 μg / kg cohort and one patient in the 50 μg / kg cohort) experienced a dose-limiting toxicity (DLT) of grade 3 febrile neutropenia and grade 1 electrocardiogram QT prolongation. No patients in the SC cohort experienced DLTs. Cytokine release syndrome (CRS) was the most commonly reported adverse event. In the IV cohort, CRS was observed in one (50.0%), four (80.0%), and six (100%) patients in the 10, 30, and 50 μg / kg cohorts, respectively. Of all IV-treated patients, six (26.1%) experienced CRS of up to grade 1, while five (21.7%) experienced CRS of up to grade 2. CRS began within the first two days of dosing for each of the 11 patients with CRS. In the three patients at 50 μg / kg, CRS also occurred after the second dose in one patient, after the second and third doses in one patient, and after the third and fourth doses in one patient.

[0354] In the SC cohort, CRS was observed in 3 (50.0%), 2 (50.0%), 3 (75.0%), 3 (75.0%), 6 (100%), and 6 (100%) patients in the 80, 130, 215, 360, 600, and 1000 μg / kg groups, respectively. Of all SC-treated patients, 18 (60.0%) experienced CRS of up to grade 1, while 5 (16.7%) experienced CRS of up to grade 2. CRS primarily began within the first 2 days of dosing. Table 13 provides further details of CRS in the SC cohort.

[0355] [Table 47]

[0356] In the IV cohort, two patients achieved a minimal response at 3 μg / kg and 50 μg / kg IV, and one patient achieved a complete response at 50 μg / kg IV. Ten subjects in the IV cohort (0.3–50 μg / kg) achieved a best response of stable disease.

[0357] Efficacy results in the SC cohort are summarized in Table 14 below.

[0358] [Table 48]

[0359] These results indicate that at the highest dose levels of 600 and 1000 μg / kg SC, clinical efficacy was seen in most patients, toxicity was tolerable and manageable, and CRS occurred less severely in SC-treated patients despite higher total dose exposure in SC-treated patients compared with IV-treated patients.

[0360] Part 1.1 of the study is an alternative maintenance dose escalation arm for single-agent PF-06863135. If excessive toxicity occurs or the maximum tolerated dose (MTD) / maximum administered dose (MAD) is reached at an earlier dose level than desired in Part 1 of the study above, a priming dose will be administered one week prior to Day 1 of Cycle 1 administration of the dose (maintenance dose) at this dose level and for all subsequent dose levels in the dose escalation initiated for Part 1.1. The priming dose will be at a lower dose level than the maintenance dose.

[0361] Clinical Outcomes for Part 1.1 of the Study. As of February 4, 2021, a total of 20 patients had been enrolled. Treatment in Part 1.1 of the study involved a 7-patient cohort receiving a 600 μg / kg priming dose followed by 1000 μg / kg Q1W dosing and a 13-patient cohort receiving a 600 μg / kg priming dose followed by 1000 μg / kg Q2W dosing. CRS in these two cohorts is listed in Table 13. The introduction of the priming dose reduced the median duration of CRS by 50%, from 4 days to 2 days. The dosing frequency (Q1W vs. Q2W) in Part 1.1 of the study had no effect on CRS. Patient responses in Part 1.1 of the study are listed in Table 14.

[0362] Part 2A of the study is a dose expansion arm of PF-06863135 as a single agent. Based on the single-agent dose escalation clinical data, either IV or SC administration, including priming and maintenance doses and either Q1W or Q2W dosing, will be selected for Part 2A of the study. In particular, SC administration at dose levels of 215, 360, 600, or 1000 μg / kg Q1W or Q2W without a priming dose, or SC administration at maintenance dose levels of 215, 360, 600, or 1000 μg / kg Q1W or Q2W with a priming dose on Day 1 of Cycle 0 at a dose level lower than that of the maintenance dose, appears promising as the RP2D for the Phase 2A study.

[0363] Preliminary pharmacokinetic (PK) analysis indicated that body weight was not a clinically relevant factor for PF-06863135 exposure. Therefore, a fixed dose is preferred for PF-06863135 dosing. Based on the encouraging efficacy and safety data from Part I of the study, a potential RP2D for Part 2A of the study could be a fixed dose equivalent to 1000 μg / kg of PF-06863135 (i.e., 76 mg) administered either Q1W or Q2W. A fixed dose equivalent to 600 μg / kg (i.e., 44 mg) would likely be used as a priming dose on Day 1 of Cycle 0. The initial 44 mg dose is designed to serve as a priming dose and alleviate CRS symptoms with the later 76 mg dose. Based on the results of Part 1 of the study, CRS primarily occurs after the initial dose. Subsequently, 44 mg (priming) and 76 mg (maintenance) were selected as single-agent RP2D doses. Patients will receive a single priming dose of PF06863135 of 44 mg SC followed by a maintenance dose of 76 mg Q1W SC or 76 mg Q2W starting 7 days after the single priming dose.

[0364] Parts 1B and 2B of the study are a combination of PF-06863135 and the PD-1 antibody, sasanlimab. Treatment cycles are 28 days. Sasanlimab is administered at 300 mg SC Q4W, starting on Day 1 of Cycle 1. PF-06863135 is administered SC or IV at the selected dose Q1W or Q2W, starting on Day 1 of Cycle 1, with or without a priming dose one week prior to Day 1 of Cycle 1.

[0365] In Part 1B, the dose of PF-06863135 will be determined based on the results of Parts 1 and 1.1 of the study, starting at the RP2D or MTD / MAD-1 level described for Part 2A of the study above, whichever is lower. If the combination regimen is not well tolerated, a taper of PF-06863135 to a lower dose level will be performed to select the dose level for Part 2B.

[0366] In Part 2B, PF06863135 will be administered at dose levels based on the results of Part 1B.

[0367] Parts 1C and 2C of the study are combination therapy with PF-06863135 and lenalidomide. Treatment cycles are 28 days. Lenalidomide is administered orally (PO) at 25 mg daily on days 1-21 without dexamethasone, starting on day 1 of cycle 1. PF-06863135 is administered SC or IV at the selected dose Q1W or Q2W, starting on day 1 of cycle 1, with or without a priming dose one week prior to day 1 of cycle 1.

[0368] In Part 1C, the dose of PF-06863135 was determined based on the results of Parts 1 and 1.1 of the study. The initial plan was to initiate at the RP2D described for Part 2A of the study above, or at the MTD / MAD, whichever was lower. If the combination regimen was not well tolerated, de-escalation of PF-06863135 to a lower dose level would be performed to select the dose level for Part 2C. It was then decided to initiate at a dose level of PF06863135 that was one level below the single-agent RP2D described in Table 12A. The starting dose of lenalidomide was modified to 15 mg QD orally on days 1-21 of a 28-day cycle, starting 7 days after the priming dose of PF06863135.

[0369] In Part 2C, PF-06863135 will be administered at dose levels based on the results of Part 1C.

[0370] Parts 1D and 2D of the study are combination therapy with PF06863135 and pomalidomide. Treatment cycles are 28 days. Pomalidomide is administered at 4 mg PO daily on days 1-21 without dexamethasone, starting on day 1 of cycle 1. PF-06863135 is administered SC or IV at the selected dose Q1W or Q2W, starting on day 1 of cycle 1, with or without a priming dose one week prior to day 1 of cycle 1.

[0371] In Part 1D, the dose of PF-06863135 will be determined based on the results of Parts 1 and 1.1 of the study, starting at the lower of the RP2D or MTD / MAD described for Part 2A of the study above. If the combination regimen is not well tolerated, a de-escalation of PF06863135 to a lower dose level will be performed to select the dose level for Part 2D. It was then decided to start at a dose level of PF06863135 that is one level below the single-agent RP2D described in Table 12A.

[0372] In Part 2D, PF-06863135 will be administered at dose levels based on the results of Part 1D.

[0373] Patient Enrollment Criteria. For all treatment arms of the studies described herein, patient enrollment criteria include that patients must have progressed on or be intolerant to established therapies known to provide clinical benefit in multiple myeloma, including proteasome inhibitors, immunomodulatory imid drugs (ImiDs), and anti-CD38 mAbs, if approved and available in combination or as single agents, and that patients must not be candidates for regimens known to provide clinical benefit in relapsed or refractory multiple myeloma based on the investigator's judgment.

[0374] The primary and secondary objectives of the study include (1) to evaluate the preliminary clinical efficacy of PF-06863135 at RP2D, (2) to further characterize the safety and tolerability, (3) to evaluate the PK of PF-06863135 at RP2D, (4) to evaluate the immunogenicity of PF-06863135, and (5) to characterize the effect of PF-06863135 on systemic soluble immune factors, where (1)–(5) are for PF-06863135 as monotherapy and in combination with sasanlimab, lenalidomide, or pomalidomide, respectively.

[0375] Example 11 A Phase 2 Clinical Trial of the BCMAxCD3 Bispecific Antibody PF-06863135 in Participants With Multiple Myeloma Refractory to At Least One Proteasome Inhibitor, One IMiD, and One Anti-CD38 Monoclonal Antibody This is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of PF-06863135 in patients with relapsed / refractory multiple myeloma (RRMM) who are refractory to at least one proteasome inhibitor (PI), one IMiD, and one anti-CD38 mAb. To determine the effect of prior BCMA-directed therapy on response to PF-06863135 monotherapy, the study will enroll two independent, parallel cohorts: one cohort containing BCMA-directed therapy-naïve participants (Cohort A; approximately 90 participants), and the other cohort containing participants who have received a prior approved or investigational BCMA-directed ADC or BCMA-directed CAT-T cell therapy (Cohort B; approximately 60 participants). The primary objective for each independent cohort is to determine the efficacy (i.e., ORR) of PF-06863135 as defined by the International Myeloma Working Group (IMWG) and assessed by blinded independent central review (BICR). The study design scheme is shown in Table 15 below.

[0376] [Table 49]

[0377] Dosing: Participants in each cohort will receive an initial dose of 44 mg of PF-06863135 administered by subcutaneous injection (SC) on Day 1 of Cycle 1 (C1D1). Each treatment cycle is 28 days. The 44 mg initial dose is expected to serve as a priming dose and reduce CRS symptoms, primarily expected after the initial dose. The priming dose was later modified so that 12 mg of PF06863135 was administered on C1D1, followed by 32 mg of PF06863135 on C1D4. The dose of PF-06863135 should be increased to 76 mg SC Q1W starting on Day 8 of Cycle 1 as long as participants meet all three criteria described below: (1) ANC≧1.0x10 9 / L; (2) Platelet count ≥ 25 x 10 9 / L; and (3) Recovery of treatment-related nonhematologic toxicity to baseline or to a severity of Grade 1 or less (or, at the investigator's discretion, Grade 2 or less if not considered a safety risk to the participant).

[0378] If a participant does not meet these criteria on Day 8 of Cycle 1, initiation of dosing with 76 mg should be postponed until these criteria are met. If a participant receives Q1W dosing for at least six cycles and achieves a PR or better IMWG response with a response sustained for at least 2 months, the dosing interval should be changed from Q1W to Q2W because a lower dose intensity may be sufficient to maintain the response given the reduced disease burden in these participants. However, participants may remain on the Q1W schedule based on the investigator's medical judgment and after consultation with the trial sponsor. After changing to Q2W intervals, the dosing interval may be changed back to Q1W, according to the investigator's medical judgment.

[0379] For each study cohort, treatment with PF-06863135 will continue until disease progression, patient refusal (withdrawal of consent), or unacceptable toxicity. The study will be completed if all participants discontinue the study intervention and have an overall survival (OS) of at least two years thereafter.

[0380] Primary endpoint: To determine the overall response rate (ORR) by blinded independent central review (BICR) by the International Myeloma Working Group (IMWG).

[0381] Secondary endpoints: (1) BICR by IMWG and investigator-performed duration of response (DOR); (2) BICR by IMWG and investigator-performed cumulative complete response rate (CCRR); (3) ORR by IMWG and investigator-performed cumulative complete response rate (DOCCR); (4) BICR by IMWG and investigator-performed progression-free survival (PFS); (6) overall survival (OS); (7) BICR by IMWG and investigator-performed cumulative complete response rate (CCRR). (8) time to response (TTR) by IMWG; (9) negativity rate of minimal residual disease (MRD) by IMWG (central laboratory); (10) severity of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) assessed according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria; (11) pre- and post-dose concentrations of PF-06863135 and (12) ADAs and NAbs against PF-06863135.

[0382] Example 12 A Phase 1 / 2, Open-Label, Multicenter Study to Evaluate Two Ascending Priming Doses and a Longer Dosing Interval of Erlanatamab (PF-06863135) Monotherapy in Participants With Relapsed / Refractory Multiple Myeloma The objective of this study is to evaluate the rate of grade 2 or higher CRS when erlanatamab is administered using two escalating priming doses and a premedication regimen. Additionally, the study will evaluate the safety, tolerability, PK, and preliminary antimyeloma activity of erlanatamab at doses higher than 76 mg using different dosing intervals (QW, Q2W, and Q4W) in participants with relapsed / refractory multiple myeloma (RRMM). A full-dose regimen of 76 mg QW followed by Q2W (Part 2) for six cycles will also be evaluated. Cycle 1 begins on the day participants receive their first priming dose.

[0383] All doses of erlanatamab are administered subcutaneously (SC).

[0384] In the first cycle (C1) of erlanatamab treatment, the following regimens will be evaluated for all participants in the study:

[0385] C1D1: premedication + erlanatamab 12 mg; C1D4: premedication + erlanatamab 32 mg; C1D8: premedication + erlanatamab 76 mg; C1D15 and C1D22: erlanatamab 76 mg.

[0386] Premedication is required approximately 60 minutes before both the priming doses of erlanatamab (C1D1 and C1D4) and the first full dose (C1D8). The premedications used are acetaminophen 650 mg (or paracetamol 500 mg), diphenhydramine 25 mg, oral or IV, and dexamethasone 20 mg (or equivalent), oral or IV.

[0387] For cycles 2 and beyond, evaluate the following:

[0388] Part 1A. In the dose level 1 cohort, participants will receive 116 mg Q2W for C2-C6, with a PR or better IMWG response for at least two cycles of Q2W, switching to 116 mg Q4W if needed. If dose level 1 is tolerated, participants will receive 152 mg Q2W for C2-C6, with a PR or better IMWG response for at least two cycles of Q2W, switching to 152 mg Q4W if needed. For both dose levels 1 and 2, if after switching to a Q4W interval, participants subsequently begin to have an increase in disease burden that has not yet been qualified as PD by IMWG criteria, the dosing interval should be reverted to Q2W at the same dose level (e.g., from 152 mg Q4W to 152 mg Q2W).

[0389] Part 1B, which will begin once the potential MTD / RP2D is identified from Part 1A and is a dose expansion cohort at selected dose levels.

[0390] Part 1C begins only if both dose levels 1 and 2 in Part 1A are tolerated. For C2-C3, participants receive 116 mg Q1W or 152 mg Q1W. For C4-C6, participants who achieve PR or better IMWG response in C2 and C3 receive 116 mg or 152 mg Q2W. For C7 and beyond, participants who achieve PR or better IMWG response for at least two cycles Q2W receive 116 mg or 152 mg Q4W.

[0391] Part 2: 76 mg Q1W is administered from C2 to C6. For participants who demonstrate a PR or better IMWG response for at least two cycles on Q1W, 76 mg Q2W is administered for C7 and beyond. If, after switching to the Q2W interval, the participant subsequently begins to have an increasing disease burden that has not yet been qualified as PD by IMWG criteria, the dosing interval should revert to 76 mg Q1W.

[0392] Example 13 An Open-Label, Multicenter, Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Erlanatamab (PF06863135) and Daratumumab in Participants With Relapsed / Refractory Multiple Myeloma (RRMM) The objective of Part 1 of this study is to evaluate the DLT, safety, and tolerability of erlanatamab plus daratumumab to select a RP3D for the combination. The objective of Part 2 is to compare the efficacy of erlanatamab (Arm A) and the combination of erlanatamab and daratumumab (Arm B) with the control arm, daratumumab plus pomalidomide plus dexamethasone (Arm C). The objective of Part 1 of this study also includes evaluating the rate of Grade 2 and above CRS when erlanatamab alone or the combination is administered in two ascending priming doses with premedication. Study treatments are described in Table 16. Cycles are 28 days.

[0393] [Table 50]

[0394] Erlanatamab Dosing: In Part 1, Dose Level -1, participants should be on 44 mg QW until the end of Cycle 6, after which participants who demonstrate a PR or better IMWG response sustained for at least 2 cycles should be dosed at 44 mg Q2W. Similarly, 76 mg QW will be switched to 76 mg Q2W in Part 1, Dose Level 1, and similarly, in Part 2, QW will be switched to Q2W in Arms A and B. Subsequently, if an increase in disease burden (not qualified as PD by IMWG criteria) is observed, the dosing interval should be switched back to QW.

[0395] Daratumumab dosing: Use 1800 mg subcutaneous injections Q1W, then Q2W, then Q4W according to the USPI dosing schedule for the FDA-approved daratumumab and hyaluronidase-fihj products.

[0396] Premedication is required approximately 60 minutes before both the priming dose of erlanatamab (C1D1 and C4D1) and the first full dose (C1D8). Premedication is also required 1 to 3 hours before each dose of daratumumab, except in Part 2, Arm C, where the dexamethasone component of the treatment regimen should be administered before daratumumab and serves as a premedication. If erlanatamab and daratumumab are to be administered on the same day, premedication should be given only once that day, before the administration of both erlanatamab and daratumumab. Premedication options include acetaminophen 650–1000 mg (or paracetamol 500 mg), diphenhydramine 25–50 mg, orally or IV, or dexamethasone 20 mg (or equivalent), orally or IV.

[0397] Example 14 A randomized, two-arm, phase 3 study of erlanatamab (PF-06863135) plus lenalidomide versus lenalidomide in patients with newly diagnosed multiple myeloma (NDMM) who are minimal residual disease (MRD) positive after receiving autologous stem cell transplantation (ASCT). The objectives of this study include comparing the efficacy of erlanatamab plus lenalidomide combination therapy (Arm A) with lenalidomide (Arm B), as well as determining the safety and tolerability of erlanatamab plus lenalidomide combination therapy. Study participants have newly diagnosed multiple myeloma who are minimal residual disease (MRD) positive after undergoing autologous stem cell transplant. Table 16 below describes the planned dosing regimens for each treatment arm of the study.

[0398] [Table 51]

[0399] Premedication is required approximately 60 minutes before both the priming doses of erlanatamab (C1D1 and C1D4) and the first full dose (C1D8). The premedications used are acetaminophen 650 mg (or paracetamol 500 mg), diphenhydramine 25 mg, oral or IV, and dexamethasone 20 mg (or equivalent), oral or IV.

[0400] Example 15 A randomized, controlled, two-arm phase 3 study of erlanatamab (PF06863135) and lenalidomide versus control in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for stem cell transplantation The objectives of this study include comparing the efficacy of erlanatamab plus lenalidomide combination therapy (Arm A) with a lenalidomide control arm, as well as determining the safety and tolerability of erlanatamab. Study participants have newly diagnosed multiple myeloma who are ineligible for stem cell transplant. Table 17 below describes the planned dosing regimens for each treatment arm of the study.

[0401] [Table 52]

[0402] Example 16 A Phase 1b / 2, Open-Label, Umbrella Study of Erlanatamab (PF06863135) in Combination with Other Anticancer Treatments in Participants with Relapsed / Refractory Multiple Myeloma (RRMM) The objectives of the study include evaluating the safety and tolerability of erlanatamab in combination with other anticancer therapies in participants with RRMM to select a RP2D for the combination. Table 18 describes some exemplary combination therapy study designs for this study.

[0403] [Table 53]

[0404] array Table 19 lists the sequences of the BCMAxCD3 bispecific antibody PF-06863135 and the PD-1 antibody sasanlimab, as well as the corresponding SEQ ID NOs described herein. SEQ ID NOs: 1-13 are the sequences of the CD3 group of PF-06863135, and SEQ ID NOs: 14-26 are the sequences of the BCMA group of PF-06863135. SEQ ID NOs: 27-34 are the sequences of the PD-1 antibody sasanlimab.

[0405] [Table 54-1]

[0406] [Table 54-2]

[0407] [Table 54-3]

Claims

1. 1. A pharmaceutical composition for treating a BCMA-expressing cancer in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a B-cell maturation antigen (BCMA) bispecific therapeutic agent and the second therapeutic agent is an immunomodulatory agent, wherein the BCMA bispecific therapeutic agent is erlanatamab and the immunomodulatory agent is lenalidomide or pomalidomide; (a) a first treatment dose of about 32 mg to about 76 mg Q1W SC starting at week 1; or (b) a priming dose during week 1 and a first treatment dose beginning in week 2, wherein the priming dose is (i) a first priming dose of about 4 mg SC to about 32 mg SC and a second priming dose of about 12 mg SC to about 44 mg SC, the first and second priming doses being administered sequentially in week 1, or (ii) a single priming dose of about 24 mg to about 44 mg SC, the first treatment dose being about 32 mg to about 76 mg Q1W starting in week 2; administering to the subject a treatment dose of erlanatamab SC or about 32 mg to about 152 mg Q2W SC, wherein the dose of the first treatment dose is higher than the dose of each of the single priming dose, the first priming dose, and the second priming dose; The pharmaceutical composition wherein week 1, week 2, and any subsequent week refer to the first, second, and any subsequent week, respectively, during which erlanatamab is administered to the subject, and the erlanatamab is administered to the subject as a pharmaceutical comprising erlanatamab.

2. 10. The pharmaceutical composition of claim 1, wherein the subject is administered a priming dose, wherein the priming dose is a single priming dose of about 24 mg SC, about 32 mg SC, or about 44 mg SC at week 1, or the priming dose is (i) a first priming dose of about 12 mg SC and a second priming dose of about 32 mg SC, (ii) a first priming dose of about 4 mg SC and a second priming dose of about 20 mg, (iii) a first priming dose of about 8 mg and a second priming dose of about 16 mg, (iv) a first priming dose of about 12 mg and a second priming dose of about 12 mg, or (v) a first priming dose of about 8 mg and a second priming dose of about 24 mg.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the first treatment dose is about 32 mg Q1W SC or about 32 mg Q2W SC, about 44 mg Q1W SC, or about 44 mg Q2W SC.

4. 4. The pharmaceutical composition of claim 3, wherein the subject is administered the first treatment dose until at least the end of cycle 1 or until at least the end of cycle 6, wherein a cycle is 21 days or 28 days, wherein cycle 1 begins on week 1, week 2, or week 3, and wherein cycle 1, cycle 2, and subsequent cycle numbers refer to the first, second, and subsequent cycle numbers, respectively, in which the subject is administered erlanatamab.

5. administering erlanatamab to a subject at about 32 mg to about 152 mg Q2W SC, about 32 mg to about 152 mg Q3W SC after the subject has already received the first treatment dose; 5. The pharmaceutical composition of claim 4, further comprising administering a second treatment dosage of about 32 mg to about 152 mg Q4W SC, or about 32 mg to about 152 mg Q4W SC, wherein the second treatment dosage is of a dosing frequency that is less frequent than the respective first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage.

6. After the first treatment dose has been administered to the subject through at least the end of cycle 6, a second treatment dose of erlanatamab may be administered to the subject in place of the first treatment dose, or the subject may continue to be administered the first treatment dose, wherein the second treatment dose is about 32 mg to about 152 mg Q2W.

5. The pharmaceutical composition of claim 4, wherein the second treatment dosage is about 32 mg to about 152 mg Q3W SC, about 32 mg to about 152 mg Q4W SC, or about 32 mg to about 152 mg Q4W SC, and wherein the second treatment dosage is of a dosing frequency that is less frequent than the first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage.

7. the first treatment dose is (i) about 76 mg Q1W SC, (ii) about 76 mg Q2W SC, or (iii) about 76 mg Q1W SC for 3 weeks followed by about 116 mg Q1W SC; 3. The pharmaceutical composition of claim 1 or 2, wherein the administration is about 76 mg Q1W SC or (iv) about 76 mg Q1W SC for 3 weeks followed by about 152 mg Q1W SC.

8. 8. The pharmaceutical composition of claim 7, wherein the subject is administered the first treatment dose until at least the end of cycle 1, at least the end of cycle 3, or at least the end of cycle 6, wherein a cycle is 21 days or 28 days, wherein cycle 1 begins on week 1, week 2, or week 3, and wherein cycle 1, cycle 2, and subsequent cycle numbers refer to the first, second, and subsequent cycle numbers, respectively, in which the subject is administered erlanatamab.

9. administering erlanatamab to a subject at about 44 mg to about 152 mg Q2W SC, about 44 mg to about 152 mg Q3W SC after the subject has already received the first treatment dose; 9. The pharmaceutical composition of claim 8, further comprising administering a second treatment dosage of about 44 mg to about 152 mg Q4W SC, or about 44 mg to about 152 mg Q4W SC, wherein the second treatment dosage is of a dosing frequency that is less frequent than the first treatment dosage, or the second treatment dosage has a lower dose than the first treatment dosage.

10. After administering the first treatment dose to the subject until at least the end of cycle 6, the subject may receive about 44 mg to about 152 mg Q2W SC, about 44 mg to about 152 mg Q3W SC, or about 44 mg to about 152 mg Q4W SC.

9. The pharmaceutical composition of claim 8, wherein the second treatment dosage is administered SC to the subject in place of the first treatment dosage, or the subject may continue to be administered the first treatment dosage, and the second treatment dosage is of an administration frequency that is less frequent than the respective first treatment dosage, or the second treatment dosage has a lower dose than that of the first treatment dosage.

11. The first treatment dose was about 76 mg Q1W SC and the second treatment dose was about 44 mg Q2W SC, about 76 mg Q2W SC, about 116 mg Q2W SC, about 152 mg Q2W SC. SC, about 44 mg Q3W SC, about 76 mg Q3W SC, about 116 mg Q3W SC, about 152 mg Q3W SC, about 44 mg Q4W SC, about 76 mg Q4W 11. The pharmaceutical composition of claim 9 or 10, wherein the pharmaceutical composition is about 116 mg Q4W SC, about 116 mg Q4W SC, or about 152 mg Q4W SC.

12. The first treatment dose was about 76 mg Q2W SC and the second treatment dose was about 44 mg Q2W SC, about 44 mg Q3W SC, about 76 mg Q3W SC, about 116 mg Q3W SC.

11. The pharmaceutical composition of claim 9, wherein the dosage is about 152 mg Q3W SC, about 152 mg Q4W SC, about 44 mg Q4W SC, about 76 mg Q4W SC, about 116 mg Q4W SC, or about 152 mg Q4W SC.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the subject is administered erlanatamab at a first treatment dose until the end of cycle 1, followed by administration of a second treatment dose, wherein one cycle is 21 days or 28 days, and cycle 1 starts on day 1 of week 1, or day 1 of week 2, or day 1 of week 3, and cycle 1, cycle 2, and subsequent cycle numbers refer to the first, second, and subsequent cycle numbers, respectively, in which the subject is administered erlanatamab.

14. The second treatment dose is administered until at least the end of cycle 6, followed by about 76 mg to about 152 mg Q3W SC or about 76 mg to about 152 mg Q4W SC.

14. The pharmaceutical composition of claim 13, wherein the third treatment dose of SC is administered to the subject in place of the second treatment dose or while the subject continues to be administered the second treatment dose.

15. The second treatment medication was administered until the end of cycle 6, and the first dose of the third treatment medication was initiated in cycle 7, with the third treatment medication being 116 mg Q4W SC or 152 mg Q4W SC. The pharmaceutical composition of claim 14, which is a SC.

16. 16. The pharmaceutical composition of claim 14 or 15, wherein the first treatment dose is about 76 mg SC Q1W, the second treatment dose is about 116 mg SC Q2W, and the third treatment dose is about 116 mg SC Q4W.

17. 16. The pharmaceutical composition of claim 14 or 15, wherein the first treatment dose is about 76 mg SC Q1W, the second treatment dose is about 152 mg SC Q2W, and the third treatment dose is about 152 mg SC Q4W.

18. A pharmaceutical composition for treating cancer, comprising administering erlanatamab to a subject according to the dosing schedule set forth below, wherein the dosing schedule is described by number of weeks, dose, and administration frequency corresponding to each week: (a) Table 1 , (b) Table 2 , (c) Table 3 , (d) Table 4 , (e) Table 5 or (f) Table 6 2. The pharmaceutical composition of claim 1, wherein, in the table, if the dose is 12 mg + 32 mg during week 1, a 12 mg dose is administered on one day followed by a 32 mg dose on another day, and A + B is 4(A) + 20(B), 8(A) + 16(B), 12(A) + 12(B), or 8(A) + 24(B), and if the dose is A mg + B mg during week 1, a A mg dose is administered on one day followed by a B mg dose on another day.

19. 19. The pharmaceutical composition of claim 18, wherein erlanatamab is administered to a subject according to the following dosing schedule: (a) Table 7 , (b) Table 8 , (c) Table 9 , (d) Table 10 , (e) Table 11 or (f) Table 12

20. 20. The pharmaceutical composition of claim 19, wherein the subject is administered erlanatamab according to dosing schedule (a), (b), or (c), and the dosing frequency for dosing schedules (a), (b), and (c) from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks.

21. 19. The pharmaceutical composition of claim 18, wherein erlanatamab is administered to a subject according to the following dosing schedule: (a) Table 13 , (b) Table 14 , (c) Table 15 , (d) Table 16 , (e) Table 17 or (f) Table 18

22. 22. The pharmaceutical composition of claim 21, wherein the subject is administered erlanatamab according to dosing schedule (a), (b), or (c), and the dosing frequency for dosing schedules (a), (b), and (c) from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks.

23. 25. The pharmaceutical composition of claim 24, wherein erlanatamab is administered to a subject according to the following dosing schedule: (a) Table 19 , (b) Table 20 , (c) Table 21 , (d) Table 22 , (e) Table 23 or (f) Table 24

24. 24. The pharmaceutical composition of claim 23, wherein the subject is administered erlanatamab according to dosing schedule (a), (b), or (c), and the dosing frequency for dosing schedules (a), (b), and (c) from week 25 onwards, week 26 onwards, and week 27 onwards, respectively, is (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks.

25. The doses and dosing frequency during week 1 are collectively referred to as priming doses; if a subject receives only one dose of erlanatamab in the priming dose, such one dose is referred to as a single priming dose; if a subject receives two doses of erlanatamab sequentially during week 1, the two doses are referred to as a first priming dose and a second priming dose, respectively, in each of dosing schedules (a) and (d), (b) and (e), and (c) and (f), respectively.

25. The pharmaceutical composition of any one of claims 18 to 24, wherein the doses and administration frequencies during weeks 2 to 24, weeks 2 to 25, and weeks 2 to 26 are collectively referred to as the first treatment dose in each dosing schedule, and the doses and administration frequencies during and after week 25, after week 26, and after week 27 in each dosing schedule (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as the second treatment dose in each dosing schedule.

26. 26. The pharmaceutical composition of claim 25, wherein the subject is administered a second treatment dose of erlanatamab for 6 to 18 cycles, after which the subject is administered a third treatment dose of erlanatamab subcutaneously, wherein the third treatment dose is 32 mg Q2W, 32 mg Q4W, 44 mg Q2W, 44 mg Q4W, 76 mg Q2W, 76 mg Q4W, 116 mg Q2W, 116 mg Q4W, 152 mg Q2W, or 152 mg Q4W, wherein one cycle is 21 days or 28 days, and wherein cycle 1 starts on week 1 day 1, week 2 day 1, or week 3 day 1.

27. i) the first treatment dose is 32 mg Q1W, the second treatment dose is 32 mg Q1W or 32 mg Q2W, and the third treatment dose is 32 mg Q2W or 32 mg Q4W; (ii) the first treatment dose is 32 mg Q1W, the second treatment dose is 32 mg Q2W, and the third treatment dose is 32 mg Q4W; (iii) the first treatment dose is 44 mg Q1W, the second treatment dose is 44 mg Q1W or 44 mg Q2W, and the third treatment dose is 44 mg Q2W or 44 mg Q4W; (iv) the first treatment dose is 44 mg Q1W and the second treatment dose is 44 mg Q2W. and the third treatment dose is 44 mg Q4W; (v) the first treatment dose is 76 mg Q1W, the second treatment dose is 76 mg Q1W or 76 mg Q2W, and the third treatment dose is 76 mg Q2W or 76 mg Q4W; (vi) the first treatment dose is 76 mg Q1W, the second treatment dose is 76 mg Q2W, and the third treatment dose is 76 mg Q4W; (vii) the first treatment dose is 116 mg Q1W, and the second treatment dose is 116 mg Q1W or 116 mg Q2W; (viii) the first treatment dose is 116 mg Q1W, the second treatment dose is 116 mg Q2W, and the third treatment dose is 116 mg Q4W; (ix) the first treatment dose is 152 mg Q1W, the second treatment dose is 152 mg Q1W or 152 mg Q2W, and the third treatment dose is 152 mg Q2W or 152 mg Q4W; or (x) the first treatment dose is 152 mg Q1W and the second treatment dose is 152 mg Q1W.

27. The pharmaceutical composition of claim 26, wherein the first treatment dose is 152 mg Q2W and the second treatment dose is 152 mg Q4W.

28. A pharmaceutical composition for treating cancer, comprising administering erlanatamab to a subject according to the dosing schedule set forth below, wherein the dosing schedule is described by number of weeks, dose, and frequency of administration corresponding to each week: Table 25 2. The pharmaceutical composition of claim 1, wherein in the table, where the dose is 12 mg + 32 mg during week 1, a 12 mg dose is administered on one day followed by a 32 mg dose on another day, and A + B is 4(A) + 20(B), 8(A) + 16(B), 12(A) + 12(B), or 8(A) + 24(B), where an A mg dose is administered on one day followed by a B mg dose on another day.

29. 29. The pharmaceutical composition of claim 28, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 26

30. 29. The pharmaceutical composition of claim 28, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 27

31. 31. The pharmaceutical composition of any one of claims 28 to 30, wherein the dose and administration frequency during week 1 are collectively referred to as the priming dose; if the subject is administered only one dose of erlanatamab in the priming dose, such one dose is referred to as the single priming dose; if the subject is administered two doses of erlanatamab sequentially during week 1, the two doses are referred to as the first priming dose and the second priming dose, respectively; the dose and administration frequency during weeks 2 to 4 are collectively referred to as the first treatment dose; the dose and administration frequency during weeks 5 to 24 are collectively referred to as the second treatment dose; and the dose and administration frequency during week 25 and thereafter are collectively referred to as the third treatment dose.

32. A pharmaceutical composition for treating cancer, comprising administering erlanatamab to a subject according to the dosing schedule set forth below, wherein the dosing schedule is described by number of weeks, dose, and administration frequency corresponding to each week: Table 28 2. The pharmaceutical composition of claim 1, wherein in the table, where the dose is 12 mg + 32 mg during week 1, a 12 mg dose is administered on one day followed by a 32 mg dose on another day, and A + B is 4(A) + 20(B), 8(A) + 16(B), 12(A) + 12(B), or 8(A) + 24(B), where an A mg dose is administered on one day followed by a B mg dose on another day.

33. 33. The pharmaceutical composition of claim 32, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 29

34. 34. The pharmaceutical composition of claim 33, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 30

35. 33. The pharmaceutical composition of claim 32, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 31

36. 33. The pharmaceutical composition of claim 32, wherein the subject is administered erlanatamab according to the following dosing schedule: Table 32

37. 43. The pharmaceutical composition of any one of claims 38 to 42, wherein the dose and administration frequency during week 1 are collectively referred to as the priming dose; if a subject is administered only one dose of erlanatamab in the priming dose, such one dose is referred to as the single priming dose; if a subject is administered two doses of erlanatamab sequentially during week 1, the two doses are referred to as the first priming dose and the second priming dose, respectively; the dose and administration frequency during weeks 2-4 and the dose and administration frequency during weeks 5-12 are all collectively referred to as the first treatment dose; the dose and administration frequency during weeks 13-24 are collectively referred to as the second treatment dose; and the dose and administration frequency during week 25 and thereafter are collectively referred to as the third treatment dose.

38. 38. The pharmaceutical composition of any one of claims 1 to 37, wherein the cancer is multiple myeloma.

39. 39. The pharmaceutical composition of any one of claims 1 to 38, further comprising administering to the subject at least one premedication dose on the day the single priming dose, first priming dose, second priming dose, or first treatment dose of erlanatamab is administered to the subject, wherein the premedication is acetaminophen, diphenhydramine, or dexamethasone.

40. 40. The pharmaceutical composition of any one of claims 1 to 39, further comprising administering to the subject a second therapeutic agent.

41. 40. The pharmaceutical composition of any one of claims 1 to 39, further comprising administering radiation therapy to the subject.

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