HK40096893A - Methods, therapies and uses for treating cancer - Google Patents

Description

Methods, therapies, and uses for treating cancer

Technical Field

This invention relates to single-formulation and combination therapies for the treatment of cancer and/or cancer-related diseases. Specifically, this invention relates to single-formulation and combination therapies comprising a BCMAx CD3 bispecific antibody.

Background Technology

B-cell maturation antigens (BCMA, CD269, or TNFRSF17) are members of the tumor necrosis factor receptor (TNFR) superfamily. BCMA has been identified in human malignant T-cell lymphomas containing the t(4;16) translocation. This gene is selectively expressed in B-cell lineages, with the highest expression in plasmablasts and plasma cells, and antibody-secreting cells. BCMA binds to two ligands: B-cell activating factor (BAFF) (also known as B-lymphocyte stimulator (BLyS) and APOL-associated leukocyte expression 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 the amplification of the signaling cascade involved in generating cell survival and proliferation signals, including NF-κB, Elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. BCMA is also expressed on 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 antibodies produce autoantibodies secreted by cells that attack themselves. BCMA is also present in the peripheral blood of patients with multiple myeloma in a soluble form (i.e., soluble BCMA or sBCMA) and may lead to a decline in the effectiveness of BCMA-specific therapies. Several BCMA-specific therapies are currently under development; however, multiple myeloma remains an incurable disease, and almost all patients develop resistance to these agents and eventually relapse.

The programmed death 1 (PD-1) receptor, along with PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively), play indispensable roles in immune regulation. PD-1 is expressed on activated T cells and is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, thereby triggering 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, in non-clinical animal models, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity (Iwai Y, et al. Proc Natl Acad SCiUSA 2002; 99:12293-97). Several antibodies exist that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2, and are currently being developed for cancer treatment.

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 its ligands (Jagged-1, 2, and Delta-1, 3, 4) and receptors (Notch-1, 2, 3, 4) are type I membrane proteins. Following direct cell-cell contact, the Notch receptor is cleaved by γ-secretase, releasing its intracellular domain (NICD), which translocates to the nucleus to regulate transcription. γ-secretase inhibitors (GSIs) have been developed for various diseases, including Alzheimer's disease and cancer.

Improved therapies are still needed to treat cancer and/or cancer-related diseases, such as multiple myeloma. Furthermore, therapies with greater efficacy than existing treatments are required. The preferred combination therapies of the present invention demonstrate greater efficacy than treatment with any one therapeutic agent alone.

Summary of the Invention

This invention relates to therapies, including combination therapies for treating cancer and/or cancer-related diseases. Methods for treating cancer and/or cancer-related diseases in a subject are provided herein. Methods for inhibiting tumor growth or progression in a subject with malignant cells are also provided. Methods for inhibiting the metastasis of malignant cells in a subject are also provided. Methods for inducing tumor regression in a subject with malignant cells are also provided.

This document discloses 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 invention further relates to a pharmaceutical agent comprising a first therapeutic agent and a second therapeutic agent for treating cancer and/or cancer-related diseases in a subject. The invention further relates to a first therapeutic agent for treating cancer and/or cancer-related diseases in a subject, wherein the first therapeutic agent is administered in combination with the second therapeutic agent.

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

In some aspects, the first therapeutic agent is a BCMA bispecific antibody. In some aspects, the second therapeutic agent is an anti-PD-1 antibody. In another aspect, the second therapeutic agent is an anti-PD-L1 antibody. In another aspect, the second therapeutic agent is an immunomodulator. In another aspect, the second therapeutic agent is GSI.

In some aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an anti-PD-1 antibody. In other aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an anti-PD-L1 antibody. In another aspect, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an immunomodulator. In yet another aspect, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is GSI.

In some aspects, the combination therapy further comprises a third, fourth, or fifth therapeutic agent. In some aspects, the combination therapy further comprises a chemotherapy agent. In some aspects, the therapeutic agents are administered to the subject simultaneously, alone, or sequentially.

In some aspects, the BCMA bispecific antibody is PF-06863135, the anti-PD-1 antibody is sasanlimab, the immunomodulator is lenalidomide or pomalidomide, and/or the GSI is nirogacestat or a pharmaceutically acceptable salt thereof. In one aspect, the BCMA bispecific antibody is PF-06863135. In one aspect, the anti-PD-1 antibody is sasanlimab. In one aspect, the immunomodulator is lenalidomide. In another aspect, the immunomodulator is pomalidomide. In one aspect, the GSI is nirogacestat or a pharmaceutically acceptable salt thereof.

In some respects, at least one therapeutic agent is administered to the subject in an intravenous (IV), subcutaneous (SC), or oral dose.

In some respects, at least one therapeutic agent is administered to the subject at the following doses: approximately 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. kg, 15μg/kg, 20μg/kg, 25μg/kg, 30μg/kg, 35μg/kg, 40μg/kg, 45μg/kg, 50μg/kg , 60μg/kg, 70μg/kg, 80μg/kg, 90μg/kg, 100μg/kg, 110μg/kg, 120μg/kg, 130μg/k g, 140μg/kg, 150μg/kg, 200μg/kg, 250μg/kg, 300μg/kg, 400μg/kg, 500μg/kg, 60 0μg/kg, 700μg/kg, 800μg/kg, 900μg/kg, 1000μg/kg, 1200μg/kg or 1400μg/kg or higher.

In some respects, at least one therapeutic agent is administered to the subject at the following doses: 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; or

In some respects, at least one therapeutic drug is administered to the subject at fixed doses of the following amounts: approximately 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. mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 350mg, 700mg, 750mg, 800mg, 900mg, 1000mg, or 1500mg or higher.

In some respects, at least one therapeutic drug is administered to the subject in the following manner: once a day, once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once a week, 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 a month, once every two months, once every three months, or once every four months.

In some aspects, the cancer and/or cancer-related disease is B-cell-related cancer and/or cancer-related disease. In some aspects, the B-cell-related cancer and/or cancer-related disease is selected from multiple myeloma, malignant plasma cell vegetations, lymphoma, Hodgkin's lymphoma, nodular lymphoblastic dominant Hodgkin's lymphoma, Kaller's disease and myeloid leukemia, 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, osteosclerotic myeloma, B-cell lymphoma, and other related diseases. Globulin leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-cell lymphoblastic lymphoma, myeloid leukemia, Waldenström macroglobulinemia, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue. 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 exudative lymphoma, lymphomatoid granulomatosis, T-cell/histiocytic rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (spread-leg type), EBV-positive diffuse large B-cell lymphoma in the elderly. This includes lymphomas, diffuse large B-cell lymphomas associated with inflammation, ALK-positive large B-cell lymphomas, plasmablastic lymphomas, large B-cell lymphomas occurring in HHV8-associated multicentric Castleman's disease, characteristic unclassified B-cell lymphomas intermediate between diffuse large B-cell lymphomas and Burkitt lymphomas, characteristic unclassified B-cell lymphomas intermediate between diffuse large B-cell lymphomas and classical Hodgkin's lymphoma, and other B-cell-related lymphomas. In some aspects, the B-cell-related cancers are multiple myelomas. In some aspects, the multiple myelomas are relapsed/refractory multiple myelomas.

This article also provides a method for treating multiple myeloma in subjects, comprising administering to the subjects 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). This article also provides a first therapeutic agent for a method of treating multiple myeloma in subjects, 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 aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an anti-PD-1 antibody. In other aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an anti-PD-L1 antibody. In other aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is an immunomodulatory agent. In other aspects, the first therapeutic agent is a BCMA bispecific antibody, and the second therapeutic agent is a GSI.

A method for treating multiple myeloma in a subject is also provided, 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 saxamerizumab.

A method for treating multiple myeloma in a subject is also provided, 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.

A method for treating multiple myeloma in a subject is also provided, 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.

A method for treating multiple myeloma in a subject is also provided, 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.

A method for treating cancer in a subject is also provided, which includes administering PF-06863135 to the subject according to a dosing regimen.

In some implementations, the dosing regimen is:

(a) 0.1, 0.3, 1, 3, 10, 30, 50 or 100 μg/kg once a week (Q1W) intravenously (IV).

(b) 0.1, 0.3, 1, 3, 10, 30, 50 or 100 μg/kg every two weeks (Q2W) IV;

(c) Approximately 0.5 to 10 Q1W IV or Q2W IV;

(d) Approximately 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5 or 8Q1W IV or Q2V IV.

(e) A single priming dose of approximately 0.5, 1, 2, 3, 4, 5, 6, 7.5, or 8 Q1W IV lasting for one week, followed by a first treatment dose of approximately 6, 7, 7.5, 8, 9, or 10 Q1W IV or Q2W IV, wherein the priming dose is less than the single dose in the treatment dose; or

(f) A pre-injection of about 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5 or 8 Q1W IV for one week, followed by a first treatment of about 6, 7, 7.5, 8, 9 or 10 Q1W IV for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by a second treatment of about 6, 7, 7.5, 8, 9 or 10 Q2W IV, wherein the pre-injection is less than the single dose in the first treatment.

In another aspect of the invention, the dosing regimen is

(a) 80, 130, 215, 360, 600 or 1000 μg/kg Q1W subcutaneous (SC);

(b) 80, 130, 215, 360, 600 or 1000 μg/kg Q2W SC;

(c) Approximately 16 to 80 Q1W SC or Q2W SC;

(d) Approximately 16 to 20, 40 to 44, or 76 to 80 Q1W SC;

(e) Approximately 16 to 20, 40 to 44, or 76 to 80 Q2W SC;

(f) Approximately 40 Q1W SC or Q2W SC;

(g) Approximately 44 Q1W SC or Q2W SC;

(h) Approximately 76Q1W SC or Q2W SC;

(i) Approximately 80Q1W SC or Q2W SC;

(j) Pre-treatment administration of approximately 44 Q1W SCs for 1–4 weeks, or pre-treatment administration of approximately 32 Q1W SCs for 1–4 weeks, followed by first treatment administration of approximately 76 Q1W SCs or Q2W SCs;

(k) Pre-injection of approximately 40 Q1W SCs for 1–4 weeks, followed by first treatment administration of approximately 80 Q1W SCs or Q2W SCs;

(l) Pre-treatment administration of approximately 44 Q1W SC for 1-4 weeks, or pre-treatment administration of approximately 32 Q1W SC for 1-4 weeks, followed by first treatment administration of approximately 76 Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment administration of approximately 76 Q2W SC;

(m) Pre-treatment administration of approximately 40 Q1W SC lasts for 1–4 weeks, followed by first treatment administration of approximately 80 Q1W SC lasts for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment administration of approximately 80 Q2W SC;

(n) Pre-injection of approximately 44 Q1W SCs continued for 1 week, followed by first treatment administration of approximately 76 Q1W SCs or Q2W SCs;

(o) Pre-injection of approximately 32 Q1W SCs for 1 week, followed by first treatment administration of approximately 76 Q1W SCs or Q2W SCs;

(p) Pre-injection of approximately 40 Q1W SCs continued for 1 week, followed by first treatment administration of approximately 80 Q1W SCs or Q2W SCs;

(q) Pre-treatment of approximately 44Q1W SCs for 1 week, followed by first treatment of approximately 76Q1W SCs for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment of approximately 76Q2W SCs;

(r) Pre-treatment administration of approximately 44 Q1W SCs continued for 1 week, followed by first treatment administration of approximately 76 Q1W SCs continued for 23 weeks, followed by second treatment administration of approximately 76 Q2W SCs;

(s) Pre-treatment administration of approximately 44 Q1W SCs continued for 1 week, followed by first treatment administration of approximately 76 Q1W SCs continued for 24 weeks, followed by second treatment administration of approximately 76 Q2W SCs.

(t) Pre-treatment administration of approximately 32Q1W SC for 1 week, followed by first treatment administration of approximately 76Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment administration of approximately 76Q2W SC;

(u) Pre-treatment administration of approximately 40 Q1W Sc for 1 week, followed by a first treatment administration of approximately 80 Q1W Sc for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by a second treatment administration of approximately 80 Q2W SC; or

(v) Pre-treatment administration of approximately 40 Q1W SC for 1 week, followed by first treatment administration of approximately 80 Q1W for 23 or 24 weeks, followed by second treatment administration of approximately 80 Q2W SC.

In some implementations, pre-administration is administered with a single pre-injection of 44Q1W SC, 40Q1W SC, or 32Q1W SC for a duration of only one week.

A method of treating cancer in a subject is also provided, comprising administering PF06863135 to the subject, (a) a single pre-injection at approximately 32 SC or approximately 44 SC in week 1, or both a first pre-injection at approximately 12 SC and a second pre-injection at approximately 32 SC in week 1, and (b) a first treatment administration at approximately 76 SC in week 2, wherein week 1, week 2 and any subsequent week refer to the first week, second week and any subsequent week in which PF06863135 is administered to the subject, and PF06863135 is administered to the subject as a pharmaceutical product comprising PF06863135.

In some embodiments, a single pre-injection of PF06863135 of approximately 44 SCs is administered to the subject during week 1. In some embodiments, a first pre-injection of approximately 12 SCs is administered to the subject on day 1 of week 1, and a second pre-injection of approximately 32 SCs is administered on day 4 of week 1.

In some embodiments, the method further includes administering PF06863135 to the subject at a second treatment dose of approximately 76 Q2 W SC starting from the first week of week 25 or week 7, wherein the administration of PF06863135 from the first treatment dose continues until the end of week 24 or week 6, wherein the cycle is 28 days, and the first cycle, second cycle, and subsequent cycles refer to the first cycle, second cycle, and subsequent cycles at which PF06863135 was administered to the subject.

In some embodiments, PF06863135 is administered to the subject as a first treatment dose of approximately 76Q1W SC, and after at least 23 weeks of receiving such a first treatment dose, PF06863135 is administered to the subject as a second treatment dose of approximately 76Q2W, or the subject continues to receive PF06863135 as the first treatment dose. In some embodiments, PF06863135 is administered to the subject as a second treatment dose after the subject has received at least 23 weeks of the first treatment dose, according to the appropriate regulatory label of the pharmaceutical product or according to the subject's response. In some embodiments, after the subject has received at least 23 weeks of first treatment administration, PF06863135 is continued to be administered to the subject in the same manner as the first treatment administration, unless the subject has demonstrated a partial or better IMWG response after receiving at least six cycles of treatment, and the response lasts for at least one month, at least two months, at least three months, at least one cycle, at least two cycles, or at least three cycles, with each cycle being 28 days, and the first cycle begins on the day of the single pre-injection of PF06863135 or the first pre-injection of PF06863135 administered to the subject.

A method for treating cancer in a subject is also provided, comprising administering PF-06863135 to the subject according to the following dosing regimen:

(a) Pre-injection of approximately 32 Q1W SCs continued for 1 week, followed by first treatment administration of approximately 44 Q1W SCs;

(b) Pre-injection of approximately 32Q1W SC for 1 week, followed by first treatment administration of approximately 44Q2W SC;

(c) Pre-treatment administration of approximately 32 Q1W SCs for 1 week, followed by first treatment administration of approximately 44 Q1W SCs for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, and a second treatment administration of approximately 44 Q2W SCs; or

(d) Pre-treatment administration of approximately 32Q1W SC for 1 week, followed by first treatment administration of approximately 44Q1W SC for 23 or 24 weeks, and second treatment administration of approximately 44Q2W SC.

In some embodiments, PF-06863135 is administered to the subject as a pre-injection of approximately 32 Q1W SC for 1 week, followed by a first treatment administration of approximately 44 Q1W SC. In some embodiments, PF-06863135 is administered to the subject as a pre-injection of approximately 32 Q1W SC for 1 week, followed by a first treatment administration of approximately 44 Q1W SC for 23 or 24 weeks, followed by a second treatment administration of approximately 44 Q2W SC.

A method for treating cancer in a subject is also provided, comprising administering PF-06863135 subcutaneously to the subject, a first treatment administration lasting 23, 24, or 25 weeks, followed by a second treatment administration.

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

In some embodiments, if the dosage of the first treatment drug is 32 or higher, the method further includes administering PF06863135 to the subject as a pre-injection, and after one week of pre-injection, administering a first dose of the first treatment drug in the week immediately following the week of pre-injection. In some embodiments, the pre-injection is a single pre-injection, and the single pre-injection is about 24. In some embodiments, the pre-injection comprises about 4 of a first pre-injection and about 20 of a second pre-injection, and the two pre-injections are administered on two different dates, with the first pre-injection administered before the second pre-injection. In some embodiments, the pre-injection comprises about 8 of a first pre-injection and about 16 of a second pre-injection, and the two pre-injections are administered on two different dates, with the first pre-injection administered before the second pre-injection. In some embodiments, the pre-injection comprises about 12 of a first pre-injection and about 12 of a second pre-injection, and the two pre-injections are administered on two different dates, with the first pre-injection administered before the second pre-injection. In some embodiments, the pre-injection administration comprises about 8 units of a first pre-injection and about 24 units of a second pre-injection, and the two pre-injection administrations are administered on two different dates, with the first pre-injection administration administered before the second pre-injection administration. In some embodiments, the pre-injection administration comprises about 4 units of a first pre-injection and about 28 units of a second pre-injection, and the two pre-injection administrations are administered on two different dates, with the first pre-injection administration administered before the second pre-injection administration.

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

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

A method for treating cancer in subjects is also provided, which includes administering PF-06863135 to the subjects.

(a) First treatment administration of approximately 32 to approximately 76 Q1W SC, starting in week 1; or

(b) Pre-injection during the first week and first treatment administration starting in the second week, wherein the pre-injection is (i) a first pre-injection of about 4 SC to about 32 SC and a second pre-injection of about 12 SC to about 44 SC, wherein the first pre-injection and the second pre-injection are administered sequentially during the first week, or (ii) a single pre-injection of about 24 to about 44 SC, and wherein the first treatment administration is about 32 to about 76 Q1W SC or about 32 to about 152 Q2W SC, starting in the second week, and wherein the dose of the first treatment administration is higher than the dose of each of the corresponding single pre-injection, the first pre-injection, and the second pre-injection;

Week 1, Week 2, and any subsequent week refer to the first week, second week, and any subsequent week when PF06863135 is administered to the subject, respectively, and PF06863135 is administered to the subject as a pharmaceutical product containing PF06863135.

In some embodiments, pre-injection is performed by administering a single pre-injection of about 24 SCs, about 32 SCs, or about 44 SCs to the subject during week 1. In some embodiments, pre-injection is performed by administering a first pre-injection of about 12 SCs and a second pre-injection of about 32 SCs to the subject during week 1. In some embodiments, pre-injection is performed by administering a single pre-injection of about 4, about 8, about 12, or about 24 SCs to the subject during week 1. In some embodiments, pre-injection is performed by administering a first pre-injection and a second pre-injection. In some embodiments, the first pre-injection is about 4 SCs and the second pre-injection is about 20 SCs. In some embodiments, the first pre-injection is about 8 SCs and the second pre-injection is about 16 SCs. In some embodiments, the first pre-injection is about 12 SCs and the second pre-injection is about 12 SCs. In some embodiments, the first pre-injection is about 8 SCs and the second pre-injection is about 24 SCs.

In some embodiments, the first treatment administration is about 32 Q1W SC or about 32 Q2W SC. In some embodiments, the first treatment administration is about 44 Q1W SC or about 44 Q2W SC. In some embodiments, the first treatment administration is given to the subject until at least the end of the first cycle or until at least the end of the sixth cycle, wherein the cycle is 21 days or 28 days, the first cycle begins on day 1 of week 1, day 1 of week 2, or day 1 of week 3, and the first cycle, the second cycle, and the subsequent cycles refer to the first cycle, the second cycle, and the subsequent cycle when PF06863135 is administered to the subject, respectively.

In some embodiments, the method further includes administering PF06863135 to the subject with a second treatment dose of about 32 to about 152Q2W SC, about 32 to about 152Q3W SC, or about 32 to about 152Q4W SC after the subject is no longer receiving the first treatment dose, wherein the second treatment dose is administered at a less frequent frequency than the corresponding first treatment dose, or the dosage of the second treatment dose is lower than the dosage of the first treatment dose. In some embodiments, wherein after administering the first treatment dose to the subject until at least the end of a 6th cycle, the second treatment dose of PF06863135 is administered to the subject in place of the first treatment dose, or the first treatment dose may continue to be administered to the subject, and wherein the second treatment dose is about 32 to about 152Q2W SC, about 32 to about 152Q3W SC, or about 32 to about 152Q4W SC, wherein the second treatment dose is administered at a less frequent frequency than the first treatment dose, or the dosage of the second treatment dose is lower than the dosage of the first treatment dose. In some embodiments, wherein (i) the first treatment administration is about 32 mg Q1W SC and the second treatment administration 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 administration is about 32 mg Q2W SC and the second treatment administration 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, wherein (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 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 dose is administered to the subject according to the appropriate regulatory label of the pharmaceutical product. In some embodiments, the second treatment dose is administered to the subject based on the subject's response to the first treatment dose. In some implementations, the first treatment administration continues to the subject unless, at the time of the first treatment administration, the subject has demonstrated an IMWG response of partial response or better, and the response lasts for at least one month, at least two months, at least three months, at least one cycle, at least two cycles, or at least three cycles.

In some embodiments, the first treatment administration is (i) about 76 Q1W SC, (ii) about 76 Q2W SC, or (iii) about 76 Q1W SC for three weeks, followed by about 116 Q1W SC, or (iv) about 76 Q1W SC for three weeks, followed by about 152 Q1W SC. In some embodiments, the subject is given the first treatment administration until at least the end of the first cycle, at least the end of the third cycle, or at least the end of the sixth cycle, wherein the cycle is 21 days or 28 days, and the first cycle begins on day 1 of the first week, day 1 of the second week, or day 1 of the third week, and the first cycle, the second cycle, and the subsequent cycles refer to the first cycle, the second cycle, and the subsequent cycle when PF06863135 is administered to the subject, respectively. In some embodiments, the method further includes administering PF06863135 to the subject with a second treatment administration of about 44 to about 152Q2W SC, about 44 to about 152Q3W SC, or about 44 to about 152Q4W SC after the subject is no longer receiving the first treatment administration, wherein the second treatment administration is administered at a less frequent frequency than the first treatment administration, or at a less frequent dose than the first treatment administration. In some embodiments, after administering the first treatment administration to the subject until at least the end of the 6th cycle, a second treatment administration of about 44 to about 152Q2W SC, about 44 to about 152Q3W SC, or about 44 to about 152Q4W SC is administered to the subject instead of the first treatment administration, or the first treatment administration may continue to be administered to the subject, wherein the second treatment administration is administered at a less frequent frequency than the corresponding first treatment administration, or at a less frequent dose than the first treatment administration. In some embodiments, the first treatment administration is about 76 Q1W SC, and the second treatment administration is about 44 Q2W SC, about 76 Q2W SC, about 116 Q2W SC, about 152 Q2W SC, about 44 Q3W SC, about 76 Q3W SC, about 116 Q3W SC, about 152 Q3W SC, about 44 Q4W SC, about 76 Q4W SC, about 116 Q4W SC, or about 152 Q4W SC. In some embodiments, the first treatment administration is about 76 Q2W SC, and the second treatment administration is about 44 Q2W SC, about 44 Q3W SC, about 76 Q3W SC, about 116 Q3W SC, about 152 Q3W SC, about 44 Q4W SC, about 76 Q4W SC, about 116 Q4W SC, or about 152 Q4W SC. In some embodiments, the first treatment administration is approximately 76 Q1W, and the second treatment administration is approximately 76 Q2W. In some embodiments, the first treatment administration is approximately 76 Q2W, and the second treatment administration is approximately 76 Q4W. In some embodiments, the second treatment administration is administered to the subject according to the appropriate regulatory label of the pharmaceutical product. In some embodiments, the second treatment administration is administered to the subject based on the subject's response to the first treatment administration. In some embodiments, the second treatment administration is administered to the subject if, at the time of the first treatment administration, the subject has demonstrated an IMWG response of partial response or better, and the response has lasted for at least one month, at least two months, at least three months, at least one cycle, at least two cycles, or at least three cycles.

In some embodiments, PF06863135 is administered to the subject as the first treatment until the end of cycle 1, followed by the second treatment, wherein the cycle is 21 or 28 days, cycle 1 begins on day 1 of 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 when PF06863135 is administered to the subject, respectively. In some embodiments, the second treatment is administered until at least the end of cycle 6, and thereafter the subject is administered a third treatment of about 76 to about 152°C 3W SC or about 76 to about 152°C 4W SC in lieu of the second treatment, or the subject continues to be administered the second treatment. In some embodiments, the second treatment is administered until at least the end of cycle 6, and thereafter a third treatment of about 76 to about 152°C 3W SC or about 76 to about 152°C 4W SC is administered. In some embodiments, the second treatment is administered until the end of cycle 6, the first dose of the third treatment is initiated in cycle 7, and the third treatment is 116Q4W SC or 152Q4W SC. In some embodiments, PF06863135 is administered to the subject as the third treatment after the subject has received the second treatment for at least cycle 6, according to the appropriate regulatory label of the pharmaceutical product or according to the subject's response. In some embodiments, PF06863135 is continued to be administered to the subject as the second treatment for at least cycle 6, unless the subject has demonstrated an IMWG response of partial response or better during the second treatment administration, and the response lasts for at least one month, at least two months, at least three months, at least one cycle, at least two cycles, or at least three cycles. In some embodiments, the first treatment is about 76Q1W SC, the second treatment is about 116Q2W SC, and the third treatment is about 116Q4W SC. In some embodiments, the first treatment administration is about 76 Q1 W SC, the second treatment administration is about 152 Q2 W SC, and the third treatment administration is about 152 Q4 W SC.

In some embodiments, the method includes administering a first treatment dose of about 32 Q1W to the subject for 23, 24, or 25 weeks, followed by a second treatment dose of about 32 Q1W or about 32 Q2W for 6 to 18 cycles, followed by a third treatment dose of about 32 Q2W or about 32 Q4W, wherein the cycles are 21 or 28 days. In some embodiments, the second treatment dose is about 32 Q2W, and the third treatment dose is about 32 Q4W.

In some embodiments, the method includes administering a first treatment dose of about 44Q1W to the subject for 23, 24, or 25 weeks, followed by a second treatment dose of about 44Q1W or about 44Q2W for 6 to 18 cycles, followed by a third treatment dose of about 44Q2W or about 44Q4W, wherein the cycles are 21 or 28 days. In some embodiments, the second treatment dose is about 44Q2W, and the third treatment dose is about 44Q4W.

In some embodiments, the method includes administering a first treatment dose of about 76 Q1W to the subject for 23, 24, or 25 weeks, followed by a second treatment dose of about 76 Q1W or about 76 Q2W for 6 to 18 cycles, followed by a third treatment dose of about 76 Q2W or about 76 Q4W, wherein the cycles are 21 or 28 days. In some embodiments, the second treatment dose is about 76 Q2W, and the third treatment dose is about 76 Q4W.

In some embodiments, the method includes administering a first treatment dose of about 116Q1W to the subject for 23, 24, or 25 weeks, followed by a second treatment dose of about 116Q1W or about 116Q2W for 6 to 18 cycles, followed by a third treatment dose of about 116Q2W or about 116Q4W, wherein the cycles are 21 or 28 days. In some embodiments, the second treatment dose is about 116Q2W, and the third treatment dose is about 116Q4W.

In some embodiments, the method includes administering a first treatment dose of about 152Q1W to the subject for 23, 24, or 25 weeks, followed by a second treatment dose of about 152Q1W or about 152Q2W for 6 to 18 cycles, followed by a third treatment dose of about 152Q2W or about 152Q4W, wherein the cycles are 21 or 28 days. In some embodiments, the second treatment dose is about 152Q2W, and the third treatment dose is about 152Q4W.

In some embodiments, the cycle is 21 days when the subject is dosing PF06863135 at the Q1W or Q3W frequency, and 28 days when the subject is dosing PF06863135 at the Q2W or Q4W frequency. In some embodiments, the cycle is 28 days unless the patient is dosing PF06863135 at the Q3W frequency. In some embodiments, the cycle is 21 days when the subject is receiving the first treatment dosing, both during the first cycle and until the end of the last cycle.

A method for treating cancer is also provided, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week:

(a)

(b)

(c)

(d)

(e)

Or (f)

When the dosage is 12 plus 32 during the first week, a dosage of 12 is administered on one day, followed by a dosage of 32 on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and wherein when the dosage is A plus B during the first week, a dosage of A is administered on one day, followed by a dosage of B on another day.

In some implementations, elranatamab (PF06863135) is administered to the subject according to a dosing schedule shown below.

(a)

(b)

(c)

(d)

(e)

Or (f)

In some embodiments, PF06863135 is administered to the subject according to dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, (iii) every three weeks; (iv) every four weeks; (v) weekly or every two weeks; (vi) weekly or every three weeks, or (vii) weekly or every four weeks. In some embodiments, PF06863135 is administered to the subject according to dosing schedule (d), (e), or (f), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (d), (e), and (f) are (i) every two weeks, (ii) every three weeks, (iii) every four weeks, (iv) every two weeks or every three weeks, or (v) every two weeks or every four weeks.

In some implementations, elranatamab (PF06863135) is administered to the subject according to a dosing schedule shown below.

(a)

(b)

(c)

(d)

(e)

Or (f)

In some embodiments, 12 mmol of elranatamab is administered to the subject on day 1 of week 1, followed by 32 mmol of elranatamab on day 4 of week 1. In some embodiments, PF06863135 is administered to the subject according to dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, after week 26, and after week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, (iii) every three weeks; (iv) every four weeks; (v) weekly or every two weeks; (vi) weekly or every three weeks, or (vii) weekly or every four weeks. In some embodiments, PF06863135 is administered to the subject according to a dosing schedule (d), (e), or (f), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (d), (e), and (f) are (i) every two weeks, (ii) every three weeks, (iii) every four weeks, (iv) every two or three weeks, or (v) every two or four weeks, respectively.

In some implementations, elranatamab (PF06863135) is administered to the subject according to a dosing schedule shown below.

(a)

(b)

(c)

(d)

(e)

Or (f)

In some embodiments, a single dose of 32 elranatamab is administered to the subject during week 1. In some embodiments, 12 elranatamab is administered to the subject on day 1 of week 1, followed by 32 elranatamab on day 4 of week 1. In some embodiments, PF06863135 is administered to the subject according to dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, after week 26, and after week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, (iii) every three weeks; (iv) every four weeks; (v) weekly or every two weeks; (vi) weekly or every three weeks, or (vii) weekly or every four weeks. In some embodiments, PF06863135 is administered to the subject according to a dosing schedule (d), (e), or (f), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (d), (e), and (f) are (i) every two weeks, (ii) every three weeks, (iii) every four weeks, (iv) every two or three weeks, or (v) every two or four weeks, respectively.

In some implementations, the dosage and frequency of administration during the first cycle are collectively referred to as pre-administration, and if only one dose of elranatamab is administered to the subject as pre-administration, such one dose is referred to as single pre-administration; if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are referred to as first pre-administration and second pre-administration, respectively; the dosage and frequency of administration during weeks 2-24, 2-25, and 2-26 in each dosing regimen (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as first treatment administration in each dosing regimen; and the dosage and frequency of administration during weeks 25 and thereafter, weeks 26 and thereafter, and weeks 27 and thereafter in each dosing regimen (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as second treatment administration in each dosing regimen.

In some embodiments, the subject is given the second treatment dose of PF06863135 for 6 to 18 cycles, thereafter, the subject is given a third treatment dose of PF06863135 subcutaneously, wherein the third treatment dose is 32Q2W, 32Q4W, 44Q2W, 44Q4W, 76Q2W, 76Q4W, 116Q2W, 116Q4W, 152Q2W, or 152Q4W, wherein the cycle is 21 days or 28 days, and the first cycle begins on day 1 of week 1, day 1 of week 2, or day 1 of week 3.

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

A method for treating cancer is also provided, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week:

Weeks Dosage (mg) Dosage frequency 1 44; or 32; or 12 plus 32; or A plus B weekly 2-4 44 to 152; weekly 5-24 44 to 152 Weekly; every two weeks After 25 44 to 152 Every two weeks; every three weeks or every four weeks

When the dosage is 12 plus 32 during the first week, a dosage of 12 is administered on one day, followed by a dosage of 32 on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and wherein a dosage of A is administered on one day, followed by a dosage of B on another day.

In some implementations, 12 elranatamab is applied to the subject on the first day of the first week, followed by 32 elranatamab on the fourth day of the first week.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

Weeks Dosage (mg) Dosage frequency 1 12 plus 32 weekly 2-4 76 weekly 5-24 116 Every two weeks After 25 116 Every two weeks; every three weeks; or every four weeks

In some implementations, the dosing frequency during the period after week 25 is every four weeks.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

Weeks Dosage (mg) Dosage frequency 1 12 plus 32 weekly 2-4 76 weekly 5-24 152 Every two weeks After 25 152 Every two weeks; every three weeks; or every four weeks

In some implementations, the dosing frequency is every four weeks during the period after week 25.

In some implementations, the dosage and frequency of administration during the first cycle are collectively referred to as pre-injection, and if only one dose of elranatamab is administered to the subject as pre-injection, such one dose is referred to as single pre-injection; if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are referred to as first pre-injection and second pre-injection, respectively; the dosage and frequency of administration during the second to fourth cycles are collectively referred to as first treatment administration; the dosage and frequency of administration during the fifth to 24 cycles are collectively referred to as second treatment administration; and the dosage and frequency of administration during the 25th week and thereafter are collectively referred to as third treatment administration.

A method for treating cancer is also provided, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week:

Weeks Dosage (mg) Dosage frequency 1 44; or 32; or 12 plus 32; or A plus B weekly 2-4 44 to 76 weekly 5-12 44 to 152; weekly 13-24 44 to 152 Weekly; every two weeks After 25 44 to 152 Every two weeks; every three weeks; or every four weeks

When the dosage during week 1 is 12 plus 32, a dosage of 12 is administered on one day, followed by a dosage of 32 on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and wherein a dosage of A is administered on one day, followed by a dosage of B on another day. In some embodiments, 12 elranatamab is administered to the subject on day 1 of week 1, followed by 32 elranatamab on day 4 of week 1.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

Weeks Dosage (mg) Dosage frequency 1 12 plus 32 weekly 2 to 4 76 weekly 5-12 116 weekly 13-24 116 Weekly; every two weeks After 25 116 Every two weeks; every three weeks; or every four weeks

In some implementations, the dosing frequency between cycles 13 and 24 is every two weeks.

In some implementations, the dosing frequency is every four weeks from week 25 onwards.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

In some implementations, the dosing frequency between cycles 13 and 24 is every two weeks.

In some implementations, the dosing frequency is every four weeks during the period after week 25.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

Weeks Dosage (mg) Dosage frequency 1 12 plus 32 weekly 2-4 76 weekly 5-12 76 weekly 13-24 76 Weekly; every two weeks After 25 76 Every two weeks; every three weeks; or every four weeks

In some implementations, the dosing frequency between cycles 13 and 24 is every two weeks.

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, with the dosing frequency every two weeks or every four weeks during week 25 and thereafter.

In some implementations, elranatamab is administered to the subject according to the following dosing schedule.

Weeks Dosage (mg) Dosage frequency 1 12 plus 32 weekly 2-4 44 weekly 5-12 44 weekly 13-24 44 Weekly or bi-weekly After 25 44 Every two weeks; every three weeks; or every four weeks

In some implementations, the dosing frequency is every two weeks during cycles 13-24. In some implementations, the dosing frequency is every four weeks after week 25.

In some implementations, the dosage and frequency of administration during the first cycle are collectively referred to as pre-injection, and if only one dose of elranatamab is administered to the subject as pre-injection, such one dose is referred to as single pre-injection; if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are referred to as first pre-injection and second pre-injection, respectively; the dosage and frequency of administration during the second to fourth cycles and the dosage and frequency of administration during the fifth to twelfth cycles are collectively referred to as first treatment administration; the dosage and frequency of administration during the thirteenth to twentieth cycles are collectively referred to as second treatment administration; and the dosage and frequency of administration during the period after the twentieth week are collectively referred to as third treatment administration.

The present invention further relates to elranatamab (PF-06853135) for a method of treating cancer with a dosing regimen as defined herein.

In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is advanced multiple myeloma. In some embodiments, the cancer is relapsed or refractory multiple myeloma.

In some embodiments, the cancer is grade 3 refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to all three types of multiple myeloma therapies: (1) prior multiple myeloma therapy containing a proteasome inhibitor, (2) prior multiple myeloma therapy containing an immunomodulatory agent, and (3) prior multiple myeloma therapy containing an anti-CD38 antibody.

In some embodiments, the cancer is grade II refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to at least two of the following three types of multiple myeloma therapies: (1) prior multiple myeloma therapy containing a proteasome inhibitor, (2) prior multiple myeloma therapy containing an immunomodulatory agent, and (3) prior multiple myeloma therapy containing an anti-CD38 antibody.

In some embodiments, the cancer is a newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma, and the subject has received a stem cell transplant. In some embodiments, the subject has received an autologous stem cell transplant. In some embodiments, the subject has received an allogeneic stem cell transplant. In some embodiments, the subject is a minimal residual disease positive individual after stem cell transplantation.

In some embodiments, the cancer is multiple myeloma, and in some embodiments, the subject has progressed or is intolerant to established multiple myeloma therapies. In some embodiments, the established multiple myeloma therapy comprises at least one drug selected from the group consisting of proteasome inhibitors, IMid drugs, and anti-CD38 antibodies.

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

In some embodiments, the cancer is multiple myeloma, the subject has received at least one, at least two, at least three, or at least four prior multiple myeloma therapies, and the subject's multiple myeloma is refractory or relapsed to: (1) prior multiple myeloma therapies containing proteasome inhibitors, (2) prior multiple myeloma therapies containing immunomodulatory agents, and (3) prior multiple myeloma therapies containing anti-CD38 antibodies, and the subject has shown disease progression to the last multiple myeloma therapy. In one aspect of this embodiment, the subject has received at least three prior multiple myeloma therapies. In another aspect of this embodiment, the subject has received at least four prior multiple myeloma therapies.

In some embodiments, the prior multiple myeloma treatment received by the subject included BCMA-guided ADC therapy or BCMA-guided CAR-T cell therapy. In some embodiments, the prior multiple myeloma treatment received by the subject included BCMA-guided therapy.

In some embodiments, the prior multiple myeloma treatment received by the subject did not include BCMA-guided ADC therapy or BCMA-guided CAR-T cell therapy. In some embodiments, the prior multiple myeloma treatment received by the subject did not include BCMA-guided therapy.

In some embodiments, the cancer is multiple myeloma, and the subject has received at least one or at least two prior multiple myeloma therapies, wherein the subject's multiple myeloma is refractory or relapsed to: (1) prior multiple myeloma therapies containing proteasome inhibitors and (2) prior multiple myeloma therapies containing immunomodulatory agents. In some embodiments, the subject has shown disease progression to the last multiple myeloma therapy.

In some embodiments, the cancer is multiple myeloma, and the subject has not received any prior multiple myeloma therapy. In some embodiments, the subject has not received any prior multiple myeloma therapy since the diagnosis of multiple myeloma. In some embodiments, the subject is not suitable for stem cell transplantation. In some embodiments, the cancer is multiple myeloma, and the subject is not suitable for stem cell transplantation. In some embodiments, the subject is not suitable for autologous stem cell transplantation. In some embodiments, the subject is not suitable for allogeneic stem cell transplantation. In some embodiments, the subject is not suitable for both autologous and allogeneic stem cell transplantation.

In some implementations, (i) the cycle is 21 days when the subject is receiving PF06863135 weekly or every three weeks, and 28 days when the subject is receiving PF06863135 bi-weekly or every four weeks; or (ii) the cycle is 28 days unless the patient is receiving PF06863135 bi-weekly.

In some implementations, the method further includes administering sashanimab to the subject.

In some implementations, both PF-06863135 and saxalamab are administered over a four-week treatment cycle for at least the first treatment cycle, wherein if a pre-injection of PF-06863135 is administered, the first treatment cycle begins on the seventh day after a single pre-injection of the pre-injection or the last dose, and saxalamab is administered at a dose of 300Q4W SC.

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 for the treatment cycle is administered on day 1 of the treatment cycle.

In some embodiments, week 1 and cycle 1 begin on the day the subject receives the single pre-injection or the first pre-injection, or if the subject does not receive a pre-injection or pre-injection of PF06863135, week 1 or cycle 1 begins on the day the subject receives the first dose of the first treatment dose of PF06863135, with the cycle lasting 28 days and saxamimab administered at a dose of 300Q4W SC. In some embodiments, the subject receives at least one pre-injection of PF6863135, and saxamimab is administered to the subject on day 8 of each cycle.

In some implementations, the method further includes administering lenalidomide to the object.

In some embodiments, both PF-06863135 and lenalidomide are administered in a four-week treatment cycle for at least the first treatment cycle, wherein if a pre-injection of PF-06863135 is administered, the first treatment cycle begins on the seventh day after a single pre-injection of the pre-injection or the last dose, and wherein lenalidomide is administered orally at a dose of 25g per day from day 1 to day 21 of each treatment cycle.

In some implementations, lenalidomide is administered orally at a dose of 25g daily from day 1 to day 21 of each treatment cycle, without dexamethasone.

In some implementations, the first dose of PF-06863135 for the treatment cycle is administered on day 1 of the treatment cycle.

In some implementations, lenalidomide is administered pre-injected over a 28-day cycle. Lenalidomide is administered at an oral dose of about 5, about 10, about 15, about 20, or about 25 per day on days 8-28 or 15-28 of the first cycle, and on days 1-28 of the second and third cycles. Thereafter, starting from the fourth cycle, lenalidomide is administered at an oral dose of about 5 to 10 per day, higher than the oral dose administered during the third cycle, or lenalidomide is continued at the same oral dose administered during days 1-28 of each cycle as in the third cycle.

In some implementations, PF06863135 is administered pre-injected, starting on day 8 of cycle 1, with lenalidomide administered at an oral dose of about 10 or about 15 per day for at least 10 consecutive days in each cycle.

In some implementations, lenalidomide is administered orally at a dose of about 10, about 15, about 20, or about 25 per day in each cycle for at least 10 consecutive days, at least 14 consecutive days, or at least 21 consecutive days.

In some implementations, PF06863135 is administered to the subject during an induction phase and a subsequent maintenance phase, wherein the induction phase begins on the day of administration of the first dose of PF06863135 pre-administration, or, if no pre-administration of PF06863135 is administered, the induction phase begins on the day of administration of the first dose of PF06863135 first therapeutic administration, and, while the subject is under the first therapeutic administration, 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 as an induction drug at an oral dose of about 5 to about 25 mmol/L for at least 10 consecutive days in each cycle of the induction phase; during the maintenance phase, PF06863135 is administered as the second treatment drug, and lenalidomide is administered as a maintenance drug at an oral dose of about 5 to about 25 mmol/L for at least 10 consecutive days in each cycle; wherein each cycle is 21 days or 28 days, and the induction phase lasts for 1 to 10 cycles. In some embodiments, the method further includes administering dexamethasone to the subject as an oral dose of about 10 to about 40 mmol/L on at least days 1 and 8 of the first cycle of the induction phase.

In some embodiments, each cycle of the induction phase is 21 or 28 days, and cycle 1 begins on day 1 of week 3. The lenalidomide induction administration is approximately 5, 10, 15, 20, or 25 units orally daily, administered from day 1 to day 14 or from day 1 to day 21 of each cycle of the induction phase. If dexamethasone is administered, it is administered at a dose of approximately 20 units orally on days 1, 8, and 15 of both cycles of the first and second induction phases. Each cycle of the maintenance phase is 28 days, and from day 1 to day 28 of each cycle of the maintenance phase, the maintenance lenalidomide administration is approximately 5, 10, or 15 units orally daily. In some embodiments, the induction phase ends after 24-26 weeks. In some embodiments, the induction phase ends after 12-14 weeks.

In some embodiments, the method further includes administering pomalidomide to the subject. In some embodiments, both PF06863135 and pomalidomide are administered in a four-week treatment cycle, continuing for at least a first treatment cycle, wherein a pre-injection of PF-06863135 is administered, the first treatment cycle beginning on the seventh day after a single pre-injection of the pre-injection or the last dose, and pomalidomide is administered orally at a dose of 4 times daily from day 1 to day 21 of each treatment cycle. In some embodiments, pomalidomide is administered orally at doses of 4 times daily, 3 times daily, 2 times daily, or 1 time daily from day 1 to day 21 of each treatment cycle, without dexamethasone. In some embodiments, the first dose of PF-06863135 for the treatment cycle is administered on day 1 of the treatment cycle.

In some embodiments, the method further includes administering daratumumab to the subject. In some embodiments, daratumumab is administered subcutaneously at approximately 1800 doses per week, every two weeks, every three weeks, or every four weeks. In some embodiments, daratumumab administration begins with approximately 1800 doses per week for approximately eight doses in cycle 1, followed by approximately 1800 doses every two weeks for approximately eight to ten doses, followed by approximately 1800 doses every four weeks.

In some embodiments, the method further includes administering isatuximab to the subject. In some embodiments, isatuximab is administered at a dose of about 5 to about 10/kg per quarter-week (QW IV), quarter-week (Q2W IV), quarter-week (Q3W IV), or quarter-week (Q4W IV). In some embodiments, the isatuximab administration to the subject may be the same or different when the subject is receiving pre-injection, first treatment, second treatment, or third treatment of PF06863135.

In some embodiments, the administration of at least one dose of premedication, wherein the premedication is acetaminophen, diphenhydramine, or dexamethasone, is further included on the same day as the administration of a first dose of PF06863135 to the subject, including a single pre-injection, a first pre-injection, a second pre-injection, or a first treatment dose. In some embodiments, dexamethasone is administered in doses of about 10 to about 40 doses daily, either orally or intravenously. In some embodiments, dexamethasone is administered at least on the same day as the administration of a first dose of PF06863135 to the subject, including a first dose of the first treatment dose. In some embodiments, the administration of dexamethasone as a premedication to the subject may be the same or different when the subject is receiving a pre-injection, a first treatment dose, a second treatment dose, or a third treatment dose of PF06863135.

In some embodiments, the method further includes 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 GSI. In some embodiments, the second therapeutic agent is nirogacestat or a pharmaceutically acceptable salt thereof.

In some implementations, the method further includes administering radiotherapy to the subject.

In relation to aspects and/or implementations of the treatment methods described herein, such aspects and/or implementations are also further aspects and/or implementations of one or more therapeutic agents for the treatment method, or alternatively, the use of one or more therapeutic agents as defined in the manufacture of one or more pharmaceutical agents for the treatment.

Attached Figure Description

Figure 1 illustrates the induction of PD-1 expression on CD8+ T cells after treatment with the BCMAxCD3 bispecific antibody.

Figures 2A and 2B depict the therapeutic activity of the BCMAxCD3 bispecific antibody in combination with the anti-PD1 antibody in A) an in situ MM.1S-Luc-PDL1 multiple myeloma model and B) a subcutaneous MM.1S-PD-L1 multiple myeloma model.

Figures 3A-3E depict the upregulation of BCMA expression on the cell surface of multiple myeloma cells after treatment with GSI.

Figures 4A-4E depict the time-dependent upregulation of BCMA expression on the cell surface of multiple myeloma cells after treatment with GSI.

Figures 5A-5E depict the reduction in soluble BCMA (sBCMA) shedding in multiple myeloma cell lines following treatment with GSI.

Figures 6A-6E depict how treatment with GSI improves BCMAxCD3 bispecific mediated cell killing in multiple myeloma cell lines.

Figures 7A-7B depict A) the upregulation of BCMA expression on the cell surface of Raji lymphoma cells after treatment with GSI, and B) the upregulation occurring in a time-dependent manner.

Figure 8 illustrates how treatment with GSI improves BCMAxCD3 bispecific mediated cell killing in lymphoma cell lines.

Invention Details

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

I. Definition

To facilitate a better understanding of the invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

As used herein, including the appended claims, unless the context clearly specifies otherwise, the singular forms of words such as “a,” “an,” and “the” include their corresponding plural references.

When used to modify parameters defining numerical values (e.g., the dose of the BCMAxCD3 bispecific antibody, or the duration of treatment for the combination therapy described herein), "about" means that the parameter can vary by as much as 10% lower or higher than its specified value. For example, a dose of about 5/kg can vary between 4.5/kg and 5.5/kg.

An "antibody" is an immunoglobulin molecule that specifically binds to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only complete polyclonal or monoclonal antibodies, but also fragments (such as Fab', F(ab')2, Fv), single-chain (scFv) and domain antibodies (including, for example, shark and camel antibodies), fusion proteins containing antibodies, and any other modified conformation of an immunoglobulin molecule containing an antigen recognition site. Antibodies include any class of antibodies, such as IgG, IgA, or IgM (or their subclasses), and the antibody need not be of any particular class. Immunoglobulins can be classified into different classes depending on the amino acid sequence of their heavy chain constant region. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are designated as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known.

As used herein, the term "antigen-binding fragment" or "antigen-binding moiety" for antibodies refers to one or more fragments of a complete 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 a complete antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" for antibodies include Fab; Fab'; F(ab')2; the Fd fragment consisting of VH and CH1 domains; the Fv fragment consisting of the VL and VH domains of a single arm of the antibody; single-domain antibody (dAb) fragments (Ward et al., Nature 341:544-546, 1989); and isolated complementarity-determining regions (CDRs).

A "bispecific antibody" is a hybrid antibody that has two different antigen-binding sites. The two antigen-binding sites of a bispecific antibody bind to two different epitopes, which can be located on the same or different protein targets.

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

"Heterodimer", "heterodimeric protein", "heterodimeric complex" or "heteropolymeric polypeptide" is a molecule comprising a first polypeptide and a second polypeptide, wherein the second polypeptide differs from the first polypeptide in its amino acid sequence by at least one amino acid residue.

Antibodies, bispecific antibodies, or peptides that “preferentially bind” or “specifically bind” to a target (e.g., the BCMA protein) (used interchangeably herein) are terms readily understood in the art, and methods for determining such specificity or preferential binding are well known in the art. A molecule is considered to exhibit “specific binding” or “preferential binding” if it responds or associates with a particular cell or substance more frequently, more rapidly, for a longer duration, and/or with a greater affinity than it does with alternative cells or substances. An antibody or bispecific antibody is “specifically bound” or “preferentially bound” to a target if it binds with a greater affinity, affinity, ease, and/or for 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 that epitope with a greater affinity, affinity, ease, and/or for a longer duration than it binds to other BCMA epitopes. It should also be understood that, by reading this definition, for example, an antibody (or part or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Therefore, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. Generally, but not necessarily, the mention of binding refers to preferential binding.

The “variable region” of an antibody refers to a variable region of the antibody light chain or a variable region of the antibody heavy chain, either alone or in combination. As is known in the art, both the heavy chain and light chain variable regions consist of four frame regions (FRs), which are connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are closely linked together by the FRs and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding site of the antibody. At least two techniques are available for determining the CDRs: (1) a scheme based on cross-species sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md)); and (2) a scheme based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273: 927-948). As used in this article, a CDR can refer to a CDR defined by any one scheme or a combination of two schemes.

The “CDR” of a variable domain is an amino acid residue within the variable region, identified according to the accumulation, AbM, contact, and/or conformation definitions of Kabat, Chothia, and both Kabat and Chothia, or any CDR determination method well known in the art. Antibody CDRs can be identified as hypervariable regions originally defined by Kabat et al. See, for example, Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. The location of a CDR can also be identified as a structural loop structure originally described by Chothia et al. See, for example, Chothia et al., Nature 342:877-883, 1989. Other schemes for CDR identification include the “AbM definition,” a compromise between Kabat and Chothia derived using Oxford Molecular’s AbM antibody modeling software (now), or a “contact definition” of the CDR based on observed antigen contact, as described in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another scheme (referred to herein as the “conformation definition” of the CDR), the position of the CDR can be identified as the residue that contributes enthalpy to antigen binding. See, for example, Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still other CDR boundary definitions may not strictly follow one of the above schemes but will still overlap with at least a portion of the Kabat CDR, although they can be shortened or lengthened depending on whether a particular residue or group of residues or even the entire CDR significantly affects the prediction or experimental results of antigen binding. As used herein, a CDR can refer to a CDR defined by any scheme known in the art, including combinations of schemes. The methods used herein can utilize a CDR defined according to any of these schemes. For any given aspect containing more than one CDR, the CDR can be defined according to any of the following definitions: Kabat, Chothia, extended, AbM, contact, and/or conformation.

"Isolated antibody" and "isolated antibody fragment" refer to a purified state, and in this context, mean that the named molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other substances, such as cell debris and growth media. Generally, the term "isolated" does not mean the complete absence of such material or the absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with the experimental or therapeutic use of the binding compound as described herein.

As used herein, “monoclonal antibody” or “mAb” refers to a group of antibodies that are substantially homogeneous, i.e., antibody molecules comprising said group are identical in amino acid sequence except for the possible presence of a small number of naturally occurring mutations. In contrast, conventional (polyclonal) antibody preparations typically comprise a variety of different antibodies with different amino acid sequences in variable domains, particularly CDRs that are typically specific to different epitopes. The modifier “monoclonal” indicates that the antibody is derived from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, the monoclonal antibody used according to the invention can be manufactured by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or by a recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). For example, “monoclonal antibodies” can also be isolated from phage antibody libraries using 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.

"Chimeric antibody" refers to an antibody in which a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody 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 or homologous to the corresponding sequence in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided they exhibit the desired biological activity.

"Human antibody" refers to an antibody that contains only the sequence of human immunoglobulin proteins. If the human antibody is produced in a mouse, mouse cell, or hybridoma derived from mouse cells, it may contain mouse sugar chains. Similarly, "mouse antibody" or "rat antibody" refers to an antibody that contains only the sequence of mouse or rat immunoglobulins, respectively.

"Humanized antibody" refers to an antibody form containing sequences derived from non-human (e.g., mouse) antibodies as well as human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. Generally, humanized antibodies will contain at least one and typically two variable domains, where all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin, and all or substantially all of the FR regions are those regions of the human immunoglobulin sequence. Humanized antibodies may also optionally contain at least a portion of the immunoglobulin constant region (Fc) (typically the constant region of human immunoglobulins). Where necessary, the prefix "hum," "hu," or "h" is added to the antibody clone name to distinguish the humanized antibody from the parent rodent antibody. Humanized forms of rodent antibodies will typically contain the same CDR sequence as the parent rodent antibody, although certain amino acid substitutions may be included to increase affinity, increase the stability of the humanized antibody, or for other reasons.

The terms “cancer,” “cancerous,” or “malignant” refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth. “Cancer” or “cancer tissue” can include tumors. Examples of cancer include, but are not limited to, malignant epithelial tumors, lymphomas, leukemias, myelomas, germ cell tumors, and sarcomas. Cancer can include cancer and/or cancer-related diseases, including B-cell-related cancers and/or cancer-related diseases, including, but not limited to, multiple myeloma, malignant plasma cell vegetations, lymphomas, Hodgkin's lymphoma, nodular lymphocytic dominant Hodgkin's lymphoma, Kallmann's disease and myeloid leukemia, 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, etc. Sclerosing myeloma, B-cell lymphoblastic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-cell lymphoblastic lymphoma, myeloid leukemia, Waldenström macroglobulinemia, diffuse large B-cell lymphoma. Lymphoma, Mucosa-associated lymphoid tissue lymphoma, Small cell 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 exudative lymphoma, Lymphomatoid granulomatosis, T-cell/histiocytic rich large B-cell lymphoma, Primary central nervous system lymphoma, Primary cutaneous diffuse large B-cell lymphoma (spreading leg type), Elderly EBV-positive diffuse large B-cell lymphoma Large B-cell lymphomas, including inflammation-associated diffuse large B-cell lymphomas, ALK-positive large B-cell lymphomas, plasmablastic lymphomas, large B-cell lymphomas in HHV8-associated multicentric Castleman's disease, characteristic unclassified B-cell lymphomas between diffuse large B-cell lymphomas and Burkitt lymphomas, characteristic unclassified B-cell lymphomas between diffuse large B-cell lymphomas and classical Hodgkin's lymphoma, and other B-cell-related lymphomas. This article further describes examples of cancer and cancer-related diseases.

"Chemotherapy drugs" are chemical compounds that can be used to treat cancer and/or cancer-related diseases. Categories of chemotherapy drugs include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle toxin phytoalkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), antiprogesters, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit the expression of genes associated with abnormal cell proliferation or tumor growth. This article further describes chemotherapy drugs.

As used herein, “chemotherapy” means a chemotherapeutic agent as defined above, used to treat cancer and/or cancer-related diseases, or a combination of one, two, three, or four chemotherapeutic agents. When chemotherapy consists of more than one chemotherapeutic agent, the chemotherapeutic agent may be administered to the patient on the same day or different days within the same treatment cycle.

As used throughout the specification and claims, variations such as “consists essentially of” and “consist essentially of” or “consisting essentially of” indicate that any of the listed elements or groups of elements may be included, as well as other elements having similar or different properties from the listed elements, without substantially altering the fundamental or novel characteristics of the specified dosage, method, or composition.

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

"Established multiple myeloma therapies" refers to multiple myeloma therapies approved by the USFDA or the European Medicines Agency, which can be a single drug or a combination of two or more drugs.

As used herein, “IMiD drug,” “imid drug,” or “immunomodulatory agent” can be used interchangeably to refer to drugs that a licensed physician treating multiple myeloma understands as IMiD drugs or immunomodulatory agents. Examples of IMiD drugs or immunomodulatory agents include, but are not limited to, thalidomide, lenalidomide, and pomalidomide.

"BCMA-guided 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-guided ADCs include, but are not limited to, belantamabmafodotin-blmf, which is approved by the US FDA and marketed under the brand name BLENREP.

As used herein, “BCMA-guided CAR-T cell therapy” or “anti-BCMACAR-T cell” can be used interchangeably to refer to a multiple myeloma therapy comprising chimeric antigen receptor T cells that recognize B cell maturation antigen (BCMA). Examples of “BCMA-guided CAR-T therapy” or “anti-BCMACAR T cell therapy” include, but are not limited to, idecabtgene vicleucel (ide cel; or bb2121) and JNJ-4528, which is also known as LCAR-B38M.

"BCMA-guided therapy" refers to a type of multiple myeloma treatment whose active ingredient contains a component that binds to B-cell maturation antigens. BCMA-guided therapies include BCMA-guided ADC therapy, BCMA-guided CAR-T therapy, and multiple myeloma therapies containing BCMA bispecific antibodies.

"Newly diagnosed multiple myeloma" refers to multiple myeloma in patients (subjects) who have not yet received any treatment for a diagnosis of multiple myeloma.

"Homology" refers to the sequence similarity of two polypeptide sequences when performing optimal alignment. Two compared sequences are homologous at positions occupied by the same amino acid monomeric subunit; for example, if a position in the CDR of the light chain of two different polypeptides is occupied by alanine, then the two polypeptides are homologous at that position. The percentage of homology is calculated by dividing the number of shared homologous positions between the two sequences by the total number of positions compared, multiplied by 100. For example, if 8 out of 10 positions in two sequences match or are homologous when performing optimal alignment, then the two sequences are 80% homologous. Typically, comparisons are made when two sequences are aligned to give the maximum percentage of homology. For example, comparisons can be made using the BLAST algorithm, where the algorithm's parameters are selected to give the maximum match between the sequences across the entire length of each reference sequence.

The following references relate to the BLAST algorithm commonly used in 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. Enzymo l.266:131-141; Altschul,S.F.,etal.,(1997)Nucleic Acids Res.25:3389-3402;Zhang,J.,et al .,(1997)GenomeRes.7:649-656; Wootton,J.C.,et al.,(1993)Comput.Chem.17:149-163;Hancock,J .M.etal.,(1994)Comput.Appl.Biosci.10:67-70;ALIGNMENT SCORING SYSTEMS:Dayhoff,M.O.,et al.,"Amodel of evolutionary change in proteins."in Atlas of ProteinSequence and Struct ure,(1978)vol.5,suppl.3.M.O.Dayhoff(ed.),pp.345-352,Natl.Biomed.Res.Found.,Washington,DC;Schwartz,R.M.,et al.,"Matrices for detecting distant relationships."in Atlas of Pro tein Sequence and Structure,(1978)vol.5,suppl.3."M.O.Dayhoff(ed.),pp.353-358,Natl.Bio med. Res. Found., Washington, DC; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et. al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc.Natl.Acad.Sci.USA89:10915-10 919;Altschul,S.F.,et al.,(1993)J.Mol.Evol.36:290-300;ALIGNMENTSTATISTICS:Karlin,S.,et al., (1990) Proc.Natl.Acad.Sci.USA 87:2264-2268; Karlin, S., et al., (1993) Proc.Natl.Acad.S ci.USA90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22: 2022-2039; and Altschul, S.F. "Evaluati ng the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S.Suhai, ed.), (1997) pp.1-14, Plenum, New York.

"Patient," "object," or "individual" means any living organism that suffers from or is susceptible to a condition (such as cancer and/or cancer-related diseases) that can be prevented or treated by the administration of therapeutic drugs or compositions or combinations as provided herein, and includes both humans and animals. The terms "patient," "object," and "individual" include, but are not limited to, mammals (e.g., rats, apes, horses, cattle, pigs, canines, felines, etc.), and preferably humans.

"Sustained response" means the continued effect of treatment after discontinuation of the therapeutic drugs or combinations of therapies described herein. In some respects, the duration of sustained response is at least the same as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

As used herein, “administration” means the delivery of a therapeutic agent to a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase “parenteral administration” refers to a mode of administration other than enteral and local administration, typically by injection, and including but not limited to intravenous, intramuscular, intraarterial, intrasheath, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as intracorporeal electroporation. Therapeutic agents can be administered via non-parenteral routes or orally. Other non-parenteral routes include local, epidermal, or mucosal administration routes, such as intranasal, vaginal, rectal, sublingual, or topical administration. Administration can also be performed, for example, as a single, multiple, and/or over one or more extended periods.

As used herein, “treat” or “treating” cancer and/or cancer-related diseases refers to the administration of a combination therapy according to the invention to a subject, patient, or individual suffering from or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, reducing the number of cancer cells, reducing tumor size, reducing the rate at which cancer cells infiltrate into surrounding organs, or reducing the rate of tumor metastasis or tumor growth, thereby reversing, alleviating, inhibiting, or preventing the progression of the condition or disease to which this term applies, or one or more symptoms of such condition or disease. As used herein, unless otherwise indicated, the term “treat” means the act of treatment, and “treatment” is as defined above. The term “treat” also includes adjuvant and neoadjuvant treatments for the subject. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting metastatic or neoplastic cells; shrinking or reducing tumor size; alleviating cancer; reducing cancer-related symptoms; improving the quality of life of cancer patients; reducing the dosage of other drugs required to treat cancer; delaying cancer progression; curing cancer; overcoming one or more cancer resistance mechanisms; and/or prolonging the survival of cancer patients. The positive therapeutic effect on cancer can be measured in a variety of ways (see, for example, W.A. Weber, J. Nucl. Med. 50: 1S-10S (2009)). In some aspects, the treatment achieved by the combination of the present invention is any one of partial response (PR), complete response (CR), overall response (OR), objective response rate (ORR), progression-free survival (PFS), radiation-induced PFS, disease-free survival (DFS), and overall survival (OS). PFS, also known as "time to cancer progression," indicates the length of time during and after treatment when cancer does not grow, and includes the amount of time a patient experiences CR or PR, as well as the amount of time a patient experiences disease stability (SD). DFS refers to the length of time a patient remains disease-free during and after treatment. OS refers to the expected lifespan extension compared to untreated or untreated subjects or patients. In some aspects, the response to the combination of the invention is any one of PR, CR, PFS, DFS, ORR, OR, or OS, which is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response criteria (Eisenhauer et al., E.A. et al., Eur. J Cancer 45:228-247 (2009)). In some respects, antimyeloma activity can be assessed using the International Myeloma Working Group (IMWG) criteria, by means of 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). Treatment regimens effective for cancer patients, such as the combination therapies described herein, can vary depending on factors such as the patient's disease status, age, weight, and the ability of the therapy to elicit an anticancer response in the subject. While any aspect of the invention may not effectively achieve a positive therapeutic effect in every subject, it should be performed with respect to the number of subjects as determined by any statistical test known in the art, such as, but not limited to, the Cox log-rank test, the Cochran-Mantel-Haenszel log-rank test, the Student's t test, the chi2 test, the U test according to Mann and Whitney, the Kruskal-Wallis test (H test), the Jonckheere-Terpstrat test, and the Wilconon test. The term "treatment" also covers, for example, the in vitro and ex vivo treatment of cells using reagents, diagnostics, conjugated compounds, or another cell.

As used herein, "drug product" refers to a drug that contains an active pharmaceutical ingredient and is regulated by the U.S. FDA, EMA, or other relevant regulatory agencies in other markets. A drug product may be an investigational drug or a drug product that has already been approved by a regulatory agency.

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.

As used herein, an “effective amount” or “effective dose” of a drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired outcomes. For preventative use, beneficial or desired outcomes include eliminating or reducing risk, lessening severity, or delaying the onset of disease, including biochemical, histological, and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes occurring during disease development. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as a reduction or improvement in the incidence of one or more symptoms of various diseases or conditions (e.g., cancer), a reduction in the dosage of other drugs required to treat the disease, an enhancement of the effect of another drug, and/or a delay in disease progression. An effective amount may be administered in a single or multiple dose manner. For the purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventative or therapeutic treatment. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be used in combination with another drug, compound, or pharmaceutical composition to achieve this effect. Therefore, in the context of administering one or more therapeutic agents, an "effective dosage" can be considered, and if the desired results can or have been achieved when used in combination with one or more other agents, administering a single formulation at an effective dosage can be considered.

As used herein, “dosage” means “amount administered,” such as 1, 20, and “frequency of administration,” such as once daily (QD), once weekly (Q1W or QW), every two weeks (Q2W), every three weeks (Q3W), and every four weeks (Q4W). Administration may also include the route of administration, such as, for example, subcutaneous (SC), intravenous (IV), or oral (PO), if so specified. Similarly, “pre-administration,” “first-treatment administration,” “second-treatment administration,” etc., each refer to both the amount and frequency of administration for such administration, and optionally also include the route of administration, if so specified. In some embodiments, administration includes one amount and one frequency. In some embodiments, administration includes more than one amount and/or more than one frequency.

As used herein, unless otherwise stated, when describing the dosage of elranatamab (also known as PF06863135), "dose level" means one of the following dosages: 4, 8, 12, 16, 20, 24, 32, 44, 76, 116, and 152, where 8, 12 mg, 16, 20, 24, 32 mg, 44, 76, 116, and 152 are each a dose level higher than 4, 8 mg, 12, 16, 24, 32, 44, 76, and 116, respectively.

As used herein, “appropriate regulatory labeling of a drug product” refers to an unexpired United States Prescribing Information (USPI) from the U.S. Food and Drug Administration (FDA), an unexpired Summary of Product Characteristics (SMPC) from the European Medicines Agency (EMA), or a similar labeling of a drug product from other market regulatory agencies. In some implementations, “appropriate regulatory labeling of a drug product” in a U.S. patent or patent application refers to an unexpired USPI of the drug product, and in patents or patent applications in European countries that have granted marketing authorization to the drug product through the EMA, it refers to an unexpired SMPC of the drug product, as well as similar cases in other jurisdictions.

As used herein, “subject response” refers to the clinical response of a subject to a potential treatment by a pharmaceutical product comprising elranatamab (PF006863135) as a monotherapy or in combination with a second treatment product. “Subject response” includes one or more aspects relating to 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.

As used in this article, “IMWG response” refers to a patient’s (subject’s) clinical response to a drug product for the treatment of multiple myeloma. The response, such as a complete response or a partial response, is defined according to the latest definition from the International Myeloma Working Group.

As used herein, when used in the context of describing methods of treating cancer (including their use, administration, or administration schedule), "cycle" and "week" refer to duration. Unless otherwise stated, a cycle is 21 days or 28 days when a subject is treated with a therapeutic agent, its pharmaceutical product (such as elranatamab (PF06863135)), or its pharmaceutical product as a monotherapy or in combination with a second therapeutic agent. Unless otherwise stated, week 1 refers to the first week of treatment of a subject according to the method or any administration or administration schedule described therein. Week 2 begins immediately after the end of week 1, week 3 begins immediately after the end of week 2, and so on. Unless otherwise stated, cycle 1 begins on the first day of week 1, the first day of week 2, or the first day of 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, and so on.

As used in this article, “unsuitable for stem cell transplantation” means that a patient diagnosed with multiple myeloma is not suitable for stem cell transplantation as a treatment for multiple myeloma.

The term "tumor" applies to any object diagnosed with or suspected of having cancer, referring to any malignant or potentially malignant growth or mass of tissue of any size, and including both primary and secondary tumors. A solid tumor is an abnormal growth or mass of tissue that typically does not contain cysts or fluid-filled areas. Different types of solid tumors are named according to the type of cells that form them. Examples of solid tumors are sarcomas, malignant epithelial tumors, and lymphomas. Leukemia (blood cancers) typically does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms). Multiple myeloma is a plasma cell cancer.

"Tumor burden," also known as "tumor load," refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor, including lymph nodes and bone stenosis. Tumor burden can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor during removal from the subject using calipers, or by measuring the size of the tumor in vivo using imaging techniques such as ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI).

The term "tumor size" refers to the total size of a tumor, which can be measured in terms of its length and width. Tumor size can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor when it is removed from the object, for example, using calipers, or by measuring the size of the tumor in vivo using imaging techniques such as bone scans, ultrasound, CT, or MRI scans.

The term "immunotherapy" refers to the treatment of a subject by means of inducing, enhancing, inhibiting, or otherwise modifying an immune response.

As used herein, the term "immune effector cell" or "effector cell" refers to cells within the natural cell pool of the human immune system that can be activated to influence the viability of target cells. The viability of target cells can include their ability to survive, proliferate, and/or interact with other cells.

"Pharmaceutical-acceptable excipients" or "pharmaceutical-acceptable carriers" refer to components that can be included in the compositions described herein without causing significant adverse toxicological effects on the subjects.

The terms “protein,” “polypeptide,” and “peptide” are used interchangeably in this document and refer to any chain of amino acids linked together by a peptide, regardless of its length as co-translated or post-translational modified.

As used in this article, “generally” or “essentially” means almost all or completely, for example, 95% or more of a given quantity.

The terms "substantially homologous" or "substantially identical" refer to a specific object sequence, such as a mutant sequence, that differs from a reference sequence by one or more substitutions, deletions, or additions, and whose net effect does not result in an undesirable functional difference between the reference and object sequences. For the purposes of this paper, sequences that have greater than 95% homology (identity), equivalent biological activity (although not necessarily equivalent biological activity intensity), and equivalent expression characteristics to a given sequence are considered substantially homologous (identical). For the purposes of determining homology, truncation of mature sequences should be ignored.

The term "synergistic effect" or "synergy" is used to mean that the result of a combination of two or more compounds, components, or targeted agents is greater than the sum of the effects of each individual agent. The term "synergistic effect" or "synergy" also means that when two or more compounds, components, or targeted agents are used, the condition or symptom of the disease being treated is improved compared to the use of each compound, component, or targeted agent alone. This improvement in the condition or symptom of the disease being treated is a "synergistic effect." The "synergistic amount" is the amount of the combination of two compounds, components, or targeted agents that produce the synergistic effect, which is defined as "synergistic" herein. To determine the synergistic interaction between one or two components, the optimal range of action and the absolute dose range of each component's effect can be precisely measured by administering components with different w/w (weight/weight) ratio ranges and doses to a patient requiring treatment. However, observing synergistic effects in in vitro or in vivo models can predict effects in humans and other species, and as described herein, there are in vitro or in vivo models to measure synergistic effects, and the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges, as well as the absolute dose and plasma concentration required in humans and other species, by applying pharmacokinetic/pharmacodynamic methods.

As used herein, PF-06863135 and elranatamab are used interchangeably. PF06863135 is a BCMAxCD3 bispecific antibody. PF-06863135 is described, for example, in U.S. Patent No. 9,969,809. The selected PF-06863135 sequence is shown in Table 15.

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 pertains. In case of conflict, this specification (including the definitions) shall prevail. Throughout this specification and claims, the word “comprising” or variations such as “comprises” or “comprising” shall be understood to imply inclusion of the stated integers or groups of integers, but not to exclude any other integers or groups of integers. Unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms.

Exemplary methods and materials are described herein, although similar or equivalent methods and materials may also be used in the practice or testing of the invention. The materials, methods, and embodiments are illustrative only and are not intended to be limiting.

II. Methods, Applications, and Reagents

This document provides methods and compositions for treating cancer and/or cancer-related diseases in subjects, the methods and compositions relating to combination therapies comprising at least a first therapeutic agent and a second therapeutic agent.

BCMA-specific treatment drugs

In some respects, therapeutic agents can be BCMA-specific treatments. In other respects, BCMA-specific treatments can be BCMA multispecific antibodies (e.g., bispecific and trispecific), BCMA antibody-drug conjugates, or BCMA chimeric antigen receptor (CAR) modified T-cell therapies. 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 plasmacytocytes and plasma cells, but is not expressed in immature 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 every stage of the disease and in patients with varying cytogenetic risks. Furthermore, BCMA expression is unaffected by autologous stem cell transplantation (ASCT) or chemotherapy. In vivo, bispecific antibodies against BCMA have been shown to induce T-cell activation, reduce tumor burden, and prolong survival.

Examples of BCMA multispecific antibodies that can be used in the combination therapies of the present invention include, but are not limited to, AMG 420 (BCMAxCD3 bispecific T-cell conjugate, Amgen), AMG 701 (BCMAxCD3 Amgen), CC-93269 (BCMAxCD3 bispecific antibody, Celgene), JNJ-64007957 (Jansee), PF-06863135 (BCMAxCD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio/AbbVie), REGN5458 (BCMAxCD3 bispecific antibody, Regeneron), AFM26 (BCMAxCD16 tetravalent bispecific antibody, Affined GmbH), and HPN217 (BCMAxALBxCD3 trispecific antibody, Harpoon Therapeutics).

In some respects, BCMA-specific therapeutics are BCMA bispecific antibody molecules. BCMA bispecific antibodies are monoclonal antibodies that have binding specificity to at least two different antigens (e.g., BCMA and CD3).

In some respects, the BCMA bispecific antibody includes a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain specifically binds to CD3, and wherein the second antibody variable domain specifically binds to BCMA.

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

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

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

In some respects, the BCMA bispecific antibody is PF-06863135, also known as elranatamab. Unless otherwise indicated, the BCMA bispecific antibody used in the examples disclosed herein is PF-06863135. PF-06863135 is a heterodimeric humanized full-length bispecific antibody consisting of a B-cell maturation antigen (BCMA) binding arm and a cluster of differentiation (CD3) binding arms paired via hinge mutation technology. It utilizes the crystallizable (Fc) region of a modified human IgG2a fragment. PF-06863135 is described, for example, in U.S. Patent No. 9,969,809, which is incorporated herein by reference for all purposes. The sequence of PF-06863135 is shown in Table 19.

An effective dose of BCMA-specific therapeutic agent can be administered according to the dosage described in this article.

Anti-PD-1 and PD-L1 antibody therapies

In some aspects, the therapeutic agents used in the combination therapy of the present invention may be anti-PD-1 and anti-PD-L1 antibodies. The programmed death 1 (PD-1) receptor, along with PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively), play an indispensable role in immune regulation. PD-1 is expressed on activated T cells and is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, thereby triggering T cell death and localized 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, in non-clinical animal models, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity (Iwai Y, et al. Proc Natl Acad Sci USA 2002; 99:12293-97).

Examples of anti-PD-1 and anti-PD-L1 antibodies that can be used in the combination therapy of the present invention include, but are not limited to, atezolizumab (MPDL3280A, Roche Holding AG), durvalumab (AstraZeneca PLC), nivolumab (ONO-4538, BMS-936558, MDX1106, Bristol-Myers Squibb Company), and pembrolizumab (MK-3475, Lambro). lizumab (Merck & Co., Inc.), BCD-100 (BIOCAD Biopharmaceutical Company), tislelizumab (BGB-A317, BeiGene Ltd./Celgene Corporation), genolimzumab (CBT-501, CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), GLS-010 (Harbin GloriaP) harmaceuticals Co., Ltd.), sintilimab (IBI308, Innovent Biologics, Inc.), WBP3155 (CStone Pharmaceuticals Co., Ltd.) , AMP-224 (GlaxoSmithKline plc), BI 754091 (Boehringer Ingelheim GmbH), BMS-936559 (Bristol-Myers SquibbCompany), CA-170 (A Urigene Discovery Technologies), FAZ053 (Novartis AG), spartalizumab (PDR001, Novartis AG), LY3300054 (Eli Lilly & Company), MEDI0680 (AstraZeneca PLC), PDR001 (Novartis AG), spartalizumab (PF-06801591, Pfizer Inc.), cemiplimab (REGN2810, R) egeneron Pharmaceuticals, Inc.), camrelizumab (SHR-1210, Incyte Corporation), TSR-042 (Tesaro, Inc.), AGEN2034 (Agen us Inc.), CX-072 (CytomX Therapeutics, Inc.), JNJ-63723283 (Johnson&Johnson), MGD013 (MacroGenics, Inc.), AN-2005 (Adlai Nor tye), ANA011 (AnaptysBio, Inc.), ANB011 (AnaptysBio, Inc.), AUNP-12 (Pierre Fabre Medicament S.A.), BBI-801 (Sumitomo Dainip pon Pharma Co., Ltd.), BION-004 (Aduro Biotech), CA-327 (Aurigene Discovery Technologies), CK-301 (Fortress Biotech, Inc.), E NUM 244C8 (EnumeralBiomedical Holdings, Inc.), FPT155 (Five Prime Therapeutics, Inc.), FS118 (F-starAlpha Ltd.), hAb21 (Sta inwei Biotech, Inc.), J43 (Transgene S.A.), JTX-4014 (Jounce Therapeutics, Inc.), KD033 (Kadmon Holdings, Inc.), KY-1003 (Kymab Ltd.), MCLA-134(Merus B.V.), MCLA-145(Merus B.V.), PRS-332(Pieris AG), SHR-1316(Atridia PtyLtd.), STI-A1010(Sorrento T herapeutics, Inc.), STI-A1014 (Sorrento Therapeutics, Inc.), STI-A1110 (Les Laboratoires Servier) and XmAb20717 (Xencor, Inc.).

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

In some aspects, the anti-PD-1 antibody comprises: three CDRs comprising the heavy chain variable region (VH) containing the amino acid sequence shown in SEQ ID NO: 27 and/or three CDRs comprising the light chain variable region (VL) containing the amino acid sequence shown in SEQ ID NO: 31. In some aspects, VH comprises: VH CDR1 containing the sequence shown in SEQ ID NO: 28, VH CDR2 containing the sequence shown in SEQ ID NO: 29, and VH CDR3 containing the sequence shown in SEQ ID NO: 30, and/or VL comprises: VL CDR1 containing the sequence shown in SEQ ID NO: 32, VLCDR2 containing the sequence shown in SEQ ID NO: 33, and VL CDR3 containing the sequence shown in SEQ ID NO: 34. In some aspects, VH comprises the sequence shown in SEQ ID NO: 27, and/or VL comprises the sequence shown in SEQ ID NO: 31.

In some respects, 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. By blocking its interaction with PD-L1 and PD-L2, the suppression of the PD-1 pathway-mediated immune response is released, leading to an anti-tumor immune response. Clinical anti-tumor activity of sasanlimab has been found in a group 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. US 10,155,037, which is incorporated herein by reference for all purposes. Unless otherwise indicated, the anti-PD-1 antibody used in the examples disclosed herein is an internally prepared therapeutic humanized anti-human PD-1 antibody (hIgG2a-D265A).

An effective amount of anti-PD-1 antibody or anti-PD-L1 antibody can be administered according to the dosage described in this article.

Gamma secretase inhibitor therapy

In some aspects, the therapeutic agent used in the combination therapy of the present invention may be a gamma-secretase inhibitor (GSI). The terms “gamma-secretase inhibitor,” “gamma-secretase inhibitor,” and “GSI” are used interchangeably herein to refer to compounds (including pharmaceutically acceptable salts, solvates, and prodrugs thereof) or other preparations that inhibit or reduce the biological activity of gamma-secretase. Membrane-bound BCMA is actively cleaved by the proteolytic activity of gamma-secretase from the surface of tumor cells and may undergo gamma-secretase-mediated shedding. This can reduce the target density on tumor cells for BCMA-specific therapeutic agents and release soluble BCMA (sBCMA) fragments that can interfere with BCMA-specific therapeutic agents. By inhibiting gamma-secretase, membrane-bound BCMA can be retained, thereby increasing the target density while reducing sBCMA levels. Therefore, administration of GSI can enhance the activity of BCMA-specific therapeutic agents.

Examples of small molecule GSIs that can be used in the combination therapies of the present invention include, but are not limited to, dipeptide classes of GSIs, sulfonamide classes of GSIs, transition state mimic classes of GSIs, benzocaprolactam classes of GSIs, and other GSIs known in the art. For example, GSIs may 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. Other examples of GSI include 1-(S)-N-(1,3,3)-trimethylbicyclo[2.2.1]hept-2-yl)-4-fluorophenylsulfonamide, WPE-III-31C, (S)-3-[N'-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alanine]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one, and (N)-[(S)-2-hydroxy-3-methyl-butyryl]-1-(L-alanine)-(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzodiazepine-2-one. SeeDe Kloe&De Strooper(2014).Small Molecules That InhibitNotch Signaling.,In Bellen&Yamamoto(Eds.),Notch Signali ng: Methods and Protocols, Methods in Mol. Biol., vol 1 187 (pp 311 -322). New York, NY: Springer-Science+Business Media.

In some aspects, the therapeutic agent in the combination therapy of the present invention is a GSI. In some aspects, the GSI may have any property or feature of any GSI provided in WO2005/092864, which is incorporated herein by reference for all purposes. In some aspects, the GSI is nirogacestat (PF-03084014, SpringWorks Therapeutics) or a pharmaceutically acceptable salt thereof. Nnirogacestat is an orally selective small molecule GSI having the following structure:

Nirogacestat is described, for example, in the following documents: U.S. Patent Nos. 7,342,118, 7,795,447, and 7,951,958, which are incorporated herein by reference for all purposes. Unless otherwise indicated, the GSI used in the examples disclosed herein is nirogacestat.

An effective amount of GSI can be administered according to the dosage described herein. In some respects, GSI is administered at a dose sufficient to upregulate the surface expression of BCMA on tumor cells. In some respects, GSI is administered at a dose sufficient to reduce the shedding of BCMA from tumor cells. In some respects, GSI is administered at a dose sufficient to reduce the level of sBCMA. In some respects, GSI is administered at a dose sufficient to enhance the activity of BCMA-specific therapeutic agents.

Treatment drugs

In some aspects, the therapeutic agents used in the combination therapies of the present invention may comprise one or more of the following: biological therapeutic agents, chemotherapeutic agents, immunomodulators (e.g., histone deacetylases, lenalidomide, pomalidomide, iberdomide, 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., selinuor). Further therapeutic agents used in the combination therapies of the present invention include cancer vaccines, immunocellular therapies (e.g., CAR-T cell-based therapies), radiotherapy, vaccines, cytokine therapies (e.g., immunostimulatory cytokines, including various signaling proteins that stimulate immune responses, such as interferon, interleukin, and hematopoietic growth factor), targeted cytokines, inhibitors of other immunosuppressive pathways, inhibitors of angiogenesis, T-cell activators, inhibitors of metabolic pathways, mTOR (the mechanistic target of rapamycin) inhibitors (e.g., rapamycin, rapamycin derivatives, sirolimus, temsirolimus, everolimus, and deforolimus), inhibitors of the adenosine pathway, etc. Gamma secretase inhibitors (e.g., nirogacestat), tyrosine kinase inhibitors, including but not limited to 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 depletion agents of Treg cells and/or myeloid-derived suppressor cells, JAK (Janus kinase) inhibitors (e.g., ruxolitinib and tofacitinib, vasitinib), and var... Citinib, filgotinib, gandotinib, lestaurtinib, momoritib, pacritinib, and updacitinib, STAT (transcriptional signal transducers and activators) inhibitors (e.g., STAT1, STAT3, and STAT5 inhibitors, such as fludarabine), cyclin-dependent kinases (CDKs) or other cell cycle inhibitors, immunogenic agents (e.g., attenuated cancer cells, tumor antigens, antigen-presenting cells, such as dendritic cells pulsed with tumor-derived antigens or nucleic acids), MEK inhibitors (e.g., trametinib, coumarinib, citinib, filgotinib, gandotinib, lestaurtinib, momoritib, pacritinib, and updacitinib), STAT (transcriptional signal transducers and activators) inhibitors (e.g., STAT1, STAT3, and STAT5 inhibitors, such as fludarabine), cyclin-dependent kinases (CDKs) or other cell cycle inhibitors, immunogenic agents (e.g., attenuated cancer cells, tumor antigens, antigen-presenting cells, such as dendritic cells pulsed with tumor-derived antigens or nucleic acids), MEK inhibitors (e.g., trametinib, coumarin ... Bismuthib (cobimetinib, binimetinib, and selumetinib), GLS1 inhibitors, PARP inhibitors (e.g., talazoparib, olaparib, rucaparib, and niraparib), oncolytic viruses, gene therapy including DNA, RNA delivered directly or via adeno-associated virus (AAV) or nanoparticles, innate immune response modulators (e.g., TLR, KIR, NKG2A), IDO (indole-pyrrole 2,3-dioxygenase) inhibitors, PRR (pattern recognition receptor) agonists, and cells transfected with genes encoding immunostimulatory cytokines (such as, but not limited to, GM-CSF).

In some aspects, the therapeutic agents used in the combination therapies of the present invention may include antibodies, including but 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-7Ralpha (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, and anti-VEGFR antibodies. 1. Antibodies, including anti-VEGFR2 antibody, anti-TNFR1 antibody, anti-TNFR2 antibody, anti-CD3 bispecific antibody, anti-CD19 antibody, anti-CD20, 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-LILRb2 antibody, anti-CXCR4 antibody, anti-CD206 antibody, anti-CD163 antibody, anti-KLRG1 antibody, anti-FLT3 antibody, anti-B7-H4 antibody, anti-B7-H3 antibody, KLRG1 antibody, BTN1A1 antibody, BCMA antibody, anti-SLAMF7 antibody, anti-avb8 antibody, anti-CD80 antibody, or anti-GITR antibody.

In some aspects, other examples of therapeutic agents used in the combination therapies of the present invention may be directed or targeted to 5T4; A33; α-folate receptor 1 (e.g., mirvetuximab soravtansine); Alk-1; BCMA (e.g., see WO2016166629 and other documents disclosed herein); BTN1A1 (e.g., see WO2018222689); CA19-9; CA-125 (e.g., abagovomab); carbonic anhydrase 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., boratumumab, MOR208); CD20 (e.g., ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumabozogamicin, moxetumab pasudotox)); CD25; CD28; CD30 (e.g., brentuxi mab 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., polatzumab vedotin); CD80; CD86; CD123; CD276/B7-H3 (e.g., omburtamab); CDH17; CEA; ClhCG; CTLA- 4 (e.g., ipilimumab, tramemumab), CXCR4; desmosome core protein 4; DLL3 (e.g., lovapituzumab tesirine); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g., cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvIII; endothelial sialic acid protein; EpCAM (e.g., oportuzumab monatox); FAP; fetal acetylcholine receptor; FLT3 (e.g., see 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); GlobH; GM1; GM2; HER2/neu [e.g., margetuximab, pertuzumab, trastuzumab; ado trastuzumab, trastuzumab duocarmazine, PF-06804103 (see US8828401)]; HER3; HER 4; ICOS; IL-10; ITG-AvB6; LAG-3 (e.g., relatlimab, IMP701); Lewis-Y; LG; Ly-6; M-CSF [e.g., PD-0360324 (see US7326414)]; (membrane-bound) IgE; MCSP; mesothelin; MIS receptor type II; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notch1; Notch3; cohesin 4 (e.g., enfortumab vedotin); OX40 [e.g., PF-04518600 (see US7960515)]; P-cadherin [e.g., PF-06671008 (see WO2016/0]]. 01810); PCDHB2; PD-1 [e.g., BCD-100, carmezumab, cimiprizumab, genolimzumab (CBT-501), MEDI0680, nivolumab, pembrolizumab, sasanlimumab (PF-06801591, see WO2016/092419), cintilimab, spartazumab, STI-A1110, tislelizumab, TSR-042 and other analogues disclosed herein]; PD-L1 (e.g., BMS-936559 (MDX-1105), LY3300054 and other analogues disclosed herein); PDGFRA (e.g., olaratumab); plasma cell antigen; PolySA; PSCA; PSMA; PTK7 [e.g., PF-0664] 7020 (see US9409995)]; Ror1; SAS; SLAMF7 (e.g., elotuzumab); SHH; SIRPa (e.g., ED9, Effi-DEM); STEAP; sTn; TGF-β; TIGIT; TIM-3; TMPRSS3; TNF-α precursor; TROP-2 (e.g., sacituzumab govitecan); TSPAN8; VEGF (e.g., bevacizumab, brolucizumab); VEGFR1 (e.g., ranibizumab); VEGFR2 (e.g., ramucirumab, ranibizumab); and Wue-1.

In some aspects, the therapeutic agent used in the combination therapy of the present invention can be a therapeutic antibody having any suitable format. For example, a therapeutic antibody can have any format as described elsewhere herein. In some aspects, the therapeutic antibody can be a naked antibody. In some aspects, the therapeutic antibody can be linked to a drug/formulation (also referred to as an "antibody-drug conjugate" (ADC)). Drugs or formulations that can be linked to antibodies in an ADC format can include, for example, cytotoxic agents, immunomodulators, imaging agents, therapeutic proteins, biopolymers, or oligonucleotides. Exemplary cytotoxic agents that can be incorporated into ADCs include anthracycline, auristatin, dolastatin, comprehetastain, duocarmycin, pyrrolobenzodiazepine dimer, dihydroindolylpyrrolobenzodiazepine dimer, enediyne, geldanamycin, maytansine, puromycin, taxane, vinca alkaloid, camptothecin, tubulolysin, hemiasterlin, spliceostatin, pladienolide, and their stereoisomers, isosteres, analogs, or derivatives thereof.

In some aspects, therapeutic antibodies targeting specific antigens can be incorporated into multispecific antibodies (e.g., bispecific or trispecific antibodies). A bispecific antibody is a monoclonal antibody that has binding specificity to at least two different antigens. In some aspects, a bispecific antibody comprises a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain is capable of supplementing the activity of human immune effector cells by specifically binding to effector antigens located on human immune effector cells, and wherein the second antibody variable domain is capable of specifically binding to target antigens as provided herein. In some aspects, the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some aspects, the antibody comprises an immune-inert Fc region. In some aspects, the antibody is a human antibody or a humanized antibody.

Human immune effector cells can be any of a variety of immune effector cells known in the art. For example, immune effector cells can be members of human lymphoid cell lineages, including but not limited to T cells (e.g., cytotoxic T cells), B cells, and natural killer (NK) cells. Immune effector cells can also be members of human myeloid lineages, including but not limited to monocytes, neutrophils, and dendritic cells. Such immune effector cells can have cytotoxic or apoptotic effects on target cells, or other desired effects upon activation by binding effector antigens.

An effector antigen is an antigen (e.g., a protein or peptide) 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 the CD3 (differentiation cluster) complex), CD16, NKG2D, NKp46, CD2, CD28, CD25, CD64, and CD89. Target antigens are typically expressed on target cells in a diseased state (e.g., cancer cells). Examples of target antigens for use with bispecific antibodies are disclosed herein.

In some respects, 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 may be advantageous, for example, in terms of increased specificity for the target cell of interest (e.g., for tumor cells expressing two specific tumor-associated antigens of interest). For example, in some respects, 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 as provided herein, and the second antibody variable domain is capable of specifically binding to a second target antigen as provided herein.

In some aspects, the therapeutic agents used in the combination therapies of the present invention may comprise immunomodulators, including thalidomide, lenalidomide, pomalidomide, ibelidomide, and aprexa, which can stimulate an immune response in the subject. Further immunomodulators include pattern recognition receptor (PRR) agonists, immunostimulatory cytokines, immunocellular therapies, and cancer vaccines.

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 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 oligomeric domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and interferon gene-stimulating factor (STING) proteins.

Exemplary TLR agonists provided herein include agonists of TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9. Examples of RLR agonists that can be used in the treatment methods, pharmaceuticals, and uses of the present invention include, for example, short double-stranded RNA with uncapped 5' triphosphates (RIG-I agonists); polyI:C (MDA-5 agonists); and BO-112 (MDA-A agonists). Examples of NLR agonists that can be used in the treatment methods, pharmaceuticals, and uses of the present invention include, for example, liposomal muramyl tripeptide/mifamurtide (NOD2 agonist). Examples of CLR agonists that can be used in the treatment methods, pharmaceuticals, and uses of the present invention include, for example, MD fraction (purified soluble β-glucan extract from Grifola frondosa) and imprime PGG (β1,3/1,6-glucan PAMP derived from yeast). Examples of STING agonists that can be used in the treatments, pharmaceuticals, and uses of the present invention include various immunostimulatory nucleic acids, such as synthetic double-stranded DNA, circular diGMP, circular GMP-AMP (cGAMP), synthetic cyclic dinucleotides (CDNs), such as MK-1454 and ADU-S100 (MIW815), and small molecules, such as PO-424. Other PRRs include, for example, DNA-dependent IFN regulator activator (DAI) and melanoma deficiency factor 2 (AIM2).

Immunostimulatory cytokines include, but are not limited to, various signaling proteins that stimulate immune responses, such as interferons, interleukins, and hematopoietic growth factors. In some aspects, exemplary immunostimulatory cytokines include, but are not limited to, GM-CSF, G-CSF, IFN, IL-2 (e.g., denifedipine interleukin), IL-6, IL-7, IL-10, IL-11, IL-12, IL-15, IL-18, IL-21, and TNF. Immunostimulatory cytokines can have any suitable format. In some aspects, immunostimulatory cytokines can be recombinant versions of wild-type cytokines. In some aspects, immunostimulatory cytokines can be mutant proteins with one or more amino acid changes compared to the corresponding wild-type cytokines. In some aspects, immunostimulatory cytokines can be incorporated into chimeric proteins containing cytokines and at least one other functional protein (e.g., antibodies). In some aspects, immunostimulatory cytokines can be covalently linked to drugs/formulations (e.g., any drug/formulation described elsewhere herein as a possible component of an ADC). In some aspects, cytokines are PEGylated.

Immunotherapy involves treating patients with immune cells that can target cancer cells. Immunotherapy includes, for example, tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor T cells (CAR-T cells).

Cancer vaccines comprise various compositions containing tumor-associated antigens (or which can be used to generate tumor-associated antigens in a subject) and are therefore capable of eliciting an immune response in a subject against tumor cells containing tumor-associated antigens. Examples of materials that can be included in cancer vaccines include attenuated cancer cells, tumor antigens, and antigen-presenting cells, such as dendritic cells with pulses of nucleic acids encoding tumor-derived antigens or tumor-associated antigens. In some aspects, cancer vaccines can be prepared using cancer cells from the patient's own body. In other aspects, cancer vaccines can be prepared using biological materials not derived from the patient's own cancer cells. Cancer vaccines include, for example, sipuleucel-T and talimogene-laherparepvec (T-VEC).

The combination therapies described in this article 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; azacyclopropanes such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including hexamethylamelamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphoramide, triethyleneethylphosphoramide, and trimethylolomelamine; and polyacetylenephosphoramide. Origin (especially bullatacin and bullatacinone); camptothecin (including synthetic analogues topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolexin, calcexin, and pyrazine); cryptophycin (especially cryptophycin 1 and cryptophycin 8); sarcosine; ducamycin (including synthetic analogues KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlornaphazine, chlorphosphamide, estradiol, ifosfamide, mechloretham Nitrosamine, oxidized nitrogen mustard hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin phil1, see, for example, Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994); dynemicin, including dynemicin A; Bisphosphonates, such as clophosphonates; esperamicin; and neocarzinostatin chromophores and related chromogenic chromophores (enediyne antibiotic chromophores), aclacinomysin, autramycin, azaserine, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diaza-5-oxo-L-leucine, doxorubicin (including morpholino doxorubicin, cyanomorpholino doxorubicin, 2-pyrrolinyl doxorubicin, and deoxydoxorubicin), epirubicin, esopycin Orubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, oligomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabin. ne), 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enoxabin, fluorouridine; androgens, such as capprotestone, dromostanolone propionate, cyclothioranolol, meandrosten, testolactone; antiadrenergic drugs, such as aminoglutethimide, mitotane, and trilosterone; folic acid supplements. Such as frolinic acid; FOLFOX, including frolinic acid, 5-FU, and oxaliplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; uracil; azartin; bestrabucil; bisantrene; edatraxate; defofarin (d efofamine; decarbonyl colchicine; diaziquone; efornithine; eletate; epokine; epomycin; etoglucoside; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansin and anserine; mitoguazone; mitoxantrone; mopidazole; nitracrine; pentostatin; phename t); Pirarubicin; Loxoanthraquinone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Procarbazine; Rhizoxin; Sizofuran; Germonispiramine; Alternaria solanilic acid; Triaminoquinone; 2,2′,2″-Trichlorotriethylamine; Trichothecene toxins (especially T-2 toxin, verracurin A, roridine A, and diacetylfusarium enol). Guidine; urethan; vincristine; dacarbazine; mannitol; dibromomannitol; dibromoeutherol; piperbbromide; gacytosine; arabinoside ('Ara-C'); cyclophosphamide; thiotepa; taxanes, such as paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as carboplatin; cisplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; Mitoxantrone; vincristine; vinorelbine; novantrone hydrochloride; teniposide; edaraxacum; donomycin; aminopterin; capecitabine; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and any of the above pharmaceutically acceptable salts, acids, or derivatives.

In some aspects, the therapeutic agents used in the combination therapy of the present invention may be anti-hormones used to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trivoxifen, raloxifene hydrochloride, LY117018, onaston, and toremifene; aromatase inhibitors that inhibit aromatase that regulates the production of estrogen in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestan, fazodazole, vorozole, letrozole, and anastrozole.

In some aspects, the therapeutic agents used in the combination therapy of the present invention may be anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprorelin, 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, and tivozanib; alk/c-Met/ROS inhibitors, such as crizotinib and lorlatinib; mTOR inhibitors, such as teremoxetine and gedatolisib; src/abl inhibitors, such as posutinib; and other similar drugs. Cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, PF-06873600, abemaciclib, and ribociclib; ERB inhibitors, such as dacomitinib; PARP inhibitors, such as taprazolepanib, olaparib, rucapapanib, and niraparib; SMO inhibitors, such as gladegib 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; TGFR r1 inhibitors, such as PF-06952229; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

treat

According to standard pharmaceutical practice, each of the therapeutic agents in the combination therapies of the present invention may be administered alone or in the form of a pharmaceutical preparation (also referred to herein as a pharmaceutical composition), the pharmaceutical preparation comprising the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents.

Each therapeutic agent in the combination therapy of the present invention may be administered simultaneously (i.e., in the same agent), co-administered (i.e., in separate agents, one after another in any order), or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy, such as chemotherapy agents administered at least daily and less frequently administered (e.g., once weekly, once every two weeks, or once every three weeks) are administered in different dosage forms (one formulation is a tablet or capsule, and the other is a sterile liquid) and/or on different dosing schedules.

In some respects, the therapeutic agents in the combination therapy may be administered using the same dosage regimen (dosage, frequency, and duration of treatment) typically employed when the formulation is used as a monotherapy for the treatment of the same cancer. In other respects, the total amount of at least one therapeutic agent received by the patient in the combination therapy may be lower than the total amount received when the formulation is used as a monotherapy, for example, with smaller doses, less frequent doses, and/or shorter durations of treatment.

The therapeutic agents in the combination therapies of this invention can be administered via any suitable enteral or parenteral route. The term "enteric route" refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, oral, and rectal routes, or intragastric routes. "Parenteral route" refers to administration routes other than enteral routes. Examples of parenteral routes include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intrabladder, intraarticular, intrasheathal, intracystic, intraorbital, intracardiac, tracheal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal, subcutaneous, or local administration. The therapeutic agents of this 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 appropriate route and method of administration can vary depending on a variety of factors, such as the specific therapeutic agent used, the desired absorption rate, the specific formulation or dosage form used, the type or severity of the condition being treated, the specific site of action, and the patient's condition. Examples of parenteral administration routes also include intraosseous and intrapleural administration.

Oral administration of a solid dosage form of a therapeutic drug can be, for example, presented in discrete units such as hard or soft capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of at least one therapeutic drug. Alternatively, oral administration can be in the form of powders or granules. Another option is sublingual administration, such as lozenges. In these solid dosage forms, the therapeutic drug is typically combined with one or more adjuvants. Such capsules or tablets may contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form may also contain buffers or may be prepared using enteric coating.

On the other hand, oral administration of therapeutic drugs can be carried out in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (e.g., water) commonly used in the art. Such compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), and/or aromatizers.

In some respects, therapeutic drugs are administered in parenteral doses. “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 using suitable dispersants, wetting agents, and/or suspending agents according to known techniques, and include reservoir preparations.

In some respects, therapeutic agents are administered in the form of localized doses. “Localized administration” includes, for example, transdermal administration, such as via transdermal or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for localized administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When therapeutic agents are administered via transdermal devices, reservoirs and porous membrane-type or solid matrix-type patches are used to complete the administration. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oils, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. It can be incorporated with a permeation enhancer, see, for example, Finnin and Morgan, J. Pharm. Sci., 88(10), 955-958 (1999).

Other carrier materials and administration modalities known in the pharmaceutical field can also be used with therapeutic drugs. The above considerations regarding effective formulations and administration procedures are well-known in the art and are described in standard textbooks. Drug formulations are discussed in, for example, the following literature: Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999.

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 serum or tissue turnover of the entity, symptom level, immunogenicity of the entity, and accessibility of target cells, tissues, or organs in the treated subject. Preferably, the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient while being consistent with acceptable levels of side effects. Therefore, the dosage and frequency of administration of each therapeutic agent or chemotherapeutic agent in the combination 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 Therapyin Autoimmune Diseases,Marcel Dekker,New York,NY;Baert et al.(2003)NewEngl.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 Engl.J.Med.342:613-619;Ghosh et al.(2003)New Engl.J.Med.348:24-32;Lipsky eta l. (2000) New Engl.J.Med.343:1594-1602; Physicians'Desk Reference 2003 (Physicians'Desk Reference, 57th Ed); Medical Economics Company; ISBN: 1563634457; 57th edition (November 2002). Clinicians may determine an appropriate dosage regimen, for example, using parameters or factors known or suspected to affect or expected to affect treatment, and the determination will depend on, for example, the patient’s clinical history (e.g., previous therapy), the type and stage of the cancer to be treated, and biomarkers of response to one or more therapeutic agents in combination therapy.

In some aspects, the therapeutic agents in the combination therapy of the present invention can be administered to the subject at the following dosages: approximately 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, 1 0μg/kg, 15μg/kg, 20μg/kg, 25μg/kg, 30μg/kg, 35μg/kg, 40μg/kg, 45μg/kg, 50μg /kg, 60μg/kg, 70μg/kg, 80μg/kg, 90μg/kg, 100μg/kg, 110μg/kg, 120μg/kg, 130μg /kg, 140μg/kg, 150μg/kg, 200μg/kg, 250μg/kg, 300μg/kg, 400μg/kg, 500μg/kg, 6 00μg/kg, 700μg/kg, 800μg/kg, 900μg/kg, 1000μg/kg, 1200μg/kg or 1400μg/kg or higher.

In some aspects, the therapeutic agents of the combination therapy of the present invention can be administered to the subject at the following doses: 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.

In some respects, the therapeutic agents in the combination therapy of the present invention can be administered to the subject at the following doses: 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, for example, Yang et al. (2003) New Engl.J.Med.349:427-434; Herold et al. (2002) New Engl.J.Med.346:1692-1698; Liu eta l. (1999) J. Neurol. Neurosurg. Psych. 67: 451-456; Portielji et al. (20003) Cancer Immunol. Immunother. 52: 133-144.

In some respects, a fixed dose of the therapeutic drug of about or at least about the following can be administered to the subject: 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. 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 350mg, 700mg, 750mg, 800mg, 900mg, 1000mg, or 1500mg or higher. Fixed doses can be administered at the following intervals: for example, daily, every other day, three times a week, or once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, etc.

For oral administration, the therapeutic agent may be provided in tablet form at the dosage of the therapeutic agent described herein (e.g., typically a small molecule chemotherapeutic agent).

In some respects, the therapeutic agents in the combination therapy of the present invention can be administered to the subject orally, IV or SC in the following manner: at least once a day, once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once a week, 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 a month, once every two months, once every three months or once every four months.

The treatment methods described herein may continue as long as the clinician supervising patient care deems the treatment methods effective. Non-limiting parameters indicating the effectiveness of a treatment method include any one or more of the following: tumor shrinkage (expressed as 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 well-known in the art can be employed, such as computed tomography (CT scan), dual-energy CDT, positron emission tomography, ultrasound, CAT scan, and MRI. In some aspects, the combination therapy of the present invention is used to treat sufficiently large tumors that can be detected by palpation or by imaging techniques well-known in the art, such as MRI, ultrasound, or CAT scan.

Exemplary time lengths associated with the treatment process include approximately one week; approximately two weeks; approximately three weeks; approximately four weeks; approximately five weeks; approximately six weeks; approximately seven weeks; approximately eight weeks; approximately nine weeks; approximately ten weeks; approximately eleven weeks; approximately twelve weeks; approximately thirteen weeks; approximately fourteen weeks; approximately fifteen weeks; approximately sixteen weeks; approximately seventeen weeks; approximately eighteen weeks; approximately nineteen months; approximately ten months; approximately eleven months; approximately twelve months; approximately thirteen months; approximately fourteen months; approximately fifteen months; approximately sixteen months; approximately seventeen months; approximately eighteen months; approximately nineteen months; approximately twenty months; approximately twenty-one months; approximately twenty-two months; approximately twenty-three months; approximately twenty-four months; approximately thirty months; approximately three years; approximately four years; and approximately five years.

The combinations and methods described herein can be used to treat patients suffering from any condition (such as cancer and/or cancer-related diseases) that can be remedied or prevented by the methods provided herein.

In some respects, the condition is cancer, including but not limited to malignant epithelial tumors, lymphoma, leukemia, myeloma, germ cell tumors, and sarcomas. In other respects, cancer can include cancer-related diseases, including B-cell-related cancers and/or cancer-related diseases, including but not limited to multiple myeloma, malignant plasma cell vegetations, lymphoma, Hodgkin's lymphoma, nodular lymphodominant Hodgkin's lymphoma, Kallmann's disease and myeloid leukemia, plasma cell leukemia, plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis, osteosclerotic myeloma, and B-cell lymphoglobulinic leukemia. Diseases, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic 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 macroglobulinemia, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue Tissue lymphoma, small cell 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 exudative lymphoma, lymphomatoid granulomatosis, large B-cell lymphoma rich in T cells/histocytes, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (spread leg type), EBV-positive diffuse large B-cell lymphoma in the elderly. Inflammation-associated diffuse large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma in HHV8-associated multicentric Castleman disease, characteristic unclassified B-cell lymphoma between diffuse large B-cell lymphoma and Burkitt lymphoma, characteristic unclassified B-cell lymphoma between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell-related lymphomas.

In some respects, cancers include stomach cancer, small intestine cancer, head and neck cancer (e.g., squamous cell head and neck cancer), thymic cancer, epithelial cancer, salivary cancer, liver cancer, bile duct cancer, neuroendocrine tumors, gastric 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, malignant epithelial tumors, glioblastoma, brain tumors, bone cancer, eye cancer, melanoma, or cancers with high microsatellite instability (MSI-H).

The combination therapy of the present invention can be used to remove tumors before or after surgery, and can be used before, during or after radiotherapy.

In some aspects, the combination therapy of the present invention is administered to a patient who has not previously been treated with therapeutic agents or chemotherapy drugs, i.e., the patient has never received treatment. In other aspects, the combination therapy of the present invention is administered to a patient who has failed to achieve a sustained response after prior therapy with therapeutic agents or chemotherapy drugs, i.e., the patient has undergone treatment. In some aspects, the subject has received prior therapy for treating a tumor, and the tumor is recurrent or refractory.

The inventions provided herein cover combination therapies with additive potency or additive therapeutic effects while reducing or avoiding undesirable or adverse effects. The invention also covers synergistic combinations where the therapeutic effect is greater than that of additives while reducing or avoiding undesirable or adverse effects. In some aspects, the methods and compositions provided herein allow for the treatment or prevention of diseases and conditions, wherein a lower and/or less frequent dose of at least one therapeutic agent in the combination therapy can achieve an enhanced antitumor response, thereby improving treatment to at least one of the following: i) reducing the incidence of undesirable or adverse effects caused by the administration of a therapeutic agent alone, while at least maintaining the efficacy of treatment; ii) increasing patient compliance; and iii) improving the efficacy of antitumor treatment.

Reagent test kit

The therapeutic agents of the combination therapy of the present invention can be conveniently combined in the form of a kit suitable for co-administration of the composition.

In one aspect, the kit comprises at least a first container and a second container, as well as instructions for use. The first container contains at least one dose of a first therapeutic agent, and the second container contains at least one dose of a second therapeutic agent for combination therapy. The instructions for use/label contain instructions for treating patients with cancer and/or cancer-related diseases. The first and second containers may be made of the same or different shapes (e.g., vials, syringes, and bottles) and/or materials (e.g., plastic or glass). The kit may further comprise other materials that can be used to administer the therapeutic agent, such as diluents, filters, IV bags and sutures, needles, and syringes.

Clinical research

A Phase 1, open-label, multi-dose, multicenter, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic study (NCT03269136) of PF-06863135 was conducted in adult patients with relapsed or refractory advanced multiple myeloma who were receiving standard therapy. This was a two-part study that assessed the safety and tolerability of increasing the dose level of PF-06863135 in Part 1 and confirmed the recommended Phase 2 dose (RP2D) in Part 2. This Phase 1 study is described in Example 10. Two additional clinical studies of PF06863135 (elranatamab) monotherapy are described in Examples 11 and 12.

Further clinical evaluations of PF-06863135 in combination with any of the therapeutic agents disclosed herein are possible: PF-06863135 in combination with anti-PD-1/PD-L1 antibodies (e.g., saxamimab/PF-06801591); PF-06863135 in combination with immunomodulators (e.g., thalidomide, lenalidomide, pomalidomide, ibelidomide, and aprexa); PF-06863135 in combination with gamma-secretase inhibitors (e.g., nirogacestat); and PF-06863135 in combination with other therapeutic agents, such as biotherapy. Drugs (e.g., CD38 antibody daratumumab, daratumumab and hyaluronidase, as well as isatuximab, and SLAMF7 antibody erlotuzumab), chemotherapy drugs (e.g. melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin and dendamustine), proteasome inhibitors (e.g. bortezomib, carfilzomib and ethazomib), corticosteroids (e.g. dexamethasone and prednisone), histone deacetylase (HDAC) inhibitors (e.g. pannostat), and nuclear export inhibitors (e.g. celiniso).

Examples 12 through 16 describe some planned combination therapy clinical studies of PF06863135 (elranatamab).

General methods

The following literature describes standard methods in molecular biology: Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 3rd Edition) 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. The standard method is also presented in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugate and protein expression (Vol. 3), and bioinformatics (Vol. 4).

Methods for protein purification are described, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). It describes chemical analysis, chemical modification, post-translational modification, fusion protein generation, and protein glycosylation (see, for example, 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., NY, 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, N.J., pp. 384-391). The generation, purification, and fragmentation of polyclonal and monoclonal antibodies are 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, ibid.). Standard techniques for characterizing ligand/receptor interactions are available (see, for example, Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

Monoclonal, polyclonal, and humanized antibodies can be prepared (see, for example, Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. 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 Harbor Laboratory). Bac a 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; U.S. Patent No. 6,329,511).

Alternatives to humanization include using human antibody libraries displayed on phages 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:ALaboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NewYork; Kay et al. (1996) Phage Display o f Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

Antigen purification is not necessary for antibody production. Animals can be immunized with cells carrying the antigen of interest. Spleen cells can then be isolated from the immunized animal and fused with myeloma cell lines to generate hybridomas (see, for example, Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., ibid.; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

Antibodies can be conjugated, for example, to small drug molecules, enzymes, liposomes, or polyethylene glycol (PEG). Antibodies can be used for therapeutic, diagnostic, kit, or other purposes, and include, for example, antibodies conjugated to dyes, radioisotopes, enzymes, or metals (e.g., colloidal gold) (see 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).

Methods for use in 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 ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids (including nucleic acid primers and probes, peptides and antibodies) for use as, for example, diagnostic reagents are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

The standard approach to immune system histology is described (see, for example, 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).

Software packages and databases for identifying, for example, antigenic fragments, leader sequences, protein folds, functional domains, glycosylation sites, and sequence alignments are available (see, for example, GenBank, VectorSuite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformat ics 16:741-742; Menne, et al. (2000) Bioinformatics Applications Note16: 741-742; Wren, et al. (2002) Comput.Methods Pro grams Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133: 17-21; von Heijne (1986) Nucleic Acids Res. 14: 4683-4690).

Example

Example 1: In vitro study of PD-1 induction in CD8+ T cells co-cultured with MM.1S multiple myeloma cells treated with BCMAxCD3 bispecific antibody.

This example illustrates that treatment with BCMAxCD3 bispecificity induces PD-1 expression on CD8 ⁺ T cells.

Negative selection of CD3+ T cells from PBMCs (StemCell Technologies) was performed using the EasyStep Human T Cell Enrichment Kit (Stem Cell Technologies). 10,000 luciferase-expressing target multiple myeloma MM.1S cells (MM.1S-Luc) were seeded with 50,000 CD3 ⁺ pan T cells in clear 96-well V plates. Cells were treated with 1 nM BCMAxCD3 bispecific antibody, and PD-1 expression was analyzed at 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 at room temperature for 20 min, followed by staining with antibodies against human CD8 and PD-1 (Biolegend). Samples were analyzed using FlowJo flow cytometry software. Dead cells were removed from the analysis by gating on the ZombieNIR negative population. Further gating of samples was performed on the CD8 ⁺ positive population. The percentage of PD-1 ⁺ cells expressing PD-1+ was defined as the percentage of PD-1+ positive cells within the CD8 ⁺ population. The results are summarized in Figure 1, and Table 1 shows that treatment with the BCMAxCD3 bispecific antibody on BCMA-expressing MM.1S multiple myeloma cells induced PD-1 expression on CD8+ T cells.

Table 1. % of PD-1 cells after treatment with BCMAxCD3 bispecific therapy

Example 2: In vivo study of BCMAxCD3 bispecific antibody in combination with anti-PD-1 antibody in MM.1S-PDL1 orthotopic and subcutaneous mouse models.

This example illustrates the combined efficacy of BCMAxCD3 bispecific antibody and anti-PD-1 antibody in (A) in situ MM.1S-Luc-PD-L1 and (B) MM.1S-PD-L1 multiple myeloma models compared to either BCMAxCD3 bispecific antibody or anti-PD-1 antibody alone.

A. Orthotopic mouse model

MM.1S-Luc multiple myeloma cells were engineered to express PD-L1 and were named MM.1S-Luc-PD-L1. MM.1S-Luc-PD-L1 cells were prepared into single-cell suspensions of 5 x ^10⁶ cells for intravenous (IV) inoculation into NSG mice.

Tumor growth was monitored by intraperitoneal (IP) injection of DPBS containing fluorescein solution, followed by chemiluminescence imaging and imaging using a Perkin Elmer IVIS Spectrum imaging system. Nineteen days after tumor cell inoculation, animals were IV-administered with 2 x ^10⁷ expanded human T cells. Two days after T cell administration, a single dose (10 μg/kg) of BCMAxCD3 bispecific antibody was administered via IV bolus injection. Anti-PD-1 antibody was administered via IP bolus injection at a dose of 5 μg/kg twice weekly for a total of six injections.

Tumor growth was monitored via imaging measurements collected twice weekly. Mice were imaged using the Perkin Elmer IVISSpectrum imaging system, where parameters were automatically determined and the maximum imaging time was 3 minutes. Data were collected using Living Image software. Regions of interest (ROIs) were plotted around the entire body of the mice, excluding the tail whenever possible. Background flux, as measured on the anesthesia manifold, was subtracted from each ROI. Tumor measurements were expressed as total flux in photons per second (p/s). The study was terminated on day 40 post-tumor inoculation. Results are summarized in Figure 2A, and Table 2 demonstrates that treatment with BCMAxCD3 bispecific and anti-PD-1 antibodies was more effective than treatment with bispecific or antibody alone.

Table 2. Tumor measurements expressed as total flux p/s after treatment

B. Subcutaneous mouse model

MM.1S multiple myeloma cells were engineered to express PD-L1 and designated MM.1S-PD-L1. Preactivated and expanded T cells (20 x ^10⁶ ) were administered on day 19 following subcutaneous (SC) inoculation of MM.1S-PD-L1 tumor cells. On day 21, BCMAxCD3 bispecific (0.3 or 1/kg) or negative bispecific (1/kg) was administered intravenously, Q7Dx3. Starting on day 21, anti-PD-1 mAb was administered intraperitoneally (IP) at 5/kg twice weekly. Tumor measurements were recorded 2–3 times weekly using digital calipers. N (at the start of the study) was 5–12 animals per group. Results are summarized in Figure 2B, and Table 3 demonstrates that treatment with BCMAxCD3 bispecific and anti-PD-1 antibody was more effective than treatment with bispecific or antibody alone.

Table 3. Tumor measurements after treatment (tumor volume ± SEM (mm ³ )).

Example 3: In vitro study of BCMA expression on cell surface in multiple myeloma cell lines treated with γ-secretase inhibitors (GSI).

This example illustrates the upregulation of BCMA expression on the cell surface in multiple myeloma cell lines treated with GSI.

Multiple myeloma cells (MM.1S, OPM2, H929, Molp8, RPMI8226) were seeded at 40,000 cells/well in 96-well U-plates. Cells were incubated for 24 hours in RPMI (0.1% DMSO) diluted with GSI. The following GSI concentrations 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 and washed with PBS + 2% FBS, followed by staining with ZombieNIR Viability dye (Biolegend) at a 1/500 dilution in PBS at room temperature for 20 minutes. Next, cells were washed with PBS + 2% FBS and stained with PBS + 2% FBS diluted with anti-BCMA PE-labeled antibody (Biolegend) at 4°C for 30 minutes. Cells were collected using a BD flow cytometer and analyzed using FlowJo flow cytometry software. Dead cells were removed from the analysis by gating on a ZombieNIR-negative population. The mean fluorescence intensity (MFI) of BCMA was plotted against GSI concentration to confirm EC50.

The results are summarized in Figures 3A-3E, and Table 4 shows that GSI treatment upregulated BCMA expression on the cell surface of multiple myeloma cell lines MM.1S, OPM2, H929, Molp8, and RPMI8226.

Table 4. Mean fluorescence intensity ± standard deviation

Example 4: In vitro study of time-dependent expression of BCMA on cell surface in multiple myeloma cell lines treated with GSI.

This example illustrates that treatment of multiple myeloma cell lines with GSI increases BCMA cell surface expression in a time-dependent manner, and that BCMA surface levels return to baseline after removal of GSI from the culture.

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

The results are summarized in Figures 4A-4E, and Table 5 shows that GSI upregulated BCMA expression on the cell surface of MM.1S, OPM2, H929, Molp8, and RPMI8226 cells in a time-dependent manner, and the upregulated surface BCMA expression did not persist after GSI was removed from the culture.

Table 5. Mean fluorescence intensity ± standard deviation

Example 5: In vitro study of soluble BCMA (sBCMA) levels in GSI-treated multiple myeloma cell lines

This example illustrates the reduced sBCMA shedding in multiple myeloma cell lines treated with GSI.

Multiple myeloma cells (MM.1S, OPM2, H929, Molp8, RPMI8226) were seeded at 40,000 cells/well in 96-well U-plates. Cells were incubated for 24 hours in RPMI medium (0.1% DMSO) diluted with GSI. The following GSI concentrations 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 sBCA concentration in the supernatant was measured using the Human BCMA/TNFRSF17 DuoSet ELISA Kit (R&D Systems) according to the manufacturer's instructions.

The results are summarized in Figures 5A-5E, and Table 6 shows that GSI treatment blocked the shedding of sBCMA in multiple myeloma cell lines MM.1S, OPM2, H929, Molp8, and RPMI8226, respectively.

Table 6. Mean fluorescence intensity ± standard deviation

Example 6: BCMAxCD3 bispecific antibody in combination with GSI in multiple myeloma

This example illustrates that treatment with a BCMAxCD3 bispecific antibody in combination with GSI showed enhanced cell killing in multiple myeloma cells cultured with human T cells, compared to treatment with a BCMAxCD3 bispecific antibody alone.

Negative selection of CD3 ⁺ T cells from PBMCs (StemCell Technologies) was performed using the EasyStep Human T Cell Enrichment Kit (Stem Cell Technologies). Multiple myeloma cells expressing luciferase (MM.1S-luc, OPM2-luc, H929-luc, Molp8-luc, RPMI8226-luc) were treated with 1 μM GSI 10,000. Twenty-four hours later, the cells were seeded with 50,000 CD3 ⁺ pan T cells in clear 96-well V plates. Cells were further treated with a series of BCMAxCD3 bispecific antibody concentrations (with or without 1 μM GSI). Sixty hours post-treatment, luciferase activity in treated cells was analyzed using the NeoLite Reagent Kit (PerkinElmer) and acquired on a VictorX multimodal plate reader (PerkinElmer). Cell viability was calculated by dividing the luciferase activity of treated cells by the luciferase activity of untreated controls (without BCMAxCD3 bispecific antibody).

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

Table 7. Mean fluorescence intensity ± standard deviation

Table 8. Mean fluorescence intensity ± standard deviation

Example 7: In vitro study on the expression of BCMA on the cell surface in lymphoma cell lines treated with GSI

This example illustrates the upregulation of BCMA expression on the cell surface in lymphoma cells treated with GSI.

Lymphoma cells (Raji cell line) were seeded at 40,000 cells/well in 96-well U-plates. Cells were incubated for 24 hours in RPMI medium (0.1% DMSO) diluted with GSI. GSI concentrations were tested at the following levels: 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 collected and washed with PBS + 2% FBS, followed by staining with ZombieNIR Viability dye (Biolegend) at a 1/500 dilution in PBS for 20 minutes at room temperature. Next, cells were washed with PBS + 2% FBS and stained with PBS + 2% FBS diluted with anti-BCMAPE marker antibody (Biolegend) for 30 minutes at 4°C. Cells were collected using a BD flow cytometer and analyzed using FlowJo flow cytometry software. Dead cells were removed from the analysis by gating on the ZombieNIR negative population. BCMA MFI was plotted against GSI concentration to confirm EC50.

The results are summarized in Figure 7, and Table 9 shows that GSI treatment upregulated BCMA expression on the cell surface of Raji lymphoma cells.

Table 9. Mean fluorescence intensity ± standard deviation

GSI[nM] BCMA MFI 1000.00 534.5±67.2 500.00 568.5±50.3 100.00 498.5±20.6 50.00 535±65.1 25.00 532±42.5 10.00 515.5±47.4 5.00 484±43.9 2.50 469±31.2 1.00 398±34 0.10 147.5±20.6 0.01 142.5±0.8 0.0 141±4.3

Example 8: In vitro study of time-dependent expression of BCMA on cell surface in GSI-treated lymphoma cell lines

This example illustrates that treatment of lymphoma cell lines with GSI increases BCMA cell surface expression in a time-dependent manner, and that BCMA surface levels return to baseline after removal of GSI from the culture.

Lymphoma cells (Raji) were seeded at 800,000 cells/2 ml/well in 6-well plates with GSI diluted 1 μM in RPMI medium (containing 0.1% DMSO). Cells were collected to evaluate BCMA expression on the cell surface at baseline, and then evaluated at 3, 6, and 24 hours after adding GSI. After 24 hours of incubation with GSI, cells were washed twice in PBS and re-plated into fresh 6-well plates. Cells were further collected for staining at 3, 6, and 24 hours after washing with GSI. At the indicated time points, samples were stained for 20 minutes at room temperature with ZombieNIR Viability dye (Biolegend) at a 1/500 dilution in PBS, washed with PBS + 2% FBS, and further stained for 30 minutes at 4°C with PBS + 2% FBS diluted with anti-BCMA PE-labeled antibody. Samples were collected 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.

The results are summarized in Figure 7B, and Table 10 shows that GSI upregulated the expression of cell surface BCMA on Raji cells in a time-dependent manner, and the upregulated surface BCMA expression did not persist after GSI was removed from the culture.

Table 10. Mean fluorescence intensity ± standard deviation

Example 9A: BCMAxCD3 bispecific antibody combined with GSI in lymphoma cells

This example illustrates that treatment with a BCMAxCD3-bispecific antibody in combination with GSI, compared to a BCMAxCD3 bispecific antibody alone, showed enhanced cytotoxicity in lymphoma cells expressing low BCMA levels co-cultured with human T cells.

Negative selection of CD3 ⁺ T cells from PBMCs (StemCell Technologies) was performed using the EasyStep Human T Cell Enrichment Kit (Stem Cell Technologies). 10,000 target lymphoma cells expressing luciferase (Raji-luc) were treated with 1 μM GSI. Twenty-four hours later, the cells were seeded together with 50,000 CD3 ⁺ pan T cells in clear 96-well V plates. Cells were further treated with a series of BCMAxCD3 bispecific concentrations (with or without 1 μM GSI). Sixty hours post-treatment, luciferase activity in treated cells was analyzed using the NeoLite Reagent Kit (Perkin-Elmer) and acquired on a VictorX multimodal plate reader (PerkinElmer). Cell viability was calculated by dividing the luciferase activity of treated cells by the luciferase activity of untreated controls (without BCMAxCD3 bispecific antibody).

The results are summarized in Figure 8, and Table 11A shows that treatment with GSI when co-cultured with human T cells enhanced BCMAxCD3 bispecific antibody-mediated cell killing in the lymphoma cell line (Raji).

Table 11A. Cell viability ± standard deviation

Example 9B: γ-secretase inhibitor activity enhanced the in vitro cytotoxicity of the BCMAxCD3 bispecific antibody PF06863135 (elranatamab) against multiple myeloma cells in a co-culture assay.

This example illustrates the combined benefits of treating multiple myeloma cells with the GSI and BCMAxCD3 bispecific antibody PF06863135 (elranatamab) in cytotoxic T lymphocytes (CTLs) in an in vitro co-culture assay, compared to BCMAxCD3 antibody alone.

Multiple myeloma cell lines expressing luciferase (H929-Luc, Molp8-Luc, OPM2-Luc, and RPMI8226-Luc) were _cultured at 37°C and 5% CO2 for 24 hours with 1 mM GSI or kept untreated. Myeloma cells were then harvested and transferred to 96-well U-plates at 10,000 cells/well and 50,000 CD3+ T cells/well. These cells were enriched from human PBMCs using a negative-selection Pan T cell isolation kit (Miltenyi Biotec). Before incubating the plates at 37°C and 5% _CO2 for 72 hours, a series of dilutions of BCMAxCD3 bispecific PF06863135, with or without 1 mM GSI, were added to the wells. At the end of the incubation period, Bright Glo matrix (Promega) was added to the wells, and luminescence was measured on a SpectraMax plate reader. Cell viability percentage was calculated as follows: the luminescence signal value of each test well was taken, divided by the average signal from the antibody-free treatment control wells, and then multiplied by 100. _EC50 values were further calculated by fitting cell viability data to a four-parameter dose-response curve using GraphPad Prism. Table 11B shows that treatment with GSI improved BCMAxCD3 antibody-mediated killing of multiple myeloma cells (H929, Molp8, OPM2, and RPMI8226) treated in a co-culture with human T cells.

Table 11B. Killing of multiple myeloma cells mediated by the BCMAxCD3 bispecific antibody PF06863135

Example 10: First-in-human Phase 1 clinical trial of BCMAxCD3 bispecific antibody elranatamab (PF-06863135).

This example illustrates an ongoing Phase 1 open-label, multicenter clinical study of PF-06863135 (BCMAxCD3 bispecific) as monotherapy and in combination with saxanilimab, lenalidomide, or pomalidomide in adult patients with advanced multiple myeloma who are relapsed or refractory to standard therapy. The study is registered on ClinicalTrials.gov under the identifier NCT03269136 and was first published in August 2017. Results from Part 1 of the trial and additional cohorts of the study are described in this example.

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

Table 12. First-time human clinical trial treatment of PF-06863135

Subsequently, the RP2D dose was determined based on the clinical results from Part 1 and selected as a maintenance dose of 76Q1W SC, with a single pre-injection of 44 SC administered one week prior to the first maintenance dose.

In Part 1, combination dose discovery, it was decided to administer a fixed dose of PF06863135 to subjects, with a maintenance dose starting one week after pre-injection and an initial dose one level below the single-drug RP2D, gradually increasing to the RP2D dose or gradually decreasing to the RP2D minus 2 level. Table 12A describes the potential fixed dose levels in the combination study of PF06863135 with a second therapeutic agent. For Part 1C, in a 28-day cycle starting 7 days after pre-injection of PF06863135, the initial dose of lenalidomide was modified to 15 QD orally on days 1–21.

Table 12A shows the potential fixed dose levels in the combination study.

dose level Pre-injection (mg) Maintenance dose (mg) PR2D minus 2 twenty four 32 RP2D minus 1 32 44 RP2D dosage 44 76

Part 1 of this study is a single-dose escalation arm for PF-06813135, administered intravenously (IV) at dose levels of 0.1, 0.3, 1, 3, 10, 30, and 50 μg/kg Q1W, and subcutaneously (SC) at dose levels of 80, 130, 215, 360, 600, and 1000 μg/kg Q1W. Upon reaching the maximum tolerated dose (MTD)/maximum administered dose (MAD), patients can be treated at dose levels selected from the aforementioned dose levels described in this paragraph, and at a lower MTD/MAD than those for Q2W administration (both IV and SC), to further support the recommended Phase 2 dose (RP2D) decision. For this study, the dose-limiting toxicity observation period was set at 21 days for Q1W administration and 28 days for Q2W administration. The treatment cycle (also referred to as the cycle) for Q1W administration was 3 weeks, and for Q2W administration, it was 4 weeks.

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

In the IV cohort, two patients (one out of 30 and one out of the 50 μg/kg cohort) experienced grade 3 febrile neutropenia and grade 1 dose-limiting toxicity (DLT) with QT prolongation on ECG. No patients in the SC cohort experienced DLT. Cytokine release syndrome (CRS) was the most common adverse event reported. In the IV cohort, CRS was observed in 1 (50.0%), 4 (80.0%), and 6 (100.0%) patients in the 10, 30, and 50 μg/kg cohorts, respectively. Of all patients treated with IV, 6 (26.1%) experienced a maximum grade 1 CRS, and 5 (21.7%) experienced a maximum grade 2 CRS. Each of the 11 patients with CRS developed CRS within the first 2 days of administration. Of the 3 patients at 50 μg/kg, 1 developed CRS after the second dose, 1 after both the second and third doses, and 1 after both the third and fourth doses.

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. Among all patients treated with SC, 18 (60.0%) experienced a maximum grade 1 CRS, while 5 (16.7%) experienced a maximum grade 2 CRS. CRS primarily began within the first 2 days of administration. Table 13 describes further details of CRS in the SC cohort.

Table 13. Cytokine Release Syndrome (CRS) in the SC cohorts of Part 1 and Part 1.1 of this study

In the IV cohort, two patients achieved 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 optimal response with stable disease.

In the SC cohort, the efficacy outcomes are summarized in Table 14 below.

Table 14. Patient responses in the SC cohorts of Part 1 and Part 1.1 of this study.

These results show that clinical efficacy was observed in most patients at the highest dose levels of 600 and 1000 μg/kg SC, and that toxicity was tolerable and manageable. Although the total dose exposure was higher in patients treated with SC than in those treated with IV, the CRS in patients treated with SC was less severe.

Part 1.1 of this study is an alternative maintenance dose escalation arm for the single-formulation PF-06863135. If excessive toxicity occurs or the maximum tolerated dose (MTD)/maximum administered dose (MAD) is reached earlier than the dose level expected in Part 1 of the study described above, a pre-injection will be administered one week prior to Day 1 of Cycle 1 at that dose level (maintenance dose), and this dose will be used for all subsequent dose levels in any dose escalation that may be initiated in Part 1.1. The pre-injection will be at a dose level below the maintenance dose.

Clinical outcomes of Part 1.1 of this study. As of February 4, 2021, a total of 20 patients participated and were treated in Part 1.1 of this study. One cohort of 7 patients received a pre-injection of 600 μg/kg followed by 1000 μg/kg Q1W, and another cohort of 13 patients received a pre-injection of 600 μg/kg followed by 1000 μg/kg Q2W. CRS in both cohorts is described in Table 13. The introduction of pre-injection reduced the mid-term duration of CRS by 50%, from 4 days to 2 days. The dosing frequency (Q1W vs. Q2W) in Part 1.1 of this study had no effect on CRS. Patient responses in Part 1.1 of this study are described in Table 14.

Part 2A of this study is the dose extension arm for the single-formulation PF-06863135. Based on the single-formulation dose escalation clinical data, Part 2A of this study will select IV or SC administration, including initiation and maintenance doses, as well as Q1W or Q2W dosing. Specifically, SC will be administered at dose levels of 215, 360, 600, or 1000 μg/kg at Q1W or Q2W without pre-administration, or at maintenance dose levels of 215, 360, 600, and 1000 μg/kg at both Q1W and Q2W, with pre-administration on day 1 of cycle zero having a dose level lower than the maintenance dose, which is expected to serve as the RP2D for the Phase 2A study.

Preliminary pharmacokinetic (PK) analysis indicated that body weight was not a clinically relevant factor for PF-06863135 exposure. Therefore, a fixed dose was appropriate for the administration of PF-06863135. Based on the encouraging efficacy and safety data obtained from Part 1 of the study, the promising RP2D for Part 2A of this study is likely a fixed dose equivalent of 1000 μg/kg (i.e., 76) of PF-06863135 in either Q1W or Q2W. On Day 1 of Cycle Zero, a fixed dose equivalent of 600 μg/kg (i.e., 44) will likely be used as a pre-injection. The initial dose of 44 was used as a pre-injection and was designed to alleviate CRS symptoms at the latter dose of 76. Based on the results of Part 1 of the study, CRS occurred primarily after the initial dose. Subsequently, 44 (initiation) and 76 (maintenance) were selected as single-formulation RP2D doses. The patient will be given a single pre-injection of PF06863135 in 44 SCs, followed by maintenance dosing of 76 Q1 W SCs or 76 Q2 W SCs 7 days after the single pre-injection.

Parts 1B and 2B of this study involved a combination therapy of PF-06863135 and sazamorimab (a PD-1 antibody). The treatment cycle was 28 days. Sazamorimab was administered at 300 SCs every 4 weeks, starting on day 1 of cycle 1. PF-06863135 was administered at the selected dose (Q1W or Q2W) SC or IV, with or without pre-administration one week prior to day 1 of cycle 1.

In Part 1B, the dose of PF-06863135 will be determined based on the results of Parts 1 and 1.1 of this study, starting with the RP2D described in Part 2A of this study above, or with one level less than the MTD/MAD, whichever is lower. If the combination regimen is poorly tolerated, PF-06863135 will be downgraded to a lower dose level to select the dose level in Part 2B.

In Part 2B, PF06863135 will be administered at a dose level based on the results of Part 1B.

Parts 1C and 2C of this study involved combination therapy with PF-06863135 and lenalidomide. The treatment cycle was 28 days. Lenalidomide was administered orally (PO) daily for days 1–21, starting on day 1 of cycle 1, without dexamethasone. PF-06863135 was administered SC or IV at the selected dose (Q1W or Q2W) starting on day 1 of cycle 1, with or without pre-administration one week prior to day 1 of cycle 1.

In Part 1C, the dosage of PF-06863135 will be determined based on the results of Parts 1 and 1.1 of this study, and the initial plan is to start with the RP2D described in Part 2A of this study above, or with the MTD/MAD, whichever is lower. If the combination regimen is poorly tolerated, PF-06863135 will be downgraded to a lower dose level to select the dose level of Part 2C. Subsequently, a dose level of PF06863135 will be determined to start at, for example, one level lower than the single-formulation RP2D described in Table 12A. In a 28-day cycle beginning 7 days after the pre-injection of PF06863135, the starting dose of lenalidomide will be modified to 15 QD orally on days 1–21.

In Part 2C, PF-06863135 will be administered at a dose level based on the results of Part 1C.

Parts 1D and 2D of this study involved combination therapy with PF06863135 and pomalidomide. The treatment cycle was 28 days. Pomalidomide was administered daily at 4 PO doses, without dexamethasone, starting on day 1 of cycle 1, from days 1 to 21. PF06863135 was administered intravenously or intravenously at the selected dose (Q1W or Q2W), with or without pre-administration one week prior to day 1 of cycle 1.

In Part 1D, the dose of PF-06863135 will be determined based on the results of Parts 1 and 1.1 of this study, starting with the RP2D described in Part 2A of this study above, or with the MTD/MAD, whichever is lower. If the combination regimen is poorly tolerated, PF06863135 will be downgraded to a lower dose level to select the dose level for Part 2D. Subsequently, a dose level for starting with PF06863135 will be determined, such as one level lower than the single-formulation RP2D described in Table 12A.

In Part 2D, PF-06863135 will be administered at a dose level based on the results of Part 1D.

Patient participation criteria. For all groups of the studies described in this article, patient participation criteria included that the patient had progressed on or was intolerant of established therapies known to provide clinical benefit for multiple myeloma, including proteasome inhibitors, immunomodulatory imide drugs (imids), and anti-CD38 mAbs (if approved and available) in combination or as a single agent, and that, based on the investigator's judgment, the patient was not a candidate for a regimen known to provide clinical benefit in relapsed or refractory multiple myeloma.

The primary and secondary objectives of this study include (1) evaluating the preliminary clinical efficacy of PF-06863135RP2D, (2) further characterizing safety and tolerability, (3) evaluating the pharmacokinetics of PF-06863135 at RP2D, (4) evaluating the immunogenicity of PF-06863135, and (5) characterizing the effects of PF-06863135 on systemic soluble immune factors. Each of (1) to (5) pertains to PF-06863135 as a monotherapy and in combination with saxanilimab, lenalidomide, or pomalidomide.

Example 11. A Phase 2 clinical study of BCMAxCD3 bispecific antibody PF-06863135 monotherapy in participants with multiple myeloma who were refractory to at least one proteasome inhibitor, an IMiD and an anti-CD38 monoclonal antibody.

This study is an open-label, multicenter, non-randomized phase 2 trial to evaluate the efficacy and safety of PF-06863135 in participants with refractory/relapsed multiple myeloma (RRMM) who are refractory to at least one proteasome inhibitor (PI), one IMiD, and one anti-CD38 mAb. To determine the impact of prior BCMA-guided therapy on response to PF-06863135 monotherapy, the study will recruit two independent and parallel cohorts: one cohort including participants who have not received BCMA-guided therapy (cohort A; approximately 90 participants), and the other cohort including participants who have received prior BCMA-guided ADC therapy or BCMA-guided CAR-T cell therapy, both of which are approved or investigational (cohort B; approximately 60 participants). The primary objective of each independent cohort was to determine the efficacy (i.e., ORR) of PF-06863135, as assessed by blinded independent central review (BICR), as defined by the International Myeloma Working Group (IMWG). The study design is shown in Table 15 below.

Table 15. Study Treatments in Phase 2 Clinical Trials of BCMAxCD3 Bispecific Antibody PF-06863135 Monotherapy

Dosage: Participants in each cohort will be administered an initial dose of PF-06863135 via subcutaneous injection (SC) on day 1 of cycle 1 (C1D1). Each treatment cycle consists of 28 days. The initial dose of PF-06863135 is used as a pre-injection and is intended to alleviate CRS symptoms, which are primarily expected after the initial dose. The pre-injection will then be modified to 12 PF-06863135 administered on C1D1, followed by 32 PF-06863135 administered on C1D4. Starting from day 8 of cycle 1, the dose of PF-06863135 should be increased to 76 SC Q1W, provided that the participant meets all three of the following criteria:

(1) ANC ≥ 1.0 × ^10⁹ /L;

(2) Platelet count ≥25× ^10⁹ /L; and

(3) Treatment-related non-hematologic toxicities return to baseline or severity level ≤1 (or, at the investigator’s discretion, level ≤2 if no safety risk is considered for the participant).

If a participant does not meet these criteria on day 8 of cycle 1, initial dosing should be postponed for 76 days until these criteria are met. If a participant has received at least 6 cycles of Q1W dosing and achieved a PR or better IMWG response that lasts for at least 2 months, the dosing interval should be changed from Q1W to Q2W, as the lower dose intensity may be sufficient to maintain the response given the reduced disease burden in these participants. However, participants may continue to participate in the Q1W program based on the investigator's medical judgment and after consultation with the trial sponsor. After changing to a Q2W interval, the dosing interval may be restored to Q1W based on the investigator's medical judgment.

For each participant in the study cohort, treatment with PF-06863135 will continue until disease progression, patient refusal (withdrawal of consent), or unacceptable toxicity occurs. The study will be completed when all participants have discontinued the study intervention and have been followed for at least 2 years for overall survival (OS).

Primary endpoint: Overall response rate (ORR) determined by blinded independent central review (BICR) according to the International Myeloma Working Group (IMWG).

Secondary endpoints: (1) Duration of response (DOR) as determined by BICR and investigator based on IMWG; (2) Cumulative complete response rate (CCRR) as determined by BICR and investigator based on IMWG; (3) ORR as determined by investigator based on IMWG; (4) Cumulative duration of complete response (DOCCR) as determined by BICR and investigator based on IMWG; (5) Progression-free survival (PFS) as determined by BICR and investigator based on IMWG; (6) Overall survival (OS); (7) Time to response (TTR) as determined by BICR and investigator based on IMWG; (8) Minimal residual disease (MRD) negative rate as determined by IMWG (central laboratory); (9) AEs and laboratory abnormalities as graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0; (10) Severity of CRS and immune effector cell-related neurotoxic syndrome (ICANS) as assessed according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. (11) Pre-dose and post-dose concentrations of PF-06863135, and (12) ADA and NAb for PF-06863135.

Example 12. A phase 1/2 open-label, multicenter study evaluating elranatamab (PF-06863135) monotherapy with two escalating pre-dose administrations and longer dosing intervals in participants with relapsed/refractory multiple myeloma.

The aim of this study is to evaluate the rate of grade 2 or higher CRS when elranatamab is administered using a dosing regimen of two escalating pre-injections and a priming dose. In addition, the study will evaluate the safety, tolerability, pharmacokinetic (PK), and preliminary antimyeloma activity of elranatamab at doses higher than 76 at different dosing intervals (QW, Q2W, and Q4W) in participants with relapsed/refractory multiple myeloma (RRMM). A full-dose elranatamab regimen of 76 QW for six consecutive cycles followed by Q2W (part 2) will also be evaluated. Cycle 1 begins on the day of the first pre-injection.

Administer all doses of elranatamab subcutaneously (SC).

During the first cycle (C1) of elranatamab treatment, the following regimen will be evaluated for all participants in this study:

C1D1: Pre-treatment + elranatamab12; C1D4: Pre-treatment + elranatamab32; C1D8: Pre-treatment + elranatamab76; C1D15 and C1D22: elranatamab76.

A pre-dose is required approximately 60 minutes before both the pre-injection of elranatamab (C1D8) (C1D1 and C1D4) and the first full dose. The pre-dose to be used is: acetaminophen 650 (or paracetamol 500), diphenhydramine 25 (orally or IV), and dexamethasone 20 (or equivalent) (orally or IV).

In the second cycle and thereafter, the following will be evaluated:

In Part 1A, in the dose level 1 cohort, participants will be administered 116Q2W within C2 through C6. For participants with a PR or better IMWG response at least two cycles at Q2W, a switch to 116Q4W may be made. If dose level 1 is tolerable, in the dose level 2 cohort, participants will be administered 152Q2W within C2 through C6. For participants with a PR or better IMWG response at at least two cycles at Q2W, a switch to 152Q4W may be made. For both dose levels 1 and 2, if, after switching to the Q4W interval, a participant subsequently begins to experience an increased disease burden but has not yet reached a PD level according to IMWG criteria, the dosing interval should be restored to the Q2W at the same dose level (e.g., from 152Q4W to 152Q2W).

Once potential MTD/RP2Ds are identified from Part 1A, Part 1B will begin and will become a dose expansion cohort for the selected dose level.

Part 1C will only begin if both dose levels 1 and 2 in Part 1A are tolerable. Here, in C2 and C3, participants will be administered 116Q1W or 152Q1W. In C4 and C6, for participants with a PR or better IMWG response at C2 and C3, 116 or 152Q2W will be administered. In C7 and thereafter, for participants with a PR or better IMWG response at Q2W for at least two cycles, 116 or 152Q4W will be administered.

Part 2: 76Q1W will be administered from C2 to C6. For participants who have a PR or better IMWG response over at least 2 cycles at Q1W, 76Q2W will be administered at C7 and thereafter. If, after switching to the Q2W interval, a participant subsequently begins to experience an increase in disease burden but has not yet reached the level of PD according to IMWG criteria, the dosing interval should be restored to Q1W at 76.

Example 13. An open-label, multicenter, randomized phase 3 study evaluating the efficacy and safety of elranatamab (PF06863135) and daratumumab in participants with relapsed/refractory multiple myeloma (RRMM).

The objective of Part 1 of this study was to evaluate the DLT, safety, and tolerability of elranatamab plus daratumumab in order to select the RP3D for combination therapy. Part 2 aimed to compare the efficacy of elranatamab (Arm A) and elranatamab plus daratumumab (Arm B), with control groups for both: daratumumab plus pomalidomide plus dexamethasone (Arm C). Part 1 also included an assessment of the rate of grade 2 or higher CRS when elranatamab was administered alone or in combination with elranatamab in two escalating pre-injections and a pre-dose. Study treatments are described in Table 16. Each cycle was 28 days.

Table 16. Study of elranatamab and daratumumab combination therapy

Elranatamab Dosage: In Part 1, the dose level is reduced by 1, and for participants who have achieved a PR or better IMWG response over at least two cycles after they have been at 44 QW until the end of Cycle 6, a further 44 QW should be administered. Similarly, in Part 1 dose level 1, the 76 QW is switched to 76 QW in Part 1, and similarly, the QW is switched to Q2W in Arms A and B of Part 2. Subsequently, if an increase in disease burden is observed (without reaching the level of PD according to IMWG criteria), the dosing interval should be restored to QW.

Daremumab administration: Following the FDA-approved USPI dosing schedule for daratumumab and hyaluronidase fihj products, administer 1800 via subcutaneous injection every 1 week, followed by 2 weeks, and then 4 weeks.

A prophylactic dose is required approximately 60 minutes before both the pre-injection of elranatamab (C1D8) (C1D1 and C4D1) and the first full dose. In addition to Part 2, Arm C, a prophylactic dose is also required 1–3 hours before each dose of daratumumab, wherein the dexamethasone component of the treatment regimen should be administered before daratumumab and used as a prophylactic dose. If elranatamab and daratumumab are to be administered on the same day, only one prophylactic dose should be given on the day preceding the administration of elranatamab and daratumumab. The prophylactic doses to be used are: acetaminophen 650–1000 mg (or paracetamol 500 mg), diphenhydramine 25–50 mg (orally or IV), or dexamethasone 20 mg (or equivalent) (orally or IV).

Example 14. A randomized, two-arm, phase 3 study of elranatamab (PF-06863135) plus lenalidomide versus lenalidomide in newly diagnosed multiple myeloma (NDMM) patients with minimal residual disease (MRD) following autologous stem cell transplantation (ASCT).

The aim of this study was to compare the efficacy of elranatamab plus lenalidomide combination therapy (Arm A) versus lenalidomide (Arm B) and to determine the safety and tolerability of the elranatamab plus lenalidomide combination therapy. Participants in this study were newly diagnosed multiple myeloma patients with minimal residual disease (MRD) following autologous stem cell transplantation. Table 16 below describes the planned dosing regimen for each arm in this study.

Table 16. Comparison of elranatamab plus lenalidomide combination therapy with lenalidomide in MRD-positive NDMM patients after treatment in the ASCT study.

A prophylactic dose is required approximately 60 minutes before both the pre-injection of elranatamab (C1D8) (C1D1 and C1D4) and the first full dose. The prophylactic doses to be used are: acetaminophen 650 (or paracetamol 500), diphenhydramine 25 (orally or IV), and dexamethasone 20 (or equivalent) (orally or IV).

Example 15. A randomized, controlled, two-arm, phase 3 study comparing elranatamab (PF06863135) and lenalidomide in newly diagnosed multiple myeloma (NDMM) patients ineligible for stem cell transplantation (ASCT).

The aim of this study was to compare the efficacy of elranatamab plus lenalidomide combination therapy (arm A) with that of the lenalidomide control arm, and to determine the safety and tolerability of elranatamab. Participants in this study would be newly diagnosed multiple myeloma patients who were not suitable for stem cell transplantation. Table 17 below describes the planned dosing regimen for each arm in this study.

Table 17. Combination therapy of elranatamab and lenalidomide for NDMM patients who are not suitable for stem cell transplantation research treatment.

Example 16. A phase 1b and 2 open-label umbrella study of elranatamab (PF06863135) in combination with other anticancer therapies in participants with relapsed/refractory multiple myeloma (RRMM).

The objectives of this study included evaluating the safety and tolerability of elranatamab in combination with other anticancer therapies in RRMM participants in order to select RP2D for combination therapy. Table 18 describes some exemplary combination therapy trial designs of this study.

Table 18. Combination therapy of elranatamab with other anticancer therapies for the treatment of relapsed/refractory multiple myeloma (RRMM) in a study.

sequence

Table 19 lists the sequences of the BCMAx CD3 bispecific antibody PF-06863135 and the PD-1 antibody saxanilimab, along with their corresponding SEQ ID NOs as described herein. SEQ ID NOs 1 to 13 are the sequences of the CD3 arm of PF-06863135, and SEQ ID NOs 14 to 26 are the sequences of the BCMA arm of PF-06863135. SEQ ID NOs 27 to 34 are the sequences of the PD-1 antibody saxanilimab.

Table 19 Sequences of PF-06863135 and Sassanlimab

Claims (51)

1. A method of treating 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) specific therapeutic agent, and the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulator, or a gamma secretase inhibitor (GSI). 2. The method or drug of claim 1, wherein the BCMA bispecific therapeutic agent is PF-06863135, the anti-PD-1 antibody is saxamerizumab, the immunomodulator is lenalidomide or pomalidomide, and/or the GSI is Nirogacestat or a pharmaceutically acceptable salt thereof. 3. A method of treating cancer in a subject, comprising administering PF-06863135 to the subject according to the following dosing regimen: (a) 80, 130, 215, 360, 600 or 1000 μg/kg Q1W subcutaneous (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 to 20, 40 to 44, or 76 to 80 mg Q1W SC; (e) Approximately 16 to 20, 40 to 44, or 76 to 80 mg Q2W SC; (f) Approximately 40 mg Q1W SC or Q2W SC; (g) Approximately 44 mg Q1W SC or Q2W SC; (h) Approximately 76 mg Q1W SC or Q2W SC; (i) Approximately 80 mg Q1W SC or Q2W SC; (j) Pre-injection of approximately 44 mg Q1W SC for 1–4 weeks, or pre-injection of approximately 32 mg Q1W SC for 1–4 weeks, followed by first treatment administration of approximately 76 mg Q1W SC or Q2W SC; (k) Pre-injection of approximately 40 mg Q1W SC for 1–4 weeks, followed by first treatment administration of approximately 80 mg Q1W SC or Q2W SC; (l) Pre-injection of approximately 44 mg Q1W SC for 1–4 weeks, or pre-injection of approximately 32 mg Q1W SC for 1–4 weeks, followed by first treatment administration of approximately 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment administration of approximately 76 mg Q2W SC; (m) Pre-injection of approximately 40 mg Q1W SC for 1–4 weeks, followed by first treatment administration of approximately 80 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment administration of approximately 80 mg Q2W SC; (n) Pre-injection of approximately 44 mg Q1W SC for 1 week, followed by first treatment administration of approximately 76 mg Q1W SC or Q2W SC; (o) Pre-injection of approximately 32 mg Q1W SC for 1 week, followed by first treatment administration of approximately 76 mg Q1W SC or Q2W SC; (p) Pre-administration of approximately 40 mg Q1W SC for 1 week, followed by first treatment administration of approximately 80 mg Q1W SC or Q2W SC; (q) Pre-injection of approximately 44 mg Q1W SC for 1 week, followed by first treatment dosing of approximately 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment dosing of approximately 76 mg Q2W SC; (r) Pre-treatment with approximately 44 mg Q1W SC for 1 week, followed by a first treatment with approximately 76 mg Q1W SC for 23 weeks, followed by a second treatment with approximately 76 mg Q2W SC; (s) Pre-treatment dosing of approximately 44 mg Q1W SC for 1 week, followed by first treatment dosing of approximately 76 mg Q1W SC for 24 weeks, followed by second treatment dosing of approximately 76 mg Q2W. (t) Pre-injection of approximately 32 mg Q1W SC for 1 week, followed by first treatment dosing of approximately 76 mg Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks, followed by second treatment dosing of approximately 76 mg Q2W SC; (u) Pre-injection of approximately 40 mg Q1W SC for 1 week, followed by a first treatment dose of approximately 80 mg Q1W SC for weeks 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48, followed by a second treatment dose of approximately 80 mg Q2W SC; or (v) Pre-treatment with approximately 40 mg Q1W SC for 1 week, followed by a first treatment with approximately 80 mg Q1W for 23 or 24 weeks, followed by a second treatment with approximately 80 mg Q2W SC. 4. The method of claim 3, wherein PF06863135 is administered to the subject as a first treatment dose of approximately 76 mg Q1W SC, and after receiving such first treatment dose for at least 23 weeks, PF06863135 is administered to the subject as a second treatment dose of 76 mg Q2W or PF06863135 is continued to be administered to the subject as the first treatment dose. 5. A method of treating cancer in a subject, comprising administering a first treatment dose of PF-06863135 subcutaneously to the subject for 23, 24, or 25 weeks, followed by a second treatment dose, wherein... (a) The first treatment is administered at approximately 4 mg every 1 week, and the second treatment is administered at approximately 4 mg every 2 weeks; (b) The first treatment is administered at approximately 12 mg every 1 week, and the second treatment is administered at approximately 12 mg every 2 weeks; (c) The first treatment is administered at approximately 24 mg Q1W, and the second treatment is administered at approximately 24 mg Q2W; (d) The first treatment is administered at approximately 32 mg every 1 week, and the second treatment is administered at approximately 32 mg every 2 weeks; (e) The first treatment is administered at approximately 44 mg every 1 week, and the second treatment is administered at approximately 44 mg every 2 weeks; or (f) The first treatment is administered at approximately 76 mg Q1W, and the second treatment is administered at approximately 76 mg Q2W. 6. The method of claim 5, wherein if the dosage of the first therapeutic administration is 32 mg or higher, the method further comprises administering PF06863135 to the subject as a pre-injection, and administering the pre-injection for one week, and administering the first dose of the first therapeutic administration within one week immediately following the administration of the pre-injection, wherein... (1) The pre-injection is a single pre-injection, and the single pre-injection is approximately 24 mg; (2) The pre-injection administration includes a first pre-injection administration of about 4 mg and a second pre-injection administration of about 20 mg, and the two pre-injection administrations are administered on two different dates and the first pre-injection administration is administered before the second pre-injection administration; (3) The pre-injection administration includes a first pre-injection administration of about 8 mg and a second pre-injection administration of about 16 mg, and the two pre-injection administrations are administered on two different dates and the first pre-injection administration is administered before the second pre-injection administration; (4) The pre-injection administration includes a first pre-injection administration of about 12 mg and a second pre-injection administration of about 12 mg, and the two pre-injection administrations are administered on two different dates and the first pre-injection administration is administered before the second pre-injection administration; (5) The pre-injection administration comprises a first pre-injection of approximately 8 mg and a second pre-injection of approximately 24 mg, and the two pre-injections are administered on two different dates, with the first pre-injection administered prior to the administration of the second pre-injection; or (6) The pre-injection includes a first pre-injection of about 4 mg and a second pre-injection of about 28 mg, and the two pre-injections are administered on two different dates and the first pre-injection is administered before the second pre-injection. 7. A method of treating cancer in a subject, comprising administering PF-06863135 to the subject. (a) First treatment administration of approximately 32 mg to approximately 76 mg Q1W SC, starting in week 1; or (b) Pre-injection during the first week and first treatment administration starting in the second week, wherein the pre-injection is (i) a first pre-injection of about 4 mg SC to about 32 mg SC and a second pre-injection of about 12 mg SC to about 44 mg SC, wherein the first pre-injection and the second pre-injection are administered sequentially during the first week, or (ii) a single pre-injection of about 24 mg to about 44 mg SC, and wherein the first treatment administration is about 32 mg to about 76 mg SC Q1W or about 32 mg to about 152 mg SC Q2W, starting in the second week, and wherein the dose of the first treatment administration is higher than the dose of each of the corresponding single pre-injection, the first pre-injection, and the second pre-injection; Week 1, Week 2, and any subsequent week refer to the first week, second week, and any subsequent week when PF06863135 is administered to the subject, respectively, and PF06863135 is administered to the subject as a pharmaceutical product containing PF06863135. 8. The method of claim 7, wherein the subject is given a pre-injection, wherein the pre-injection is a single pre-injection of about 24 mg SC, about 32 mg SC, or about 44 mg SC in week 1, or the pre-injection is (i) a first pre-injection of about 12 mg SC and a second pre-injection of about 32 mg SC; (ii) a first pre-injection of about 4 mg SC and a second pre-injection of about 20 mg; (iii) a first pre-injection of about 8 mg and a second pre-injection of about 16 mg; (iv) a first pre-injection of about 12 mg and a second pre-injection of about 12 mg; or (v) a first pre-injection of about 8 mg and a second pre-injection of about 24 mg. 9. The method of claim 7 or 8, wherein the first treatment administration is about 32 mg Q1W SC or about 32 mg Q2W SC, about 44 mg Q1W SC or about 44 mg Q2W SC. 10. The method of claim 9, wherein the first treatment is administered to the subject until at least the end of the first cycle or until at least the end of the sixth cycle, wherein the cycle is 21 days or 28 days, the first cycle begins on the first day of the first week, the first day of the second week, or the first day of the third week, and the first cycle, the second cycle, and the subsequent cycles refer to the first cycle, the second cycle, and the subsequent cycle when PF06863135 is administered to the subject, respectively. 11. The method of claim 10, further comprising administering PF06863135 to the subject at a second treatment dose 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 is no longer in the first treatment dose, wherein the second treatment dose is administered at a less frequent frequency than the corresponding first treatment dose, or the amount of the second treatment dose is less than the amount of the first treatment dose. 12. The method of claim 10, wherein after administering the first treatment dose to the subject until at least the end of the 6th cycle, a second treatment dose of PF06863135 is administered to the subject in lieu of the first treatment dose, or the first treatment dose may continue to be administered to the subject, and wherein the second treatment dose is about 32 mg to about 152 mg Q2WSC, about 32 mg to about 152 mg Q3WSC, or about 32 mg to about 152 mg Q4WSC, wherein the frequency of administration of the second treatment dose is less than the frequency of administration of the first treatment dose, or the amount of administration of the second treatment dose is less than the amount of administration of the first treatment dose. 13. The method of claim 7 or 8, wherein the first treatment administration is (i) about 76 mg Q1W SC, (ii) about 76 mg Q2W SC, or (iii) about 76 mg Q1W SC for three weeks, followed by about 116 mg Q1W SC, or (iv) about 76 mg Q1W SC for three weeks, followed by about 152 mg Q1W SC. 14. The method of claim 13, wherein the first treatment is administered to the subject until the end of at least the first cycle, at least the third cycle, or at least the sixth cycle, wherein the cycle is 21 days or 28 days, and the first cycle begins on the first day of the first week, the first day of the second week, or the first day of the third week, and the first cycle, the second cycle, and the subsequent cycles refer to the first cycle, the second cycle, and the subsequent cycle when PF06863135 is administered to the subject, respectively. 15. The method of claim 14, further comprising administering PF06863135 to the subject at a second treatment dose 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 is no longer in the first treatment dose, wherein the second treatment dose is administered at a less frequent frequency than the first treatment dose, or the amount of the second treatment dose is less than the amount of the first treatment dose. 16. The method of claim 14, wherein after administering the first treatment dose to the subject until at least the end of the 6th cycle, a second treatment dose 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 lieu of the first treatment dose, or the first treatment dose may continue to be administered to the subject, wherein the frequency of administration of the second treatment dose is less than the frequency of administration of the corresponding first treatment dose, or the amount of administration of the second treatment dose is less than the amount of administration of the first treatment dose. 17. The method of claim 15 or 16, wherein the first treatment administration is about 76 mg Q1W SC, and the second treatment administration 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. 18. The method of any one of claims 15 or 16, wherein the first treatment administration is about 76 mg Q2W SC, and the second treatment administration 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. 19. The method of any one of claims 7 to 18, wherein PF06863135 is administered to the subject during the first treatment administration until the end of the first cycle, followed by the second treatment administration, wherein the cycle is 21 days or 28 days, the first cycle begins on the first day of the first week or the first day of the second week or the first day of the third week, and the first cycle, the second cycle and the subsequent cycle refer to the first cycle, the second cycle and the subsequent cycle when PF06863135 is administered to the subject, respectively. 20. The method of claim 19, wherein the second treatment administration is administered until at least the end of the 6th cycle, and thereafter the subject is administered a third treatment administration of about 76 mg to about 152 mg Q3W SC or about 76 mg to about 152 mg Q4W SC in lieu of the second treatment administration, or the subject continues to be administered the second treatment administration. 21. The method of claim 20, wherein the second treatment administration is administered until the end of the 6th cycle, the first dose of the third treatment administration begins in the 7th cycle, and the third treatment administration is 116 mg Q4W SC or 152 mg Q4W SC. 22. The method of claim 20 or 21, wherein the first treatment administration is about 76 mg Q1W SC, the second treatment administration is about 116 mg Q2W SC, and the third treatment administration is about 116 mg Q4W SC. 23. The method of claim 20 or 21, wherein the first treatment administration is about 76 mg Q1W SC, the second treatment administration is about 152 mg Q2W SC, and the third treatment administration is about 152 mg Q4W SC. 24. A method of treating cancer, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week: (a) (b) (c) (d) (e) Or (f) When the dosage during the first week is 12 mg plus 32 mg, a dose of 12 mg is administered on one day, followed by a dose of 32 mg on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and when the dosage during the first week is A mg plus B mg, a dose of A mg is administered on one day, followed by a dose of B mg on another day. 25. The method of claim 24, wherein elranatamab (PF06863135) is administered to the subject according to the dosing schedule shown below. (a) (b) (c) (d) (e) Or (f) . 26. The method of claim 25, wherein PF06863135 is administered to the subject according to a dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, after week 26, and after week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks, respectively. 27. The method of claim 24, wherein elranatamab (PF06863135) is administered to the subject according to the dosing schedule shown below. (a) (b) (c) (d) (e) Or (f) . 28. The method of claim 27, wherein PF06863135 is administered to the subject according to a dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks, respectively. 29. The method of claim 24, wherein elranatamab (PF06863135) is administered to the subject according to the dosing schedule shown below. (a) (b) (c) (d) (e) Or (f) . 30. The method of claim 29, wherein PF06863135 is administered to the subject according to a dosing schedule (a), (b), or (c), and the dosing frequencies after week 25, week 26, and week 27 in dosing schedules (a), (b), and (c) are (i) weekly, (ii) every two weeks, or (iii) weekly or every two weeks, respectively. 31. The method of any one of claims 24 to 30, wherein the dosage and frequency of administration during the first cycle are collectively referred to as pre-administration, and if only one dose of elranatamab is administered to the subject as pre-administration, such one dose is referred to as single pre-administration, and if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are respectively referred to as first pre-administration and second pre-administration; the dosage and frequency of administration during weeks 2-24, 2-25, and 2-26 of each dosing regimen (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as first therapeutic administration in each dosing regimen, and the dosage and frequency of administration during weeks 25 and thereafter, weeks 26 and thereafter, and weeks 27 and thereafter of each dosing regimen (a) and (d), (b) and (e), and (c) and (f) are collectively referred to as second therapeutic administration in each dosing regimen. 32. The method of claim 31, wherein the subject is given PF06863135 of the second therapeutic dose for 6 to 18 cycles, thereafter the subject is given a third therapeutic dose of PF06863135 subcutaneously, wherein the third therapeutic 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 the cycle is 21 days or 28 days, and the first cycle begins on day 1 of week 1, day 1 of week 2, or day 1 of week 3. 33. The method of claim 32, wherein (i) the first treatment administration is 32 mg Q1W, the second treatment administration is 32 mg Q1W or 32 mg Q2W, and the third treatment administration is 32 mg Q2W or 32 mg Q4W, (ii) the first treatment administration is 32 mg Q1W, the second treatment administration is 32 mg Q2W, and the third treatment administration is 32 mg Q4W, (iii) the first treatment administration is 44 mg Q1W, the second treatment administration is 44 mg Q1W, and the third treatment administration is 32 mg Q4W. The first treatment is administered at 44 mg Q1W or 44 mg Q2W, and the third treatment is administered at 44 mg Q2W or 44 mg Q4W; (iv) the first treatment is administered at 44 mg Q1W, the second treatment is administered at 44 mg Q2W, and the third treatment is administered at 44 mg Q4W; (v) the first treatment is administered at 76 mg Q1W, the second treatment is administered at 76 mg Q1W or 76 mg Q2W, and the third treatment is administered at 76 mg Q2W or 76 mg Q4W. (vi) The first treatment is administered 76 mg Q1W, the second treatment is administered 76 mg Q2W, and the third treatment is administered 76 mg Q4W; (vii) The first treatment is administered 116 mg Q1W, the second treatment is administered 116 mg Q1W or 116 mg Q2W, and the third treatment is administered 116 mg Q2W or 116 mg Q4W; (viii) The first treatment is administered 116 mg Q1W, the second treatment... The first treatment is 116 mg Q2W, and the third treatment is 116 mg Q4W; (ix) the first treatment is 152 mg Q1W, the second treatment is 152 mg Q1W or 152 mg Q2W, and the third treatment is 152 mg Q2W or 152 mg Q4W; or (x) the first treatment is 152 mg Q1W, the second treatment is 152 mg Q2W, and the third treatment is 152 mg Q4W. 34. A method of treating cancer, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week: When the dosage during the first week is 12 mg plus 32 mg, a dosage of 12 mg is administered on one day, followed by a dosage of 32 mg on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and wherein a dosage of A mg is administered on one day, followed by a dosage of B mg on another day. 35. The method of claim 34, wherein elranatamab is administered to the subject according to the following dosing schedule. 36. The method of claim 34, wherein elranatamab is administered to the subject according to the following dosing schedule. 37. The method of any one of claims 34 to 36, wherein the dosage and frequency of administration during the first cycle are collectively referred to as pre-administration, and if only one dose of elranatamab is administered to the subject as pre-administration, such one dose is referred to as single pre-administration; if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are respectively referred to as first pre-administration and second pre-administration; the dosage and frequency of administration during the second to fourth cycles are collectively referred to as first therapeutic administration; the dosage and frequency of administration during the fifth to 24 cycles are collectively referred to as second therapeutic administration; and the dosage and frequency of administration during the 25th week and thereafter are collectively referred to as third therapeutic administration. 38. A method of treating cancer, comprising administering elranatamab (PF06863135) to a subject according to a dosing schedule as shown below, wherein the dosing schedule is described by the number of weeks, the dosage, and the dosing frequency corresponding to each week: When the dosage during the first week is 12 mg plus 32 mg, a dosage of 12 mg is administered on one day, followed by a dosage of 32 mg on another day, wherein A plus B is 4(A) plus 20(B), 8(A) plus 16(B), 12(A) plus 12(B), or 8(A) plus 24(B), and wherein a dosage of A mg is administered on one day, followed by a dosage of B mg on another day. 39. The method of claim 38, wherein elranatamab is administered to the subject according to the following dosing schedule. 40. The method of claim 39, wherein elranatamab is administered to the subject according to the following dosing schedule. 41. The method of claim 38, wherein elranatamab is administered to the subject according to the following dosing schedule. 42. The method of claim 38, wherein elranatamab is administered to the subject according to the following dosing schedule. 43. The method of any one of claims 38 to 42, wherein the dosage and frequency of administration during the first cycle are collectively referred to as pre-administration, and if only one dose of elranatamab is administered to the subject as pre-administration, such one dose is referred to as single pre-administration; if two doses of elranatamab are sequentially administered to the subject during the first week, the two doses are respectively referred to as first pre-administration and second pre-administration; the dosage and frequency of administration during the second to fourth cycles and the dosage and frequency of administration during the fifth to twelfth cycles are collectively referred to as first therapeutic administration; the dosage and frequency of administration during the thirteenth to twentieth cycles are collectively referred to as second therapeutic administration; and the dosage and frequency of administration during the period after the twentieth week are collectively referred to as third therapeutic administration. 44. The method of any one of claims 1 to 43, wherein the cancer is multiple myeloma. 45. The method of any one of claims 3 to 44, further comprising administering saxamerab to the subject. 46. The method of any one of claims 3 to 44, further comprising administering lenalidomide to the object. 47. The method of any one of claims 3 to 44, further comprising administering daratumumab to the subject. 48. The method of any one of claims 3 to 44, further comprising applying isatuximab to said object. 49. The method of any one of claims 3 to 44, further comprising administering at least one dose of a pre-administration to the subject on the same day as administering a first dose of a single pre-administration, a first pre-administration, a second pre-administration, or a first therapeutic administration of PF06863135, wherein the pre-administration is acetaminophen, diphenhydramine, or dexamethasone. 50. The method of any one of claims 3 to 44, further comprising administering a second therapeutic agent to the subject. 51. The method of any one of claims 3 to 44, further comprising administering radiotherapy to the subject.