CN116744924A

CN116744924A - Methods, therapies and uses for treating cancer

Info

Publication number: CN116744924A
Application number: CN202180060934.2A
Authority: CN
Inventors: N·A·巴尔迪布克桑; E·V·巴里; J·A·布莱克-哈斯金斯; G·W-L·詹; J·周; M·A·埃尔梅利加; H·I·克鲁普卡; K·H·廖; E·R·万登德利斯; A·维凯拉; P·S·维塞尔; A·伊韦
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 2020-05-13
Filing date: 2021-05-13
Publication date: 2023-09-12

Abstract

The present disclosure describes single agents and combination therapies useful for treating cancer and/or cancer-related diseases. The single formulation and combination therapy includes BCMA antibodies.

Description

Methods, therapies and uses for treating cancer

Technical Field

The present invention relates to single agents and combination therapies useful for treating cancer and/or cancer-related diseases. In particular, the invention relates to single formulations and combination therapies comprising BCMAx CD3 bispecific antibodies.

Background

The B cell maturation antigen (BCMA, CD269 or TNFRSF 17) is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily. BCMA was identified in human malignant T-cell lymphomas containing T (4; 16) translocations. The gene is selectively expressed in B cell lineages, and the expression is highest in plasmablast cells and plasma cell and antibody secretion cells. BCMA binds to two ligands, B cell activating factor (BAFF) (also known as B lymphocyte stimulator (BLyS) and APOL associated leukocyte expression ligand (tal-1)) and proliferation-inducing ligand (APRIL), with affinities of 1 μm and 16nM, respectively. Binding of APRIL or BAFF to BCMA promotes a cascade of signaling that involves NF- κ B, elk-1, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase that produce cell survival and proliferation signals. 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 plasmacytoid cells, such as Systemic Lupus Erythematosus (SLE) and rheumatoid arthritis, BCMA-expressing antibody producing cells secrete autoantibodies that attack themselves. BCMA is also present in the peripheral blood of patients with multiple myeloma in soluble form (i.e., soluble BCMA or sBCMA) and may lead to a decrease in BCMA-specific therapies. Several BCMA-specific therapies are currently being developed, however, multiple myeloma remains an incurable disease and almost all patients develop resistance to these agents and eventually relapse.

Programmed death 1 (PD-1) receptors and 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, activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, thereby eliciting 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. In contrast, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity in non-clinical animal models (Iwai Y, et al Proc Natl Acad SCi USA2002; 99:12293-97). There are several antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2, and currently are being developed for the treatment of cancer.

The Notch pathway is a conserved signaling pathway that contributes to cell fate determination, proliferation, angiogenesis, and apoptosis. The Notch pathway is uniquely characterized in that both the ligand (Jagged-1, 2 and Delta-1, 3, 4) and the receptor (Notch-1, 2, 3, 4) are type I membrane proteins. After the cell is in direct contact with the cell, the notch receptor is cleaved by gamma-secretase, releasing the intracellular domain (NICD), which translocates into the nucleus to regulate transcription. Gamma-secretase inhibitors (GSI) have been developed for a variety of diseases, such as alzheimer's disease and cancer.

There remains a need for improved therapies for treating cancer and/or cancer-related diseases, such as multiple myeloma. In addition, therapies with greater efficacy than existing therapies are needed. The preferred combination therapies of the invention show greater efficacy than treatment with either therapeutic agent alone.

Disclosure of Invention

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

Disclosed herein are methods of treating cancer and/or a cancer-related disease in a subject comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent. The invention disclosed herein further relates to a medicament comprising a first therapeutic agent and a second therapeutic agent for treating cancer and/or a cancer-related disease in a subject. The invention further relates to a first therapeutic agent for treating cancer and/or a cancer-related disease in a subject, wherein the first therapeutic agent is administered in combination with a second therapeutic agent.

In some aspects, the first therapeutic agent is a B Cell Maturation Antigen (BCMA) -specific therapeutic agent. In some aspects, the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulatory agent, 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 immunomodulatory agent. 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 another aspect, 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 immunomodulatory agent. In 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 chemotherapeutic drug. In some aspects, the therapeutic agent is administered to the subject simultaneously, separately or sequentially.

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

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

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

In some aspects, at least one therapeutic agent is administered to a subject at a dose of: about 1mg/kg to about 1000mg/kg, about 2mg/kg to about 900mg/kg, about 3mg/kg to about 800mg/kg, about 4mg/kg to about 700mg/kg, about 5mg/kg to about 600mg/kg, about 6mg/kg to about 550mg/kg, about 7mg/kg to about 500mg/kg, about 8mg/kg to about 450mg/kg, about 9mg/kg to about 400mg/kg, about 5mg/kg to about 200mg/kg, about 2mg/kg to about 150mg/kg, about 5mg/kg to about 100mg/kg, about 10mg/kg to about 100mg/kg, or about 10mg/kg to about 60 mg/kg. Or (b)

In some aspects, at least one therapeutic agent is administered to a subject at a fixed dose of: about 0.05 μg, 0.2 μg, 0.5 μg, 1 μg, 10 μg, 100 μg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 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 more.

In some aspects, at least one therapeutic agent is administered to a subject in the following manner: at least once daily, once a day, twice a day, three times a day, four times a day, every two days, every three days, once a week, every two weeks, 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 a 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 the group consisting of multiple myeloma, malignant plasma cell neoplasm, lymphoma, hodgkin's lymphoma, nodular lymphocytic dominant Hodgkin's lymphoma, kahler's disease and myelogenous leukemia, plasma cell leukemia, bone and extramedullary plasma cell neoplasm with multiple myeloma, solid bone and extramedullary plasma cell neoplasm, unidentified Monoclonal Gammaglobulopathy (MGUS), smoldering myeloma, light chain amyloidosis, osteosclerotic myeloma, B-cell lymphocytic leukemia, hairy cell leukemia, B-cell non-hodgkin's lymphoma (NHL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL), chronic Myelogenous Leukemia (CML), follicular lymphoma, burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myelogenous leukemia, megaloblastic, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymus) 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/tissue cell-enriched large B cell lymphoma, primary central nervous system lymphoma, primary diffuse large B cell lymphoma of the skin (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, ALK positive large B-cell lymphoma, plasmablasts lymphoma, large B-cell lymphoma occurring in HHV 8-associated multicenter Castleman disease, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and burkitt's lymphoma, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and classical hodgkin's lymphoma, and other B-cell-associated lymphomas. In some aspects, the B cell-related cancer is multiple myeloma. In certain aspects, the multiple myeloma is relapsed/refractory multiple myeloma.

Also provided herein are methods of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a B Cell Maturation Antigen (BCMA) bispecific antibody and the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an immunomodulatory agent, or a Gamma Secretase Inhibitor (GSI). Also provided herein is a first therapeutic agent for use in a method of treating multiple myeloma in a subject, wherein the first therapeutic agent is a B-cell maturation antigen (BCMA) bispecific antibody and is administered in combination with a second therapeutic agent selected from the group consisting of 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 another aspect, 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 immunomodulatory agent. In another aspect, the first therapeutic agent is a BCMA bispecific antibody and the second therapeutic agent is GSI.

Also provided are methods of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is sartoriab.

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

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

Also provided are methods of treating multiple myeloma in a subject, comprising administering to the subject a combination therapy comprising a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is PF-06863135 and the second therapeutic agent is nirogachita.

Also provided are methods of treating cancer in a subject comprising administering PF-06863135 to the subject according to a dosing regimen.

In some embodiments, the dosing regimen is:

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

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

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

(d) About 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5 or 8Q1w IV or Q2V IV.

(e) A priming administration of about 0.5, 1, 2, 3, 4, 5, 6, 7.5, or 8Q1W Iv for a week followed by a first therapeutic administration of about 6, 7, 7.5, 8, 9, or 10Q1W Iv or Q2W Iv, wherein the priming administration is less than the single dose in the therapeutic administration; or (b)

(f) A priming administration of a single priming administration of about 0.5, 1, 2, 3, 4, 5, 6, 7, 7.5, or 8q1w IV for one week followed by a first therapeutic administration of about 6, 7, 7.5, 8, 9, or 10q1w IV for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks followed by a second therapeutic administration of about 6, 7, 7.5, 8, 9, or 10q2w IV, wherein the priming administration is less than the single dose in the first therapeutic administration.

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) About 16 to 80Q1WSC or Q2 WSC;

(d) About 16 to 20, 40 to 44, or 76 to 80q1 wsc;

(e) About 16 to 20, 40 to 44, or 76 to 802 q2 wsc;

(f) About 40Q1 wsc or Q2 wsc;

(g) About 44Q1WSC or Q2 WSC;

(h) About 76q1wtsc or Q2 wtsc;

(i) About 80Q1WSC or Q2 WSC;

(j) About 44Q1W SC for 1-4 weeks, or about 32Q1W SC for 1-4 weeks, followed by about 76Q1W SC or Q2W SC for the first therapeutic administration;

(k) The pre-infusion administration of about 40Q1W SC continues for 1-4 weeks, followed by the first therapeutic administration of about 80Q1W SC or Q2W SC;

(l) About 44Q1W SC for 1-4 weeks, or about 32Q1W SC for 1-4 weeks, followed by about 76Q1W SC for 2-20, 21, 22, 23, 24, 25-46, 47, or 48 weeks, followed by about 76Q2W SC for a second therapeutic administration;

(m) a pre-infusion administration of about 40q1w SC for 1-4 weeks followed by a first therapeutic administration of about 80q1w SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks followed by a second therapeutic administration of about 80q2w SC;

(n) a pre-infusion administration of about 44Q1WSC for 1 week followed by a first therapeutic administration of about 76Q1WSC or Q2 WSC;

(o) a pre-infusion administration of about 32Q1W SC for 1 week followed by a first therapeutic administration of about 76Q1W SC or Q2W SC;

(p) a pre-infusion administration of about 40Q1W SC for 1 week followed by a first therapeutic administration of about 80Q1W SC or Q2W SC;

(q) a pre-infusion administration of about 44Q1W SC for 1 week followed by a first therapeutic administration of about 76Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks followed by a second therapeutic administration of about 76q2w SC;

(r) a pre-infusion administration of about 44Q1W SC for 1 week, followed by a first therapeutic administration of about 76Q1W SC for 23 weeks, followed by a second therapeutic administration of about 76Q2W SC;

(s) a pre-infusion administration of about 44Q1W SC for 1 week followed by a first therapeutic administration of about 76Q1W SC for 24 weeks followed by a second therapeutic administration of about 76Q2W

(t) a pre-infusion administration of about 32q1w SC for 1 week followed by a first therapeutic administration of about 76q1w SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks followed by a second therapeutic administration of about 76q2w SC;

(u) a pre-infusion administration of about 40q1w Sc for 1 week followed by a first therapeutic administration of about 80q1w Sc for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks followed by a second therapeutic administration of about 80q2w Sc; or (b)

(v) The pre-infusion administration of about 40Q1W SC was continued for 1 week, followed by the first therapeutic administration of about 80Q1W for 23 or 24 weeks, followed by the second therapeutic administration of about 80Q2W SC.

In some embodiments, the pre-infusion administration is administered as a single pre-infusion administration of either 44Q1W SC, 40Q1W SC, or 32Q1W SC for only one week.

Also provided are methods of treating cancer in a subject comprising administering PF06863135 to the subject, (a) a single pre-injection administration of about 32SC or about 44SC at week 1, or both a first pre-injection administration of about 12SC and a second pre-injection administration of about 32SC at week 1, and (b) a first therapeutic administration of about 76Q1W SC beginning at week 2, wherein weeks 1, 2, and any subsequent weeks are the first week, second week, and any subsequent week when PF06863135 is administered to the subject, and PF6863135 is administered to the subject as a pharmaceutical product comprising PF06863135.

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

In some embodiments, the method further comprises administering PF06863135 to the subject at a second therapeutic dose of about 76Q2W SC starting at week 25 or the first week of cycle 7, wherein PF06863135 in the first therapeutic dose is administered until week 24 ends or cycle 6 ends, wherein cycle 28 days, and cycle 1, cycle 2, and subsequent cycles are the first, second, and subsequent cycles when PF06863135 is administered to the subject.

In some embodiments, PF06863135 is administered to the subject at the first therapeutic administration of about 76Q1W SC, and PF06863135 is administered to the subject at a second therapeutic administration of about 76Q2W or PF06863135 continues to be administered to the subject at the first therapeutic administration after at least 23 weeks of receiving such first therapeutic administration. In some embodiments, PF06863135 is administered to the subject at the second therapeutic administration after the subject receives the first therapeutic administration for at least 23 weeks according to the respective regulatory label of the pharmaceutical product or according to the response of the subject. In some embodiments, administration of PF06863135 to the subject with the first therapeutic administration is continued after the subject receives the first therapeutic administration for at least 23 weeks, unless the subject has exhibited an IMWG response as a partial response or better 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, and each cycle is 28 days, and the first cycle begins on the day of administration of a single bolus administration or a first bolus administration of PF06863135 to the subject.

Also provided are methods of treating cancer in a subject comprising administering PF-06863135 to the subject according to the following dosing regimen:

(a) The pre-infusion administration of about 32Q1W SC was continued for 1 week, followed by the first therapeutic administration of about 44Q1W SC;

(b) The pre-infusion administration of about 32q1w SC was continued for 1 week, followed by the first therapeutic administration of about 44q2w SC;

(c) A pre-infusion administration of about 32Q1W SC for 1 week followed by a first therapeutic administration of about 44Q1W SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks, and a second therapeutic administration of about 44Q2W SC; or (b)

(d) The pre-infusion administration of about 32q1w SC was continued for 1 week, followed by a first therapeutic administration of about 44q1w SC for 23 or 24 weeks, and a second therapeutic administration of about 44q2w SC.

In some embodiments, PF-06863135 is administered to the subject for 1 week with a pre-infusion administration of about 32q1w SC followed by a first therapeutic administration of about 44q1w SC. In some embodiments, PF-06863135 is administered to the subject for 1 week with a pre-infusion administration of about 32q1w SC followed by a first therapeutic administration of about 44q1w SC for 23 or 24 weeks followed by a second therapeutic administration of about 44q2w SC.

Also provided are methods of treating cancer in a subject comprising subcutaneously administering PF-06863135 to the subject for 23, 24, or 25 weeks with a first therapeutic administration followed by a second therapeutic administration.

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

In some embodiments, if the amount of administration of the first therapeutic administration is 32 or greater, the method further comprises administering PF06863135 to the subject as a pre-infusion administration, and administering the pre-infusion administration for one week, then the first dose in the first therapeutic administration is administered within one week immediately after one week of administering the pre-infusion administration. In some embodiments, the pre-injection administration is a single pre-injection administration, and the single pre-injection administration is about 24. In some embodiments, the pre-infusion administration comprises a first pre-infusion administration of about 4 and a second pre-infusion administration of about 20, and the two pre-infusion administrations are administered at two different days and the first pre-infusion administration is administered before the second pre-infusion administration. In some embodiments, the pre-infusion administration comprises a first pre-infusion administration of about 8 and a second pre-infusion administration of about 16, and the two pre-infusion administrations are administered at two different days and the first pre-infusion administration is administered before the second pre-infusion administration. In some embodiments, the pre-infusion administration comprises a first pre-infusion administration of about 12 and a second pre-infusion administration of about 12, and the two pre-infusion administrations are administered at two different days and the first pre-infusion administration is administered before the second pre-infusion administration. In some embodiments, the pre-infusion administration comprises a first pre-infusion administration of about 8 and a second pre-infusion administration of about 24, and the two pre-infusion administrations are administered at two different days and the first pre-infusion administration is administered before the second pre-infusion administration. In some embodiments, the pre-infusion administration comprises a first pre-infusion administration of about 4 and a second pre-infusion administration of about 28, and the two pre-infusion administrations are administered at two different days and the first pre-infusion administration is administered before the second pre-infusion administration.

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

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

Also provided are methods of treating cancer in a subject comprising administering PF-06863135 to the subject

(a) A first therapeutic administration of about 32 to about 76Q1W SC, beginning at week 1; or (b)

(b) A pre-infusion administration during week 1 and a first therapeutic administration beginning at week 2, wherein the pre-infusion administration is (i) a first pre-infusion administration of about 4SC to about 32SC and a second pre-infusion administration of about 12SC to about 44SC, wherein the first pre-infusion administration and the second pre-infusion administration are administered sequentially at week 1, or (ii) a single pre-infusion administration of about 24 to about 44SC, and wherein the first therapeutic administration is about 32 to about 76q1w SC or about 32 to about 152q2w SC, beginning at week 2, and wherein the amount of administration of the first therapeutic administration is higher than the amount of administration of each of the respective single pre-infusion administration, first pre-infusion administration, and second pre-infusion administration;

wherein week 1, week 2 and any subsequent weeks refer to the first week, second week and any subsequent weeks, respectively, when PF06863135 is administered to the subject, and PF06863135 is administered to the subject as a pharmaceutical product comprising PF 06863135.

In some embodiments, a single pre-administration of about 24SC, about 32SC, or about 44SC is administered to the subject at week 1. In some embodiments, the subject is administered a first pre-infusion administration of about 12SC and a second pre-infusion administration of about 32SC at week 1. In some embodiments, a single pre-administration of about 4, about 8, about 12, or about 24 is administered to the subject during week 1. In some embodiments, a pre-injection administration of a first pre-injection administration and a second pre-injection administration is administered to the subject. In some embodiments, the first pre-injection administration is about 4 and the second pre-injection administration is about 20. In some embodiments, the first pre-injection administration is about 8 and the second pre-injection administration is about 16. In some embodiments, the first pre-injection administration is about 12 and the second pre-injection administration is about 12. In some embodiments, the first pre-injection administration is about 8 and the second pre-injection administration is about 24.

In some embodiments, the first therapeutic administration is about 32q1w SC or about 32q2w SC. In some embodiments, the first therapeutic administration is about 44Q1W SC or about 44Q2W SC. In some embodiments, the first therapeutic administration is administered to the subject until at least cycle 1 ends or until at least cycle 6 ends, wherein cycle 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 are the first cycle, second cycle, and subsequent cycles, respectively, when PF06863135 is administered to the subject.

In some embodiments, the method further comprises administering PF06863135 to the subject after the subject is no longer in the first therapeutic administration, with a second therapeutic administration of about 32 to about 152q2w SC, about 32 to about 152q3w SC, or about 32 to about 152q4w SC, wherein the second therapeutic administration is less frequent than the corresponding first therapeutic administration, or the second therapeutic administration is less frequent than the first therapeutic administration. In some embodiments, wherein a second therapeutic administration of PF06863135 to the subject replaces the first therapeutic administration after administration of the first therapeutic administration to the subject until the end of at least cycle 6, or the administration of the first therapeutic administration to the subject may continue, and wherein the second therapeutic administration is about 32 to about 152q2w SC, about 32 to about 152q3w SC, or about 32 to about 152q4w SC, wherein the frequency of administration of the second therapeutic administration is less than the frequency of administration of the first therapeutic administration, or the amount of administration of the second therapeutic administration is less than the amount of administration of the first therapeutic administration. In some embodiments, wherein (i) the first therapeutic administration is about 32Q1W SC and the second therapeutic administration is about 32Q2W SC, 323 w SC, 324 w SC, 44Q2W SC, 44Q3WSC, 44Q4W SC, 76Q3W SC, 76mg Q4W SC, 116Q4W SC, or 152Q4W SC, or (ii) the first therapeutic administration is about 32Q2W SC and the second therapeutic administration is about 32Q3W SC, 32Q4W SC, 44Q4W SC, 76Q3W SC, 76Q4W SC, 116Q4W SC, or 152Q4W SC. In some embodiments, wherein (i) the first therapeutic administration is about 44Q1W SC and the second therapeutic administration is about 44Q2W SC, 44Q3W SC, 44Q4W SC, 76Q2W SC, 76Q4W SC, 116Q4W SC, or 152Q4W SC, or (ii) the first therapeutic administration is about 44Q2W SC and the second therapeutic administration is about 32Q2W SC, 44Q3W SC, 76Q3W SC, 116Q3W SC, 152Q3W SC, 32Q4WSC, 44Q4W SC, 76Q4W SC, 116Q4W SC, or about 152Q4W SC. In some embodiments, the second therapeutic administration is administered to the subject according to the respective regulatory label of the pharmaceutical product. In some embodiments, the second therapeutic administration is administered to the subject in response to the subject's response to the first therapeutic administration. In some embodiments, the administration of the first therapeutic dose to the subject is continued unless the subject has demonstrated an IMWG response as a partial response or better while the subject is in the first therapeutic dose, 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 therapeutic administration is (i) about 76q1w SC, (ii) about 76q2w SC, or (iii) about 76q1w SC for three weeks, followed by about 116q1w SC, or (iv) about 76q1w SC for three weeks, followed by about 152q1w SC. In some embodiments, the first therapeutic administration is administered to the subject until at least cycle 1 ends, at least cycle 3 ends, or at least cycle 6 ends, wherein cycle 21 or 28 days, and 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 are the first cycle, second cycle, and subsequent cycles, respectively, directed to the subject when PF06863135 is administered. In some embodiments, the method further comprises administering PF06863135 to the subject after the subject is no longer in the first therapeutic administration, with a second therapeutic administration of about 44 to about 152q2w SC, about 44 to about 152q3w SC, or about 44 to about 152q4w SC, wherein the second therapeutic administration is less frequent than the first therapeutic administration, or the second therapeutic administration is less frequent than the first therapeutic administration. In some embodiments, wherein a second therapeutic 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 in place of the first therapeutic administration after the first therapeutic administration is administered to the subject until at least the end of cycle 6, or wherein the frequency of administration of the second therapeutic administration is less than the frequency of administration of the corresponding first therapeutic administration, or the amount of administration of the second therapeutic administration is less than the amount of administration of the first therapeutic administration can continue to be administered to the subject. In some embodiments, the first therapeutic administration is about 76Q1W SC and the second therapeutic administration is about 44Q2W SC, about 76Q2WSC, about 116q2w SC, about 152q2w SC, about 44Q3W SC, about 76Q3W SC, about 116q3w SC, about 152Q3W SC, about 44Q4W SC, about 76Q4W SC, about 116Q4W SC, or about 152Q4W SC. In some embodiments, the first therapeutic administration is about 76Q2W SC and the second therapeutic administration is about 44Q2W SC, about 44Q3W SC, about 76Q3W SC, about 116Q3W SC, about 152Q3W SC, about 44Q4WSC, about 76Q4W SC, about 116Q4W SC, or about 152Q4W SC. In some embodiments, the first therapeutic administration is about 76Q1W and the second therapeutic administration is about 76Q2W. In some embodiments, the first therapeutic administration is about 76Q2W and the second therapeutic administration is about 76Q4W. In some embodiments, the second therapeutic administration is administered to the subject according to the respective regulatory label of the pharmaceutical product. In some embodiments, the second therapeutic administration is administered to the subject in response to the subject's response to the first therapeutic administration. In some embodiments, the second therapeutic administration is administered to the subject if the subject has demonstrated an IMWG response as a partial response or better while the subject is at the first therapeutic 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, PF06863135 is administered to the subject with the first therapeutic administration until the end of cycle 1, followed by the second therapeutic administration, wherein cycle 21 or 28 days, cycle 1 begins on day 1 of week 1 or day 1 of week 2 or day 1 of week 3, and cycle 1, cycle 2, and subsequent cycles are the first, second, and subsequent cycles, respectively, directed to the subject when PF06863135 is administered. In some embodiments, the second therapeutic administration is administered until at least the end of cycle 6, and thereafter a third therapeutic administration of about 76 to about 152Q3W SC or about 76 to about 152Q4W SC is administered to the subject in place of, or in addition to, the second therapeutic administration is administered to the subject. In some embodiments, the second therapeutic administration is administered until at least the end of cycle 6, and thereafter a third therapeutic administration of about 76 to about 152q3w SC or about 76 to about 152q4w SC is administered. In some embodiments, the second therapeutic administration is administered until the end of cycle 6, the first dose in the third therapeutic administration begins at cycle 7, and the third therapeutic administration is 116q4w SC or 152q4w SC. In some embodiments, PF06863135 is administered to the subject with the third therapeutic administration after the subject receives the second therapeutic administration until at least cycle 6, according to the respective regulatory label of the pharmaceutical product or according to the response of the subject. In some embodiments, PF06863135 is continued to be administered to the subject with the second therapeutic administration until at least cycle 6, except that while the subject is in the second therapeutic administration, the subject has demonstrated an IMWG response as a 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 therapeutic administration is about 76Q1W SC, the second therapeutic administration is about 116q2w SC, and the third therapeutic administration is about 116q4w SC. In some embodiments, the first therapeutic administration is about 76Q1W SC, the second therapeutic administration is about 152q2w SC, and the third therapeutic administration is about 152q4w SC.

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

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

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

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

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

In some embodiments, the period is 21 days when the subject is at the Q1W or Q3W dosing frequency of PF06863135 and the period is 28 days when the subject is at the Q2W or Q4W dosing frequency of PF 06863135. In some embodiments, the period is 28 days unless the patient is at the Q3W dosing frequency of PF 06863135. In some embodiments, when the subject is in the first treatment administration, the period is 21 days in cycle 1 and until the end of the last period.

Also provided are methods of treating cancer comprising administering elranatamab (PF 06863135) to a subject according to a dosing schedule as shown below, and wherein the dosing schedule is described by a number of weeks, an amount of dosing, and a dosing frequency corresponding to each number of weeks:

(a)

(b)

(c)

(d)

(e)

or (f)

Wherein when the dose is 12 plus 32 during week 1, the dose of 12 is administered on one day followed by the dose 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 dose is a plus B during week 1, the dose of a is administered on one day followed by the dose of B on another day.

In some embodiments, elranatamab (PF 06863135) is administered to the subject according to the dosing schedule shown below,

(a)

(b)

(c)

(d)

(e)

or (f)

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

(a)

(b)

(c)

(d)

(e)

or (f)

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

(a)

(b)

(c)

(d)

(e)

or (f)

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

In some embodiments, wherein the amount administered and the frequency of administration during week 1 are together referred to as a pre-infusion administration, and if only one dose of elranatamab is administered to the subject in a pre-infusion administration, such one dose is referred to as a single pre-infusion administration, and if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are referred to as a first pre-infusion administration and a second pre-infusion administration, respectively; the amounts and frequencies of administration during weeks 2-24, weeks 2-25 and weeks 2-26 of each of the administration schedules (a) and (d), (b) and (e) and (c) and (f), respectively, are collectively referred to as first treatment administration in each of the administration schedules, and the amounts and frequencies of administration during weeks 25 and thereafter, after week 26 and after week 27 of each of the administration schedules (a) and (d), (b) and (e) and (c) and (f), respectively, are collectively referred to as second treatment administration in each of the administration schedules.

In some embodiments, PF06863135 administered the second treatment to the subject lasts for 6 to 18 cycles, after which a third treatment of PF06863135 is administered subcutaneously to the subject, wherein the third treatment is administered 32Q2W, 32Q4W, 44Q2W, 44Q4W, 76Q2W, 76Q4W, 116Q2W,116Q4W,152Q2W, or 152Q4W, wherein cycle 21 days or 28 days, cycle 1 begins at week 1, week 2, day 1, or week 3, day 1.

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

number of weeks	Dosage (mg)	Frequency of administration
			1	44; or 32; or 12 plus 32; or A and B	Weekly by week
2-4	44 to 152;	weekly by week
			5-24	44 to 152	Weekly; every two weeks
After 25 times	44 to 152	Every two weeks; every three weeks or every four weeks

Wherein when the dose is 12 plus 32 over week 1, the dose of 12 is administered on one day followed by the dose 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 the dose of a is administered on one day followed by the dose of B on another day.

In some embodiments, the subject is administered elranatamab of 12 on day 1 of week 1, followed by administration of elranatamab of 32 on day 4 of week 1.

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

Number of weeks	Dosage (mg)	Frequency of administration
			1	12 and 32	Weekly by week
2-4	76	Weekly by week
			5-24	116	Every two weeks
After 25 times	116	Every two weeks; every three weeks; or every four weeks

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

Number of weeks	Dosage (mg)	Frequency of administration
			1	12 and 32	Weekly by week
2-4	76	Weekly by week
			5-24	152	Every two weeks
After 25 times	152	Every two weeks; every three weeks; or every four weeks

In some embodiments, the dosing frequency during the 25 th week and later is every four weeks.

In some embodiments, the dose and frequency of administration during week 1 are together referred to as a pre-infusion dose, and if only one dose of elranatamab is administered to the subject in a pre-infusion dose, such one dose is referred to as a single pre-infusion dose, if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are referred to as a first pre-infusion dose and a second pre-infusion dose, respectively, the dose and frequency of administration during weeks 2-4 are together referred to as a first therapeutic dose, the dose and frequency of administration during weeks 5-24 are together referred to as a second therapeutic dose, and the dose and frequency of administration during weeks 25 and thereafter are together referred to as a third therapeutic dose.

Number of weeks	Dosage (mg)	Frequency of administration
			1	44; or 32; or 12 plus 32; or A and B	Weekly by week
2-4	44 to 76	Weekly by week
			5-12	44 to 152;	weekly by week
13-24	44 to 152	Weekly; every two weeks
			After 25 times	44 to 152	Every two weeks; every three weeks; or every four weeks

Wherein when the dose is 12 plus 32 over week 1, the dose of 12 is administered on one day followed by the dose 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 the dose of a is administered on one day followed by the dose of B on another day. In some embodiments, the subject is administered elranatamab of 12 on day 1 of week 1, followed by administration of elranatamab of 32 on day 4 of week 1.

Number of weeks	Dosage (mg)	Frequency of administration
			1	12 and 32	Weekly by week
2 to 4	76	Weekly by week
			5-12	116	Weekly by week
13-24	116	Weekly; every two weeks
			After 25 times	116	Every two weeks; every three weeks; or every four weeks

In some embodiments, the dosing frequency during weeks 13-24 is every two weeks.

In some embodiments, the dosing frequency at week 25 and later is every four weeks.

Number of weeks	Dosage (mg)	Frequency of administration
			1	12 and 32	Weekly by week
2-4	76	Weekly by week
			5-12	76	Weekly by week
13-24	76	Weekly; every two weeks
			After 25 times	76	Every two weeks; every three weeks; or every four weeks

In some embodiments, the dosing frequency at week 25 and later is every four weeks. In some embodiments, the dosing frequency during weeks 13-24 is every two weeks, wherein the dosing frequency during weeks 25 and thereafter is every two weeks or every four weeks.

Number of weeks	Dosage (mg)	Frequency of administration
			1	12 and 32	Weekly by week
2-4	44	Weekly by week
			5-12	44	Weekly by week
13-24	44	Weekly or biweekly
			After 25 times	44	Every two weeks; every three weeks; or every four weeks

. In some embodiments, the dosing frequency during weeks 13-24 is every two weeks. In some embodiments, the dosing frequency during the 25 th week and later is every four weeks.

In some embodiments, the dose and frequency of administration during week 1 are together referred to as a pre-infusion administration, and if only one dose of elranatamab is administered to the subject in a pre-infusion administration, such one dose is referred to as a single pre-infusion administration, if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are referred to as a first pre-infusion administration and a second pre-infusion administration, respectively, the dose and frequency of administration during weeks 2-4 and the dose and frequency of administration during weeks 5-12 are together referred to as a first therapeutic administration, the dose and frequency of administration during weeks 13-24 are together referred to as a second therapeutic administration, and the dose and frequency of administration during weeks 25 and thereafter are together referred to as a third therapeutic administration.

The invention further relates to elranatamab (PF-06853135) for use in 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 tertiary refractory multiple myeloma. In some embodiments, the subject's multiple myeloma is refractory to all three types of multiple myeloma therapies: (1) a prior multiple myeloma therapy comprising a proteasome inhibitor, (2) a prior multiple myeloma therapy comprising an immunomodulatory agent, and (3) a prior multiple myeloma therapy comprising an anti-CD 38 antibody.

In some embodiments, the cancer is bipolar refractory multiple myeloma. In some embodiments, the subject's multiple myeloma is refractory to at least two of the following three types of multiple myeloma therapies: (1) a prior multiple myeloma therapy comprising a proteasome inhibitor, (2) a prior multiple myeloma therapy comprising an immunomodulatory agent, and (3) a prior multiple myeloma therapy comprising an anti-CD 38 antibody.

In some embodiments, the cancer is newly diagnosed with multiple myeloma. In some embodiments, the cancer is multiple myeloma and the subject has received stem cell transplantation. In some embodiments, the subject has received autologous stem cell transplantation. In some embodiments, the subject has received allogeneic stem cell transplantation. In some embodiments, the subject is the least residual disease positive following stem cell transplantation.

In some embodiments, the cancer is multiple myeloma, wherein 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 a proteasome inhibitor, an IMid drug, and an anti-CD 38 antibody.

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) a prior multiple myeloma therapy comprising a proteasome inhibitor, (2) a prior multiple myeloma therapy comprising an immunomodulatory agent, and (3) a prior multiple myeloma therapy comprising an anti-CD 38 antibody, and wherein the subject has exhibited disease progression to the last therapy. In one aspect of these embodiments, the subject has received prior therapy for BCMA-targeted ADC or BCMA-targeted CAR-T. In another aspect of these embodiments, the subject does not receive any prior therapy of 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 previous multiple myeloma therapies, and the subject's multiple myeloma is refractory or relapsed to: (1) a prior multiple myeloma therapy comprising a proteasome inhibitor, (2) a prior multiple myeloma therapy comprising an immunomodulatory agent, and (3) a prior multiple myeloma therapy comprising an anti-CD 38 antibody, and the subject has demonstrated 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 subject received prior multiple myeloma therapy comprises BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the subject received prior multiple myeloma therapy comprises BCMA-guided therapy.

In some embodiments, the subject received prior multiple myeloma therapy does not comprise BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the subject received prior multiple myeloma therapy does not comprise BCMA-guided therapy.

In some embodiments, the cancer is multiple myeloma and the subject has received at least one or at least two previous multiple myeloma therapies, the multiple myeloma of the subject being refractory or relapsed to: (1) Previous multiple myeloma therapies comprising a proteasome inhibitor and (2) previous multiple myeloma therapies comprising an immunomodulatory agent. In some embodiments, the subject has demonstrated disease progression for the last multiple myeloma therapy.

In some embodiments, the cancer is multiple myeloma and the subject does not receive any prior multiple myeloma therapy. In some embodiments, the subject does not receive any prior multiple myeloma therapy following 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 autologous stem cell transplantation, and is also not suitable for allogeneic stem cell transplantation.

In some embodiments, (i) the period is 21 days when the subject is at a weekly or every three weeks dosing frequency of PF06863135, and the period is 28 days when the subject is at a bi-weekly or every four weeks dosing frequency of PF 06863135; or (ii) a period of 28 days unless the patient is at a frequency of dosing every three weeks of PF 06863135.

In some embodiments, the method further comprises administering to the subject sartoriab.

In some embodiments, both PF-06863135 and sartan Li Shan antibodies are administered in four weeks of treatment cycles for at least a first treatment cycle, and wherein if a pre-infusion of PF-06863135 is administered, the first treatment cycle begins on the seventh day after a single pre-infusion or last dose of the pre-infusion is administered, and sartan is administered in a dose of 300q4w SC.

In some embodiments, wherein the first dose of sartoriab is administered on the first day of the first treatment cycle. In some embodiments, the first dose of PF-06863135 in the treatment cycle is administered on day 1 of the treatment cycle.

In some embodiments, week 1 and cycle 1 begin on the day of administration of the single pre-infusion administration or the first pre-infusion administration to the subject, or if no pre-infusion administration or pre-infusion administration of PF06863135 is administered to the subject, week 1 or cycle 1 begins on the day of administration of the first dose of the first treatment of PF06863135 to the subject, with a cycle of 28 days, and administration of the salstuzumab at a dose of 300q4w SC. In some embodiments, at least one pre-injection administration of PF6863135 is administered to the subject, and the subject is administered with sartoriab on day 8 of each cycle.

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

In some embodiments, both PF-06863135 and lenalidomide are administered in four treatment cycles for at least a first treatment cycle, and wherein if a pre-infusion administration of PF-06863135 is administered, the first treatment cycle begins on the seventh day after a single pre-infusion administration or the last dose of the pre-infusion administration, and wherein lenalidomide is administered at a dose of 25 per day oral administration on days 1 through 21 of each treatment cycle.

In some embodiments, lenalidomide is administered at a daily oral dose of 25 per day on days 1-21 of each treatment cycle, without dexamethasone (dexamethasone).

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

In some embodiments, a pre-infusion administration of PF6863135 is administered for a period of 28 days, on days 8-28 or 15-28 of the first period, and on days 1-28 of the second and third periods, with a daily oral dose of about 5, about 10, about 15, about 20, or about 25, after which, starting from the fourth period, with a daily oral dose of about 5 to 10 higher than the daily oral dose administered during the third period, or continuing on days 1-28 of each period with the same daily oral dose as the daily oral dose of the third period.

In some embodiments, a pre-infusion administration of PF06863135 is administered, beginning on day 8 of cycle 1, with lenalidomide administered at an oral daily dose of about 10 or about 15 for at least 10 consecutive days in each cycle.

In some embodiments, the pre-infusion administration of PF06863135 is not administered and lenalidomide is administered at a daily oral dose of about 10, about 15, about 20, or about 25 for at least 10 consecutive days, at least 14 consecutive days, or at least 21 consecutive days per cycle.

In some embodiments, 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 the pre-infusion administration of PF06863135, or if the pre-infusion administration of PF06863135 is not administered, the induction phase begins on the day of administration of the first dose of the first treatment administration of PF06863135, and when the subject is in the first treatment administration, the induction phase ends on the last day of the last week or the last day of the last cycle, whichever is later;

wherein during the induction phase, lenalidomide is administered in an oral daily dose of about 5 to about 25 for an induction administration of lenalidomide during at least 10 consecutive days of each cycle of the induction phase; during the maintenance phase, PF06863135 is administered as the second therapeutic administration, lenalidomide being administered as a daily oral dose of about 5 to about 25 of lenalidomide maintenance administration over a period of at least 10 consecutive days; 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 comprises administering dexamethasone to the subject during the induction phase, at least day 1 and day 8 of the first cycle of the induction phase, with a daily oral administration of about 10 to about 40 dexamethasone.

In some embodiments, each cycle of the induction phase is 21 days or 28 days, and cycle 1 begins at week 3, day 1, the lenalidomide induction dosing is about 5, about 10, about 15, about 20, or about 25 orally per day and is administered from day 1 to day 14 or 1-21 of each cycle of the induction phase, and if dexamethasone is administered, dexamethasone is administered at a dose of about 20 per day on days 1, 8, and 15 of the first and second cycles of the induction phase; wherein each cycle of the maintenance phase is 28 days, and on days 1 through 28 of each cycle of the maintenance phase, the maintenance lenalidomide administration is orally administered about 5, about 10, or about 15 per day. 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 comprises administering pomalidomide to the subject. In some embodiments, both PF06863135 and pomalidomide are administered for at least a first treatment period beginning on the seventh day after a single pre-injection or last dose of the pre-injection administration, for at least a first treatment period, and pomalidomide is administered at a dose of 4 per day oral administration on days 1 through 21 of each treatment period, and wherein the pre-injection administration of PF-06863135 is administered. In some embodiments, pomalidomide is administered without dexamethasone at a dose of 4 per day, 3 per day, 2 per day, or 1 per day of each treatment cycle from day 1 to day 21. In some embodiments, the first dose of PF-06863135 in the treatment cycle is administered on day 1 of the treatment cycle.

In some embodiments, the method further comprises administering daratumumab (daratumumab) to the subject. In some embodiments, the darunazumab is administered subcutaneously with approximately 1800 darunazumab per week, every two weeks, every three weeks, or every four weeks. In some embodiments, administration of darimumab begins with about 1800 per week for about 8 doses, followed by about 1800 per two weeks, followed by about 8 to 10 doses, followed by about 1800 per four weeks in cycle 1.

In some embodiments, the method further comprises administering isatuximab (isatuximab) to the subject. In some embodiments, isatuximab is administered as an isatuximab dose of about 5 to about 10 kg QW IV, Q2W IV, Q3W IV, or Q4W IV. In some embodiments, the administration of isatuximab to the subject may be the same or different when the subject is at the pre-infusion administration, the first therapeutic administration, the second therapeutic administration, or the third therapeutic administration of PF 06863135.

In some embodiments, further comprising administering at least one dose of a precursor drug (precursor) to the subject on the day of the single pre-injection drug, the first pre-injection drug, the second pre-injection drug, or the first dose of the first therapeutic drug of PF06863135 to the subject, wherein the precursor drug is acetaminophen (acetaminophen), diphenhydramine (diphenhydramine), or dexamethasone. In some embodiments, dexamethasone is administered orally or intravenously daily with about 10 to about 40 dexamethasone. In some embodiments, dexamethasone is administered orally or intravenously daily as dexamethasone in an amount of about 10 to about 40, at least on the day of the first dose of the first therapeutic administration of PF06863135 to the subject. In some embodiments, when the subject is at a pre-injection administration, a first treatment administration, a second treatment administration, or a third treatment administration of PF06863135, the dexamethasone administration to the subject administered as a precursor to the subject may be the same or different.

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

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

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

Drawings

FIG. 1 depicts the induction of PD-1 expression on CD8+ T cells following treatment with BCMA xCD3 bispecific antibodies.

FIGS. 2A and 2B depict therapeutic activity of BCMA xCD3 bispecific antibodies in combination with anti-PD 1 antibodies in A) an in situ MM.1S-Luc-PDL1 multiple myeloma model and B) a subcutaneous MM.1S-PD-L1 multiple myeloma model.

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

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

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

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

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

Fig. 8 depicts that treatment with GSI improved BCMAxCD3 bispecific mediated cell killing in lymphoma cell lines.

Detailed Description

The present 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 to the individual 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 of the definition

In order that the invention may be more readily understood, certain technical and scientific terms are defined below. Unless otherwise defined explicitly in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

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

When used to modify a numerical defined parameter (e.g., the dose of BCMAxCD3 bispecific antibody, or the length of treatment time with respect to a combination therapy described herein), about means that the parameter can vary by as much as 10% below the prescribed value for the parameter. For example, a dose of about 5/kg may vary between 4.5/kg and 5.5/kg.

An "antibody" is an immunoglobulin molecule capable of specifically binding 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 intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab ', F (ab') 2, fv), single chain (scFv) and domain antibodies (including, for example, shark and camelbody), as well as fusion proteins comprising antibodies, and any other modified configuration of immunoglobulin molecules comprising an antigen recognition site. Antibodies include any class of antibodies, such as IgG, igA, or IgM (or subclasses thereof), and the antibodies need not be of any particular class. Immunoglobulins can be assigned to different classes depending on the antibody amino acid sequence of their heavy chain constant region. Immunoglobulins fall into five main categories: igA, igD, igE, igG and IgM, and several of these may be further divided into subclasses (isotypes), for example IgG1, igG2, igG3, igG4, igA1 and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively. Subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

As used herein, the term "antigen-binding fragment" or "antigen-binding portion" of an antibody refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen. The antigen binding function of an antibody may be performed by a fragment of an intact antibody. Examples of binding fragments encompassed within the term "antigen binding fragment" of an antibody include Fab; fab'; f (ab') 2; fd fragment consisting of VH and CH1 domains; fv fragments consisting of the VL and VH domains of a single arm of an antibody; single domain antibodies (dAb) fragments (Ward et al, nature 341:544-546,1989), and isolated Complementarity Determining Regions (CDRs).

A "bispecific antibody" or "dual specific antibody" is a hybrid antibody having two different antigen binding sites. The two antigen binding sites of a bispecific antibody bind to two different epitopes, which may be located on the same or different protein targets.

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

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

Antibodies, bispecific antibodies, or polypeptides that "preferentially bind" or "specifically bind" (used interchangeably herein) to a target (e.g., BCMA protein) are terms that are readily understood in the art, and methods for determining such specific or preferential binding are also well known in the art. A molecule is considered to exhibit "specific binding" or "preferential binding" if it responds or associates more frequently, more rapidly, has a longer duration, and/or has a greater affinity with a particular cell or substance than it responds or associates with an alternative cell or substance. An antibody or bispecific antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, more readily, 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 the epitope with greater affinity, avidity, more readily, and/or for a longer duration than it binds to other BCMA epitopes or BCMA epitopes. It will also be appreciated that by reading this definition, for example, an antibody (or portion or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

"variable region" of an antibody refers to either the antibody light chain variable region or the antibody heavy chain variable region, alone or in combination. As known in the art, the heavy and light chain variable regions each consist of four Framework Regions (FR) joined by three Complementarity Determining Regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FR 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 CDRs: (1) A scheme based on cross species sequence variability (i.e., kabat et al sequences of Proteins of Immunological Interest, (5 th ed.,1991,National Institutes of Health,Bethesda Md)); and (2) a protocol based on crystallographic studies of antigen-antibody complexes (Al-lazikani et Al, 1997, J.molecular. Biol. 273:927-948). As used herein, a CDR may refer to a CDR defined by either scheme or by a combination of both schemes.

"CDRs" of a variable domain are amino acid residues within the variable region that are identified according to the cumulative, abM, contact and/or conformational definition of both Kabat, chothia, kabat and Chothia or any CDR determination method well known in the art. Antibody CDRs can be identified as hypervariable regions initially defined by Kabat et al. See, e.g., kabat et al, 1992,Sequences of Proteins of Immunological Interest,5th ed, public Health Service, NIH, washington d.c. The positions of the CDRs can also be identified as structural loop structures originally described by Chothia et al. See, e.g., chothia et al, nature 342:877-883,1989. Other schemes for CDR identification include "AbM definition", which is a compromise between Kabat and Chothia and uses Oxford Molecular AbM antibody modeling software (now ) Derived, or based on the "contact definition" of the CDRs of the observed antigen contacts, as set forth in MacCallum et al, j.mol.biol.,262:732-745,1996. In another approach (referred to herein as "conformational definition" of CDRs), the positions of the CDRs can be identified as residues that contribute enthalpy to antigen binding. See, e.g., 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 CDRs, although they may be shortened or lengthened depending on the prediction or experimental outcome that the particular residue or residue set, or even the entire CDR, does not significantly affect antigen binding. As used herein, a CDR may refer to a CDR defined by any scheme known in the art, including combinations of schemes. The methods used herein may utilize CDRs defined according to any of these schemes. For any given aspect containing more than one CDR, the CDR may be according toKabat, chothia, extended, abM, contact and/or conformational definition.

"isolated antibody" and "isolated antibody fragment" refer to a purified state and in this context means 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" is not intended to 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 compounds as described herein.

As used herein, "monoclonal antibody" or "mAb" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except that there may be a small number of mutations that may occur naturally. In contrast, conventional (polyclonal) antibody preparations typically include a plurality of different antibodies having different amino acid sequences in the variable domains, particularly in the CDRs which are typically specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention may be produced by the hybridoma method described first by Kohler et al (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). For example, the "monoclonal antibodies" can also be isolated from phage antibody libraries using 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 and/or light chain is identical or homologous to a 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 a 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, so long as they exhibit the desired biological activity.

"human antibody" refers to an antibody comprising only human immunoglobulin protein sequences. If the human antibody is produced in a mouse, a mouse cell or a hybridoma derived from a mouse cell, the human antibody may contain a murine sugar chain. Similarly, "mouse antibody" or "rat antibody" refers to an antibody comprising only mouse or rat immunoglobulin sequences, respectively.

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

The term "cancer," "cancerous," or "malignant" refers to or describes the physiological condition of mammals that is generally characterized by uncontrolled cell growth. "cancer" or "cancerous tissue" may include tumors. Examples of cancers include, but are not limited to, malignant epithelial tumors, lymphomas, leukemias, myelomas, blastomas, and sarcomas. Cancers may include cancers 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 neoplasm, lymphoma, hodgkin's lymphoma, nodular lymphocytic dominant Hodgkin's lymphoma, kahler's disease and myelogenous leukemia, plasma cell leukemia, bone and extramedullary plasma cell neoplasm with multiple myeloma, solid bone and extramedullary plasma cell neoplasm, monoclonal Gammaglobulopathy (MGUS) of unknown significance, smoldering myeloma, light chain amyloidosis, osteosclerotic myeloma, B-cell lymphocytic leukemia, hairy cell leukemia, B-cell non-hodgkin's lymphoma (NHL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL), chronic Myelogenous Leukemia (CML), follicular lymphoma, burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myelogenous leukemia, megaloblastic, diffuse large B-cell lymphoma, mucosa-associated lymphohistiocyte lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymus) 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/histiocyte-enriched large B-cell lymphoma, primary central nervous system lymphoma, primary skin diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell lymphoma in elderly people, diffuse large B-cell lymphoma associated with inflammation, ALK-positive large B-cell lymphoma, plasmablastoid lymphoma, large B-cell lymphoma occurring in HHV 8-associated multicenter Castleman disease, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and Burkitt's lymphoma, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma, and other B-cell-related lymphomas. Examples of cancers and cancer-related diseases are further described herein

A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer and/or cancer-related diseases. Classes of chemotherapeutic drugs include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and Selective Estrogen Receptor Modulators (SERMs), antiprogestins, estrogen Receptor Downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors and antisense oligonucleotides, which inhibit the expression of genes associated with abnormal cell proliferation or tumor growth. Chemotherapeutic agents are further described herein.

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

As used throughout the specification and claims, "consisting essentially of (consists essentially of)" and variations such as "consisting essentially of (Consist essentially of)" or "consisting essentially of (consisting essentially of)" are intended to include any recited element or group of elements, and optionally other elements having similar or different properties than the recited elements, without substantially altering the basic or novel characteristics of the specified dosage regimen, method, or composition.

"multiple myeloma therapy" refers to a drug, a combination of two or more drugs, (1) which is approved by the U.S. food and drug administration (United States Food and Drug Administration, USFDA) or european drug administration (European Medicines Agency) for the treatment of multiple myeloma, or (2) which is or has been undergoing clinical trials for the treatment of multiple myeloma in the united states or europe.

By "established multiple myeloma therapy" is meant multiple myeloma therapy approved by the USFDA or european medicines agency, which may be a drug, a combination therapy of two or more drugs.

As used herein, "IMiD drug" or "immunomodulator" interchangeably refer to a drug that in the context of treating multiple myeloma, the practitioner treating multiple myeloma understands the IMiD drug or immunomodulator. Examples of IMid drugs or immunomodulators include, but are not limited to, thalidomide (thalidomide), lenalidomide, and pomalidomide.

"BCMA-directed ADC therapy" refers to a multiple myeloma therapy comprising an antibody drug conjugate, wherein the antibody binds to B Cell Maturation Antigen (BCMA). Examples of BCMA-directed ADCs include, but are not limited to belantamab mafodotin-blmf, which is USFDA approved and sold under the BLENREP brand name.

As used herein, "BCMA-directed CAR-T cell therapy" or "anti-BCMACAR-T cell" interchangeably refers to a multiple myeloma therapy comprising chimeric antigen receptor T cells, wherein the chimeric antigen receptor recognizes B Cell Maturation Antigen (BCMA). Examples of "BCMA targeted CAR-T therapies" or "anti-BCMACAR T cell therapies" include, but are not limited to idecabtgene vicleucel (ide cel; or bb 2121) and JNJ-4528, which is also known as LCAR-B38M.

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

"newly diagnosed multiple myeloma" refers to multiple myeloma for which the patient (subject) has not received any treatment to diagnose multiple myeloma.

"homology" refers to the sequence similarity of two polypeptide sequences when optimally aligned. When a position in two comparison sequences is occupied by the same amino acid monomer subunit, for example, if a position in the light chain CDR of two different abs is occupied by alanine, then the two abs are homologous at that position. The percent homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared by 100. For example, two sequences are 80% homologous if 8 of the 10 positions of the two sequences match or are homologous when optimally aligned. Typically, the comparison is made when two sequences are aligned to give the maximum percent homology. For example, the comparison may be made by the BLAST algorithm, where the parameters of the algorithm are selected to give the greatest match between the individual sequences over the entire length of the individual reference sequences.

The following references relate to BLAST algorithms commonly used for sequence analysis: BLAST ALGORITHMS: altschul, S.F., et al, (1990) J.mol.biol.215:403-410; gish, W., et al, (1993) Nature Genet.3:266-272; madden, t.l., et al, (1996) meth. Enzymol.266:131-141; altschul, S.F., et al, (1997) Nucleic Acids Res.25:3389-3402; zhang, j et al, (1997) Genome res.7:649-656; wootton, j.c., et al, (1993) comp.chem.17:149-163; hancock, J.M. et al, (1994) Comput. Appl. Biosci.10:67-70; ALIGNMENT SCORING SYSTEMS Dayhoff, M.O., et al, "Amodel of evolutionary change in proteins," in Atlas of Protein Sequence and Structure, (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 Protein Sequence and Structure, (1978) vol.5, suppl.3, "M.O. Dayhoff (ed.), pp.353-358, natl.biomed.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.USA89:10915-10919; altschul, S.F., et al, (1993) J.mol.Evol.36:290-300; ALIGNMENT STATISTICS Karlin, S., et al, (1990) Proc.Natl. Acad.Sci. USA 87:2264-2268; karlin, S., et al, (1993) Proc.Natl. Acad.Sci.USA90:5873-5877; dembo, A., et al, (1994) Ann.Prob.22:2022-2039; and Altschul, s.f. "Evaluating 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," "subject," or "individual" refers to any living organism suffering from or susceptible to a condition (such as cancer and/or a cancer-related disease) that can be prevented or treated by administration of a therapeutic drug or composition or combination as provided herein, and includes both humans and animals. The terms "patient," "subject," and "individual" include, but are not limited to, mammals (e.g., mice, apes, horses, cattle, pigs, dogs, cats, etc.), and are preferably humans.

By "sustained response" is meant a sustained therapeutic effect after cessation of treatment with the therapeutic agents or combination therapies described herein. In some aspects, the duration of the sustained response is at least the same as the duration of the treatment, or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of the treatment.

As used herein, "administering" refers to delivering a therapeutic drug to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, sub-stratum corneum, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. The therapeutic agents may be administered via a non-parenteral route or orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual, or topical. It is also possible, for example, to perform one, multiple administrations and/or to perform the administration over one or more extended periods.

As used herein, "treating" or "treatment" cancer and/or cancer-related diseases refers to the administration of a combination therapy according to the present 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 the size of a tumor, reducing the rate of infiltration of cancer cells into surrounding organs, or reducing the rate of metastasis or growth of a tumor, thereby reversing, alleviating, inhibiting or preventing the progression of a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, unless otherwise indicated, the term "treatment" refers to the act of treating, "treatment" as defined above. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing (or destroying) proliferation of neoplastic or cancerous cells; inhibiting metastatic or neoplastic cells; reducing or decreasing the size of the tumor; alleviating cancer; reducing symptoms caused by cancer; improving the quality of life of cancer patients; reducing the dosage of other drugs required to treat cancer; delay the progression of cancer; cure cancer; one or more resistance mechanisms that overcome cancer; and/or to extend survival of cancer patients. The positive therapeutic effect of cancer can be measured in a variety of ways (see, e.g., W.A.Weber, J.Nucl.Med.50:1S-10S (2009)). In some aspects, the treatment achieved by the combination of the invention is any one of Partial Response (PR), complete Response (CR), total response (OR), objective Response Rate (ORR), progression Free Survival (PFS), radiation PFS, disease Free Survival (DFS), and total survival (OS). PFS is also referred to as "tumor progression time", indicating the length of time during and after treatment that the cancer is not growing, and includes the amount of time that the patient experiences CR or PR, as well as the amount of time that the patient experiences disease Stabilization (SD). DFS refers to the length of time a patient remains disease free during and after treatment. OS refers to an increase in life expectancy compared to untreated or untreated subjects or patients. In some aspects, the response to the combination of the invention is either PR, CR, PFS, DFS, ORR, OR or OS, which is assessed using a solid tumor response assessment criteria (Response Evaluation Criteria in Solid Tumors, RECIST 1.1) response criteria (Eisenhauer et al, E.A. et al, eur. J Cancer45:228-247 (2009)). In some aspects, anti-myeloma activity can be assessed by total response rate (ORR), time To Response (TTR), complete Response Rate (CRR), duration of response (DOR), duration of complete response (DoCR), duration of disease stability (DOSD), progression Free Survival (PFS), total survival (OS) using international myeloma working group (International Myeloma Working Group, IMWG) standards. The treatment regimen of the combination therapy as provided herein that is effective for treating a cancer patient can vary depending on factors such as the disease state, age and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While one of the aspects of the present invention may not be effective in achieving a positive therapeutic effect in each subject, it should be performed 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-terpstat test, and the wilcon test, in terms of the statistically significant number of subjects. The term "treatment" also encompasses in vitro and ex vivo treatment of a cell, e.g., by an agent, diagnosis, binding compound, or another cell.

As used herein, "pharmaceutical product" refers to a drug that contains an active pharmaceutical ingredient and is administered by the U.S. FDA, EMA, or other corresponding regulatory agency of the market. The pharmaceutical product may be a clinically research drug, or may be a pharmaceutical product that has been approved by a regulatory agency.

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

As used herein, an "effective amount" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include elimination or reduction of risk, lessening the severity, or delaying the onset of a disease, including biochemical, histological, and/or behavioral symptoms of a disease, complications thereof, and intermediate pathological phenotypes that occur during the development of a disease. For therapeutic use, beneficial or desired results include clinical results such as reducing the incidence or amelioration of one or more symptoms of various diseases or conditions (such as, for example, cancer), reducing the dosage of other drugs required to treat the disease, enhancing the effect of another drug, and/or slowing the progression of the disease. The effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, in the context of administration of one or more therapeutic agents, an "effective amount" may be considered, and if the desired result may or has been achieved in combination with one or more other agents, administration of a single formulation in an effective amount may be considered.

As used herein, "dose" refers to "dose amount", e.g., 1, 20, and "frequency of administration", e.g., 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 routes of administration of the drug, such as, for example, subcutaneous (SC), intravenous (IV), oral (PO), if so specified. Similarly, "pre-administration," "first therapeutic administration," "second therapeutic administration," and the like each refer to both the amount and frequency of administration of such administration, and also optionally include the route of administration, if so specified. In some embodiments, there is one dose and one frequency of administration. In some embodiments, there is more than one dose and/or more than one frequency of administration.

As used herein, unless otherwise indicated, when used to describe the amount of elranatamab (also known as PF 06863135), a "dose level" refers to one of the following doses: 4. 8, 12, 16, 20, 24, 32, 44, 76, 116, and 152, wherein 8, 12mg, 16, 20, 24, 32mg, 44, 76, 116, and 152 are each at a dosage level greater than 4, 8mg, 12, 16, 24, 32, 44, 76, and 116, respectively.

As used herein, "corresponding regulatory label of a drug product" means an unexpired U.S. prescription information (United States Prescribing Information, USPI) from the U.S. Food and Drug Administration (FDA), an unexpired product feature digest (Summary of Product Characteristics, SMPC) from the European Medicines Administration (EMA), or a similar label of a drug product from other market regulatory authorities. In some embodiments, the "corresponding regulatory label for a drug product" in U.S. patent or patent application refers to an unexpired USPI for the drug product, and in patents or patent applications in european countries where the use of a drug product EMA is licensed to market, refers to an unexpired SMPC for the drug product, and similar conditions in other jurisdictions.

As used herein, "response of a subject" refers to the clinical response of a subject to a potential treatment that is treated with a pharmaceutical product comprising elranatamab (PF 006863135) as monotherapy or in combination with a second therapeutic product. The ' subject's response ' includes one or more aspects related to clinical efficacy, such as complete response, partial response, and response duration. The "response of a subject" may also include additional aspects such as toxicity and adverse events.

As used herein, "IMWG response" refers to a clinical response of a patient (subject) to a pharmaceutical product for treating multiple myeloma, wherein the response, such as a complete response or a partial response, is defined according to the latest definition of the international myeloma working group.

As used herein, "cycle" and "week" refer to durations when used in the context of describing a method of treating cancer (including its use, administration, or dosing schedule). Unless otherwise indicated, when a subject is treated with a therapeutic agent, its pharmaceutical product (e.g., elranatamab (PF 06863135)), or its pharmaceutical product as monotherapy or in combination with a second therapeutic agent, the period is 21 days or 28 days. Week 1 refers to the first week of treatment of a subject according to the method or any administration or dosing schedule of the method, unless otherwise indicated. Week 2 starts immediately after week 1 ends, week 3 starts immediately after week 2 ends, and so on. Unless otherwise indicated, cycle 1 starts on the first day of week 1, the first day of week 2, or the first day of week three. Unless otherwise stated, cycle 2 starts immediately after cycle 1 ends, cycle 3 starts immediately after cycle 2 ends, and so on.

As used herein, "stem cell transplantation unsuitable" refers to stem cell transplantation unsuitable for patients diagnosed with multiple myeloma as treatment for multiple myeloma.

"tumor" applies to a subject diagnosed with or suspected of having cancer, refers to malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary and secondary tumors. A solid tumor is an abnormal growth or mass of tissue that is generally free of cysts or areas of fluid. Different types of solid tumors are named according to the cell type from which they are formed. Examples of solid tumors are sarcomas, malignant epithelial tumors and lymphomas. Leukemia (hematological cancer) generally does not form a solid tumor (national cancer institute (National Cancer Institute), cancer term dictionary (Dictionary of Cancer Terms)). Multiple myeloma is a plasma cell cancer

"tumor burden" is also referred to as "tumor burden" and refers to the total amount of tumor mass distributed throughout the body. Tumor burden refers to the total number of systemic 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, measuring the size of the tumor by, for example, using calipers when removed from the subject, or using imaging techniques in vivo, such as ultrasound, bone scanning, computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scanning.

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

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

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

"pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a component that can be included in the compositions described herein without causing significant adverse toxicological effects to the subject.

The terms "protein," "polypeptide," and "peptide" are used interchangeably herein and refer to any peptide-linked chain of amino acids, whether of length co-translated or post-translationally modified.

As used herein, "substantially" or "essentially" means almost entirely or completely, e.g., 95% or more of a given amount.

The term "substantially homologous" or "substantially identical" means that a particular subject sequence, e.g., a mutant sequence, differs from a reference sequence by one or more substitutions, deletions or additions, the net effect of which does not result in an adverse functional difference between the reference sequence and the subject. For purposes herein, sequences having greater than 95% homology (identity), equivalent biological activity (although not necessarily equivalent biological activity strength), and equivalent expression characteristics to a given sequence are considered to be substantially homologous (identical). For the purpose of determining homology, truncations of the mature sequence should be ignored.

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

As used herein, PF-06863135 is used interchangeably with elranatamab. PF06863135 is a BCMA xCD3 bispecific antibody. PF-06863135 is described, for example, in U.S. Pat. No. 9,969,809. The selected PF-06863135 sequence is shown in Table 15.

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

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

II methods, uses and medicaments

Provided herein are methods and compositions for treating cancer and/or cancer-related diseases in a subject, the methods and compositions involving combination therapies comprising at least a first therapeutic agent and a second therapeutic agent.

BCMA-specific therapeutic agent

In some aspects, the therapeutic agent may be a BCMA specific therapeutic agent. In another aspect, the BCMA specific therapeutic agent can be a BCMA multispecific antibody (e.g., bispecific and trispecific), a BCMA antibody-drug conjugate, or a BCMA Chimeric Antigen Receptor (CAR) modified T cell therapy. B cell maturation antigen (BCMA, also known as TNFRSF17 and CD 269) is a candidate for bispecific antibody-based immunotherapy. BCMA expression is upregulated during maturation of B cells into plasmablasts and plasma cells, but not on naive B cells, hematopoietic stem cells or normal tissues like heart, lung, kidney or tonsils. In multiple myeloma BCMA expression was identified at each disease stage and on patients with different cytogenetic risks. In addition, BCMA expression is not affected by Autologous Stem Cell Transplantation (ASCT) or chemotherapy treatment. In vivo, bispecific antibodies against BCMA have been shown to induce T cell activation, reduce tumor burden and extend survival.

Examples of BCMA multispecific antibodies that can be used in combination therapies of the present invention include but are not limited to AMG 420 (BCMAxCD 3 bispecific T cell cement,Amgen)、AMG 701(BCMAxCD3amgen), CC-93269 (BCMA xCD3 bispecific antibody, celgene), JNJ-64007957 (Jansee), PF-06863135 (BCMA xCD3 bispecific antibody, pfizer Inc.), TNB-383B (TeneoBio/AbbVie), REGN5458 (BCMA CD3 bispecific antibody, regeneron), AFM26 (BCMA CD16 tetravalent bispecific antibody, affined GmbH), HPN217 (BCMA ALBxCD3 trispecific, harpoon Therapeutics).

In some aspects, the BCMA specific therapeutic agent is a BCMA bispecific antibody molecule. BCMA bispecific antibodies are monoclonal antibodies that have binding specificity for at least two different antigens (e.g., BCMA and CD 3).

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

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

In some aspects, the first antibody variable domain specifically binds to CD 3. Information about CD3 is provided, for example, via uniprotkb#p07766. In some aspects, the first antibody variable domain comprises: comprising SEQ ID NO:1 and/or a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:9, and a light chain variable region (VL) of the amino acid sequence shown in seq id no. In some aspects, VH comprises: comprising SEQ ID NO: 2. 3 or 4, a VH CDR1 comprising the sequence set forth in SEQ ID NO:5 or 6, a VH CDR2 comprising the sequence set forth in SEQ ID NO:7, and/or VL comprises: comprising SEQ ID NO:10, a VL CDR1 comprising the sequence set forth in SEQ ID NO:11, a VL CDR2 comprising the sequence set forth in SEQ ID NO:12, and VL CDR3 of the sequences shown in seq id no. In some aspects, VH comprises SEQ ID NO:1, and/or VL comprises the sequence set forth in SEQ ID NO: 9. In some aspects, the first antibody comprises: comprising SEQ ID NO:8 and/or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:13, and a light chain of the amino acid sequence shown in seq id no.

In some aspects, the second antibody variable domain specifically binds BCMA. Information about BCMA is provided, for example, via UniProtKB ID #q 02223. In some aspects, the second antibody variable domain comprises: comprising SEQ id no:14 and/or a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:22, and a light chain variable region (VL) of the amino acid sequence shown in seq id no. In some aspects, VH comprises: comprising SEQ ID NO: 15. 16 or 17, a VH CDR1 comprising the sequence set forth in SEQ ID NO:18 or 19, a VH CDR2 comprising the sequence set forth in SEQ ID NO:20, and/or VL comprises: comprising SEQ ID NO:23, comprising the sequence set forth in SEQ ID NO:24, a VL CDR2 comprising the sequence set forth in SEQ ID NO:25, and VL CDR3 of the sequences shown in seq id no. In some aspects, VH comprises SEQ ID NO:14, and/or VL comprises the sequence set forth in SEQ ID NO: 22. In some aspects, the second antibody comprises: comprising SEQ ID NO:21 and/or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:26, and a light chain of the amino acid sequence shown in seq id no.

In some aspects, the BCMA bispecific antibody is PF-06863135, also known as elranatamab. The BCMA bispecific antibody used in the examples disclosed herein is PF-06863135 unless indicated otherwise. PF-06863135 is a heterodimeric humanized full-length bispecific antibody consisting of one B Cell Maturation Antigen (BCMA) binding arm paired by hinge mutation technology and a cluster of differentiation (CD 3) binding arms. It utilizes a modified human IgG2 a fragment that can crystallize (Fc) region. PF-06863135 is described, for example, in U.S. Pat. No. 9,969,809, which is incorporated herein for all purposes. The sequence of PF-06863135 is shown in Table 19.

An effective amount of BCMA specific therapeutic agent can be administered according to the dosages described herein.

anti-PD-1 and PD-L1 antibody therapeutic agents

In some aspects, the therapeutic agents used in the combination therapies of the invention may be anti-PD-1 and PD-L1 antibodies. Programmed death 1 (PD-1) receptors and 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, activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, thereby eliciting 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. In contrast, inhibition of this interaction can enhance local T cell responses and mediate antitumor activity in non-clinical animal models (Iwai Y, et al Proc Natl Acad SCi USA2002; 99:12293-97).

anti-PD-1 and anti-PD-L1 antibodies that can be used in combination therapies of the inventionExamples of (a) include, but are not limited to, alemtuzumab (atezolizumab)MPDL3280A, roche Holding AG), du Luoshan anti (durvalumab) (-A->AstraZeneca PLC), sodium Wu Liyou mab (nivolumab) (-A.sup.L.>ONO-4538, BMS-936558, MDX1106, bristol-Myers Squibb Company), pembrolizumab (pembrolizumab)>MK-3475,lambrolizumab,Merck&Co., inc.), BCD-100 (BIOCAD Biopharmaceutical Company), tisleelizumab (Tisleelizumab) (BGB-A317, beiGene Ltd./Celgene Corporation), ji Nuozhu mab (genolimzumab) (CBT-501,CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), GLS-010 (Harbin Gloria Pharmaceuticals Co., ltd.), xin Dishan anti (sintillimab) (IBI 308, innovent Biologics, inc.), WBP3155 (CStone Pharmaceuticals Co., ltd.), AMP-224 (GlaxoSmithKline plc), BI 754091 (Boehringer Ingelheim GmbH), BMS-936559 (Bristol-Myers Squibb Company), CA-170 (Aurigene Discovery Technologies), FAZ053 (Novartis AG), studizumab (spartalizumab) (PDR 001, novartis AG), LY3300054 (elily)&Company), MEDI0680 (AstraZeneca PLC), PDR001 (Novartis AG), sago Li Shan anti (PF-06801591,Pfizer Inc), simipn Li Shan anti (cemiplimab) (. About. >REGN2810, regeneron Pharmaceuticals, inc.), calomelizumab (SHR-1210,Incyte Corporation), TSR-042 (Tesaro, inc.), AGEN2034 (agalus inc.), CX-072 (CytomX Therapeutics, inc.), JNJ-63723283 (Johnson)&Johnson)、MGD013(MacroGenics,Inc.)、AN-2005(Adlai Nortye)、ANA011(AnaptysBio,Inc.)、ANB011(AnaptysBio,Inc. ) AUNP-12 (Pierre Fabre Medicament S.A.), BBI-801 (Sumitomo Dainippon Pharma Co., ltd.), BION-004 (Aduro Biotech), CA-327 (Aurigene Discovery Technologies), CK-301 (Fortress Biotech, inc.), ENUM 244C8 (Enumeral Biomedical Holdings, inc.), FPT155 (Five Prime Therapeutics, inc.), FS118 (F-star Alpha Ltd.), hAb21 (Stainwei Biotech, inc.), J43 (Transgene S.A.), JTX-4014 (Jounce Therapeutics, inc.), KD033 (Kadmon Holdings, inc.), KY-1003 (KymLtd.), MCLA-134 (Merues B.V.), MCLA-145 (Merues B.V.), PRS-332 (Pieris AG), R-6 (Atdia Pty) 1010, STI-1010, inc.), and Indoc-95 (Xiden) and (Xiden) are disclosed.

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

In some aspects, the anti-PD-1 antibody comprises: comprising SEQ ID NO:27 and/or a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:31, and a light chain variable region (VL) of the amino acid sequence shown in seq id no. In some aspects, VH comprises: comprising SEQ ID NO:28, a VH CDR1 comprising the sequence set forth in SEQ ID NO:29, a VH CDR2 comprising the sequence set forth in SEQ ID NO:30, and/or VL comprises: comprising SEQ ID NO:32, a VL CDR1 comprising the sequence set forth in SEQ ID NO:33, a VL CDR2 comprising the sequence set forth in SEQ ID NO:34, and VL CDR3 of the sequences shown in seq id no. In some aspects, VH comprises SEQ ID NO:27, and/or VL comprises the sequence set forth in SEQ ID NO: 31.

In some aspects, the anti-PD-1 antibody is a Sashan Li Shan antibody (PF-06801591). Sardine Li Shan antibody is a humanized immunoglobulin G4 (IgG 4) monoclonal antibody (mAb) that binds to the PD-1 receptor. By blocking its interaction with PD-L1 and PD-L2, inhibition of the immune response mediated by the PD-1 pathway is released, resulting in an anti-tumor immune response. The clinical antitumor activity of sartoriab has been found in a group of anti-PD 1 sensitive solid tumor types, including non-small cell lung cancer and urothelial cancer. Sartorimab is described, for example, in U.S. patent No. US 10,155,037, which is incorporated herein for all purposes. Unless indicated otherwise, the anti-PD-1 antibodies used in the examples disclosed herein are internally prepared therapeutic humanized anti-human PD-1 antibodies (hIgG 2 a-D265A).

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

Gamma secretase inhibitor therapeutic agent

In some aspects, the therapeutic agent used in the combination therapies of the 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 a compound (including pharmaceutically acceptable salts, solvates and prodrugs thereof) or other formulation that inhibits or reduces the biological activity of gamma secretase. Membrane-bound BCMA is actively cleaved by protease activity from gamma secretase on the surface of tumor cells and may undergo gamma secretase-mediated shedding. This can reduce 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 target density while reducing sBCMA levels. Thus, administration of GSI may enhance the activity of BCMA specific therapeutic drugs.

Examples of small molecule GSIs that may be used in combination therapies of the invention include, but are not limited to, dipeptide classes of GSIs, sulfonamide classes of GSIs, transition state mimetic classes of GSIs, benzocaprolactam classes of GSIs, and other GSIs known in the art. For example, GSI may be selected from MK-0752 (Merck & Co., inc.), MRK-003 (Merck & Co., inc.), nirogachtat (PF-03084014,SpringWorks Therapeutics), RO4929097 (Roche), span Ma Xite (semagastat) (LY 450139, eli Lilly & Company), BMS-906024 (Bristol-Myers Squibb Company), and DAPT, or pharmaceutically acceptable salts thereof. Other examples of GSI include 1- (S) -endo-N- (1, 3) -trimethylbicyclo [2.2.1] hept-2-yl) -4-fluorophenyl sulfonamide, WPE-III-31C, (S) -3- [ N' - (3, 5-difluorophenyl- α -hydroxyacetyl) -L-alaninyl ] amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one and (N) - [ (S) -2-hydroxy-3-methyl-butyryl ] -1- (L-alaninyl) - (S) -1-amino-3-methyl-4, 5,6, 7-tetrahydro-2H-3-benzazepin-2-one. See De Kloe & De Strooper (2014) Small Molecules That Inhibit Notch Signaling, in Bellen & Yamamoto (eds.), notch Signaling: methods and Protocols, methods In mol. Biol., vol 1 187 (pp 311-322), new York, NY: springer-science+Business Media.

In some aspects, the therapeutic agent in the combination therapies of the invention is GSI. In some aspects, the GSI may have any of the features or characteristics of any of the GSIs provided in WO2005/092864, which is incorporated herein by reference for all purposes. In some aspects, the GSI is nirogachitat (PF-03084014,SpringWorks Therapeutics) or a pharmaceutically acceptable salt thereof. The nnirogacetat is an orally selective small molecule GSI having the structure:

nirogachitat is described, for example, in the following documents: U.S. patent No. 7,342,118, U.S. patent No. 7,795,447, and U.S. patent No. 7,951,958, which are incorporated herein for all purposes. Unless indicated otherwise, the GSI used in the examples disclosed herein is nirogachitat.

An effective amount of GSI may be administered according to the dosages described herein. In some aspects, GSI is administered at a dose sufficient to up-regulate surface expression of BCMA on tumor cells. In some aspects, the GSI is administered at a dose sufficient to reduce shedding of BCMA on tumor cells. In some aspects, GSI is administered at a dose sufficient to reduce the level of sBCMA. In some aspects, the GSI is administered at a dose sufficient to increase the activity of the BCMA specific therapeutic agent.

Therapeutic agent

In some aspects, the therapeutic agent for use in the combination therapy of the present invention may comprise one of the followingOr a plurality of: biotherapeutic drugs, chemotherapeutic drugs, immunomodulators (e.g. histone deacetylases, lenalidomide, pomalidomide, iraterone Bei Du amine (iberdomide) and apremilast), proteasome inhibitors (e.g. bortezomib (bortezomib), carfilzomib (carfilzomib) and ezetimibe (ixazomib)), corticosteroids (e.g. dexamethasone and prednisone), histone Deacetylase (HDAC) inhibitors (e.g. panobinostat) and nuclear export inhibitors (e.g. plug Li Nisuo (selinuor)). Further therapeutic agents for use in combination therapies of the invention include cancer vaccines, immune cell therapies (e.g., CAR-T cell based therapies), radiation therapies, vaccines, cytokine therapies (e.g., immunostimulatory cytokines including various signaling proteins that stimulate an immune response, such as interferons, interleukins, and hematopoietic growth factors), targeted cytokines, inhibitors of other immunosuppressive pathways, inhibitors of angiogenesis, T cell activators, inhibitors of metabolic pathways, inhibitors of mTOR (a mechanical target of rapamycin) such as rapamycin, rapamycin derivatives, sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), and difolimus), inhibitors of the adenosine pathway, gamma secretase inhibitors (e.g., niagastat), tyrosine kinase inhibitors, including but not limited to ALK (anaplastic lymphoma kinase) inhibitors (e.g., crizotinib, ceritinib, aletinib, and sunitinib), BRAF inhibitors (e.g., vemurafenib and dabrafenib), PI3K inhibitors, HPK1 inhibitors, epigenetic modifiers, inhibitors or depleting agents of Treg cells and/or myeloid-derived suppressor cells, JAK (Janus kinase) inhibitors (e.g., ruxotinib and tofacitinib), ceritinib (varitinib), non-golitinib (filgoninib), gan Duo tinib, letinib (leutinib), mortinib (mortinib), panitinib (pacrotinib) and Wu Pati (STAT)), transcription inhibitors (e.g., crizotinib), and tofacitinib (soritinib), and combinations thereofNumber transducers and activators), inhibitors (e.g., STAT1, STAT3, and STAT5 inhibitors, such as fludarabine), cyclin-dependent kinase (CDK) or other cell cycle inhibitors, immunogenic agents (e.g., attenuated cancerous cells, tumor antigens, antigen presenting cells, such as dendritic cells pulsed with tumor-derived antigens or nucleic acids), MEK inhibitors (e.g., trametinib (trametinib), cobimetinib, bimetatinib (binimeinib) and semetatinib), GLS1 inhibitors, PARP inhibitors (e.g., tazopanib (talazopanib), glapalib (obapanib), rukapanib (rucapab)), oncolytic viruses, gene therapies including DNA, RNAs delivered directly or by adeno-associated viruses (AAV) or nanoparticles, innate immune response modulators (e.g., TLR, KIR, NKG a), indoxyl (indoxyl 2, 3-dioxygenase) and receptor-encoding agonists such as human cell-specific agonists.

In some aspects, therapeutic agents for use in combination therapies of the invention may include antibodies, including but not limited to anti-CTLA-4 antibodies, anti-CD 3 antibodies, anti-CD 4 antibodies, anti-CD 8 antibodies, anti-4-1 BB antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIM 3 antibodies, anti-LAG 3 antibodies, anti-TIGIT antibodies, anti-OX 40 antibodies, anti-IL-7 Ralpha (CD 127) antibodies, anti-IL-8 antibodies, anti-IL-15 antibodies, anti-HVEM antibodies, anti-BTLA antibodies, anti-CD 38 antibodies, anti-CD 40L antibodies, anti-CD 47 antibodies, anti-CSF 1R antibodies, anti-CSF 1 antibodies, anti-IL-7R antibodies, anti-MARCO antibodies, anti-CXCR 4 antibodies, anti-VEGF antibodies, anti-VEGFR 1 antibodies, anti-VEGFR 2 antibodies anti-TNFR 1 antibody, anti-TNFR 2 antibody, anti-CD 3 bispecific antibody, anti-CD 19 antibody, anti-CD 20, anti-Her 2 antibody, anti-EGFR antibody, anti-ICOS antibody, anti-CD 22 antibody, anti-CD 52 antibody, anti-CCR 4 antibody, anti-CCR 8 antibody, anti-CD 200R antibody, anti-VISG 4 antibody, anti-CCR 2 antibody, anti-LILRb 2 antibody, anti-CXCR 4 antibody, anti-CD 206 antibody, anti-CD 163 antibody, anti-KLRG 1 antibody, anti-FLT 3 antibody, anti-B7-H4 antibody, anti-B7-H3 antibody, KLRG1 antibody, BTN1A1 antibody, BCMA antibody, anti-SLAMF 7 antibody, anti-avb 8 antibody, anti-CD 80 antibody, or anti-GITR antibody.

In some aspects, other examples of therapeutic agents for use in the combination therapies of the invention may be directed or targeted to 5T4; a33; alpha-folate receptor 1 (e.g., rituximab (mirvetuximab soravtansine)); alk-1; BCMA (see, e.g., WO2016166629 and other documents disclosed herein); BTN1A1 (see, e.g., WO 2018222689); CA19-9; CA-125 (e.g., aba Fu Shan anti (abagnomoab)); carbonic anhydrase IX; CCR2; CCR4 (e.g., mo Geli bead mab); CCR5 (e.g., leronelimab); CCR8; CD3[ e.g., bonatumomab (CD 3/CD19 bispecific), PF-06671008 (CD 3/P cadherin bispecific), PF-06863135 (CD 3/BCMA bispecific) ]; CD19 (e.g., bolafungin, MOR 208); CD20 (e.g., ibritumomab (ibritumomab tiuxetan), atozumab (obinutuzumab), ofatumumab, rituximab (rituximab), ublituximab (ublituximab)); CD22 (oagatuzumab (inotuzumab ozogamicin), mositumomab (moxetumab pasudotox)); CD25; CD28; CD30 (e.g., bentuximab (brentuximab vedotin)); CD33 (e.g., gemtuzumab (gemtuzumab ozogamicin)); CD38 (e.g., darunazumab and hyaluronidase, and isatuximab), CD40; CD-40L; CD44v6; CD47 (e.g., hu5F9-G4, CC-90002, SRF231, B6H 12); CD52 (e.g., alemtuzumab); CD56; CD63; CD79 (e.g., bolazuki mab (polatuzumab vedotin)); CD80; CD86; CD123; CD276/B7-H3 (e.g., obutyramib (ombustamab)); CDH17; CEA; clhCG; CTLA-4 (e.g., ipilimumab, tremelimumab), CXCR4; desmosome core protein 4; DLL3 (e.g., lovatuzumab (rovalpituzumab tesirine)); DLL4; e-cadherin; EDA; EDB; EFNA4; EGFR (e.g., cetuximab, dituximab (depatuxizumab mafodotin), cetuximab (necitumumab), panitumumab); EGFRvIII; endosialin; epCAM (e.g., omalizumab (oportuzumab monatox)); FAP; a fetal acetylcholine receptor; FLT3 (see, for example, WO 2018/220584); 4-1BB (CD 137) [ e.g., wu Tuolu mab (utomiumab)/PF-05082566 (see WO 2012/032333) or UreLeumab (urelumab)/BMS-663513 ]; GD2 (e.g., denotuximab, 3F 8); GD3; GITR (e.g., TRX 518); globH; GM1; GM2; HER2/neu [ e.g., margetuximab, pertuzumab, trastuzumab; ado trastuzumab, multi-card Ma Qinqu tobulab (trastuzumab duocarmazine), PF-06804103 (see US 8828401) ]; HER3; HER4; ICOS; IL-10; ITG-AvB; LAG-3 (e.g., rella Li Shan anti (rellatimab), IMP 701); lewis-Y; LG; ly-6; M-CSF [ e.g., PD-0360324 (see US 7326414) ]; (membrane-bound) IgE; MCSP; mesothelin; MIS receptor type II; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; notch1; notch3; fibronectin 4 (e.g., vitamin-enfrazumab (enfortumab vedotin)); OX40[ e.g. PF-04518600 (see US 7960515) ]; p-cadherins [ e.g., PF-06671008 (see WO 2016/001810) ]; PCDHB2; PD-1[ e.g., BCD-100, carmezumab, simipu Li Shan antibody, ji Nuozhu monoclonal antibody (genolimzumab) (CBT-501), MEDI0680, na Wu Liyou monoclonal antibody, pembrolizumab, saran Li Shan antibody (PF-06801591, see WO 2016/092419), xin Dishan antibody, stdazumab, STI-A1110, tirilizumab, TSR-042 and other analogs disclosed herein ]; PD-L1 (e.g., BMS-936559 (MDX-1105), LY3300054, and other analogs disclosed herein); PDGFRA (e.g., olapariumab); plasma cell antigens; polySA; PSCA; PSMA; PTK7[ e.g. PF-06647020 (see US 9409995) ]; ror1; SAS (SAS); SLAMF7 (e.g., erlotinuzumab); SHH; SIRPa (e.g., ED9, effi-DEM); STEAP; sTn; TGF- β; TIGIT; TIM-3; TMPRSS3; TNF-alpha precursors; TROP-2 (e.g., gor Sha Tuozhu mab (sacituzumab govitecan)); TSPAN8; VEGF (e.g., bevacizumab, brolizumab); VEGFR1 (e.g., ranibizumab); VEGFR2 (e.g., ramucirumab); and Wue-1.

In some aspects, the therapeutic agent for use in the combination therapies of the invention may be a therapeutic antibody having any suitable format. For example, the therapeutic antibody may have any format as described elsewhere herein. In some aspects, the therapeutic antibody may be a naked antibody. In certain aspects, the therapeutic antibody may be linked to a drug/formulation (also referred to as an "antibody-drug conjugate" (ADC)). Drugs or agents that may be linked to antibodies in the ADC format may include, for example, cytotoxic agents, immunomodulatory agents, imaging agents, therapeutic proteins, biopolymers, or oligonucleotides. Exemplary cytotoxic agents that may be incorporated into the ADC include anthracycline (anthracycline), duloxetine (auristatin), dolastatin (dolastatin), combretastatin (combretastatin), du Kamei (duocarmycin), pyrrolobenzodiazepine (pyrrolobenzodiazepine) dimer, indolinyl pyrrolobenzodiazepine dimer, enediyne, geldanamycin (geldanamycin), maytansine (maytansine), puromycin (puromycin), taxane (taxane), vinca alkaloid (vinca alkaloid), camptothecins (camptothecin), tubulysins, semi-star (hemasterlin), splice inhibitors (splicostin), pladienolide (plastolide), and stereoisomers, electronic isosteres, analogues, or derivatives thereof.

In some aspects, therapeutic antibodies against a particular antigen may be incorporated into a multispecific antibody (e.g., bispecific or trispecific antibody). Bispecific antibodies are monoclonal antibodies that have binding specificities for 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 a human immune effector cell by specifically binding to an effector antigen located on the human immune effector cell, and wherein the second antibody variable domain is capable of specifically binding to a target antigen as provided herein. In some aspects, the antibody has an IgG1, igG2, igG3, or IgG4 isotype. In some aspects, the antibody comprises an immunologically inert Fc region. In some aspects, the antibody is a human antibody or a humanized antibody.

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

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

In some aspects, 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 having increased specificity for target cells of interest (e.g., for tumor cells expressing two particular tumor-associated antigens of interest). For example, in some aspects, 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, therapeutic agents for combination therapies of the invention may comprise immunomodulators, including thalidomide, lenalidomide, pomalidomide, ifenprodil Bei Du, and aplidine, which may stimulate an immune response in a subject. Further immunomodulators include Pattern Recognition Receptor (PRR) agonists, immunostimulatory cytokines, immune cell therapies and cancer vaccines.

Pattern Recognition Receptors (PRRs) are receptors that are expressed by cells of the immune system and recognize various molecules associated with pathogen and/or cell damage or death. PRR is involved in both the innate and adaptive immune responses. PRR agonists can be used to stimulate an immune response in a subject. PRR molecules come in a variety of classes including toll-like receptors (TLRs), RIG-I like receptors (RLRs), nucleotide binding oligomerization domain (NOD) like receptors (NLRs), C-type lectin receptors (CLRs), and interferon gene stimulatory factor (STING) proteins.

Exemplary TLR agonists provided herein include agonists of TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8 and TLR 9. Examples of RLR agonists useful in the methods of treatment, medicaments and uses of the invention include, for example, short double-stranded RNA (RIG-I agonists) with uncapped 5' triphosphates; poly I: C (MDA-5 agonist) and BO-112 (MDA-A agonist). Examples of NLR agonists that can be used in the methods of treatment, medicaments and uses of the invention include, for example, liposomal muramyl tripeptide/mifamurtide (NOD 2 agonist). Examples of CLR agonists useful in the methods of treatment, medicaments and uses of the invention include, for example, MD fractions (purified soluble β -glucan extract from Grifola frondosa) and imprime PGG (yeast derived β1,3/1, 6-glucan PAMP). Examples of STING agonists that can be used in the methods of treatment, medicaments and uses of the invention include various immunostimulatory nucleic acids, such as synthetic double stranded DNA, cyclic di-GMP, cyclic GMP-AMP (cGAMP), synthetic Cyclic Dinucleotides (CDN), such as MK-1454 and ADU-S100 (MIW 815), and small molecules, such as P0-424. Other PRRs include, for example, DNA-dependent IFN-modulating factor activators (DAI) and melanoma-deficient factor 2 (AIM 2).

Immunostimulatory cytokines include, but are not limited to, various signaling proteins that stimulate an immune response, 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, IFN, IL-2 (e.g., dinium interleukin), IL-6, IL-7, IL-10, IL-11, IL-12, IL-15, IL-18, IL-21, and TNF. The immunostimulatory cytokine may have any suitable format. In some aspects, the immunostimulatory cytokine may be a recombinant version of the wild-type cytokine. In some aspects, the immunostimulatory cytokine may be a mutant protein having one or more amino acid changes as compared to the corresponding wild-type cytokine. In some aspects, the immunostimulatory cytokine may be incorporated into a chimeric protein containing the cytokine and at least one other functional protein (e.g., an antibody). In some aspects, the immunostimulatory cytokine may be covalently linked to a drug/formulation (e.g., any drug/formulation as described elsewhere herein as a possible ADC component). In some aspects, the cytokine is pegylated.

Immune cell therapy involves treating a patient with immune cells capable of targeting cancer cells. Immune cell therapies include, for example, tumor Infiltrating Lymphocytes (TILs) and chimeric antigen receptor T cells (CAR-T cells).

Cancer vaccines include various compositions that contain a tumor-associated antigen (or that can be used to generate a tumor-associated antigen in a subject), and thus can be used to elicit an immune response in a subject that will be directed against tumor cells that contain the tumor-associated antigen. Example materials that may be included in a cancer vaccine include attenuated cancerous cells, tumor antigens, antigen presenting cells, such as dendritic cells pulsed with a tumor derived antigen or a nucleic acid encoding a tumor associated antigen. In some aspects, cancer vaccines can be prepared with cancer cells of the patient themselves. In some aspects, the cancer vaccine may be prepared with biological material that is not derived from cancer cells of the patient themselves. Cancer vaccines include, for example, sipuleucel-T and talarogenin-lahererepvec (T-VEC).

The combination therapies provided herein may comprise one or more chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan (busulfan), imperoshu (imposulfan) and piposulfan (piposulfan); aziridines, such as benzodopa (benzodopa), carboquinone (carboquone), mei Tulei dopa (meturedada) and Wu Leiduo bar (uredada); ethyleneimine and ethylmelamine (ethylmelamine), including altretamine, triamcinolone acetoamide, triethylenephosphoramide, triethylenethiophosphamide, triethylenephosphoramide and trimethylmelamine; polyacetyl (acetogenin) (especially bullatacin and bullatacin); camptothecins (including the synthetic analog topotecan); bryostatin (bryostatin); calistatin (calistatin); CC-1065 (including adoxolone, calzelone and bizelone analogues thereof); nostoc (cryptophycin) (in particular, nostoc 1 and nostoc 8); dolastatin; du Kamei (including synthetic analogs KW-2189 and CBI-TMI); eleutherobin (eleutherobin); a podocarpine (pancratistatin); muscle anabaenamine (sarcodactylin); halichondrin (spongostatin); nitrogen mustards, such as chlorambucil, napthalene (chlorambucil), cyclophosphamide (chlorophosphamide), estramustine, ifosfamide, mechlorethamine (mechlorethamine), oxidized mechlorethamine hydrochloride, melphalan (melphalan), novobixing (novembichin), mechol (phenacetine), prednisone (prednisone), qu Luolin amine (trofosfamide), uramustine (uracil mustard); nitrosoureas such as carmustine, chlorouremycin (chlorozotocin), fotemustine, lomustine (lomustine), nimustine, and ranimustine (ranimustine); antibiotics, such as enediyne antibiotics (e.g., calicheamicin), especially calicheamicin γ1i and calicheamicin phil1, for example, see, for example, agnew, chem. Intl. Ed. Engl.,33:183-186 (1994); daptomycin (dyneimicin), including daptomycin a; bisphosphates, such as chlorophosphonates; espell-mycin (esperamicin), and newly prepared and related chromogen enediyne antibiotic chromophores, aclacinomycin (acryiomycin), amphotericin (authamycin), azaserine (azaserine), azaserine, bleomycin (bleomycin), actinomycin (calicheamicin), carboxin (carboxin), carboxin (Mi Mei), acidophilin (carzinophilin), chromomycin, dactinomycin (dactinomycin), daunorubicin (dactinomycin), dithicin (detorubicin), 6-diaza-5-oxo-norleucine, doxorubicin (including morpholinoducin, cyanomorpholinoducin, 2-pyrrolidoubicin and deoxydoxorubicin), epirubicin, epothilone, doxorubicin (carzinostacin), dactinomycin (dactinomycin), mitomycin (mitomycin), mitomycin (streptomycin), and other drugs (dactinomycin) Tuberculin, ubenimex, hexastatin (zinostatin), zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as, for example, dimethyl folic acid (denopterin), methotrexate, ptertrexate (pteroprerin), trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine (thiamiprine), thioguanine; pyrimidine analogs such as ambriseine (ancitabine), 6-azauridine, carmofur (carmofur), cytarabine, dideoxyuridine (dideoxyuridine), doxifluridine, enocitabine, fluorouridine; androgens, such as carbosterone, drotasone propionate (dromostanolone propionate), cyclothiolane, mestrane, testosterone (testolactone); anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid (folinic acid); FOLFOX, including folinic acid, 5-FU and oxaliplatin (oxaliplatin); acetoglucurolactone (aceglatone); aldehyde phosphoramidate glycoside (aldophosphamide glycoside); aminolevulinic acid; enuracil; amsacrine; armustine (bestabucil); bisantrene (bisantrene); eda Qu Zhi (edatraxate); deffamin (defofame); decarbonylated colchicine; filoquinone (diaziquone); ornithine difluoride; ammonium elegance; epothilones; eggshell robust; gallium nitrate; hydroxyurea; lentinan; lonidamine (lonidamine); maytansinoids (maytansinoids) such as maytansine and ansamitocins; mitoguazone (mitoguazone); mitoxantrone; mo Pai dar alcohol; ni Qu Ading (nittracrine); prastatin; benamet (phenamet); pirarubicin; losoxantrone; podophylloic acid (podophyllinic acid); 2-ethyl hydrazide; procarbazine; propylimine; rhizomycin (rhizoxin); schizophyllan (sizofuran); germanium spiroamine; tenuazonic acid; triiminoquinone; 2,2',2 "-trichlorotriethylamine; trichothecene toxins (especially T-2 toxin, mucomycin (verraculin) a, cyclosporin (roridine) a and diacetyl ribes falcarinol (anguidine)); urethane (urethane); vindesine; dacarbazine; mannitol; dibromomannitol; dibromodulcitol; pipobromine; a gacytosine; arabinoside ('Ara-C'); cyclophosphamide; thiotepa; taxanes, such as paclitaxel and taxotere (doxetaxel); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as carboplatin; cisplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; mitoquinone hydrochloride (novantrone); teniposide; eda traxas; daunomycin; aminopterin; hilded; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids (retinoids), such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

In some aspects, the therapeutic agents used in the combination therapies of the invention may be anti-hormones, such as antiestrogens and Selective Estrogen Receptor Modulators (SERMs), for modulating or inhibiting the effects of the hormone on tumors, including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxy tamoxifen, troxifene, raloxifene hydrochloride (keoxifene), LY117018, onaston, and toremifene (farston); aromatase inhibitors which inhibit aromatase enzymes which regulate the production of estrogen in the adrenal gland, such as 4 (5) -imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole (vorozole), letrozole and anastrozole.

In some aspects, the therapeutic agent for the combination therapy of the invention may be an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprorelin, fludil, letatide (aplutamide), enzalutamide, cimetidine Ding Hege sertraline; KRAS inhibitors; MCT4 inhibitors; MAT2a inhibitors; tyrosine kinase/Vascular Endothelial Growth Factor (VEGF) receptor inhibitors such as sunitinib, axitinib, sorafenib, tivozanib; alk/c-Met/ROS inhibitors such as crizotinib, refatinib (lorelatinib); mTOR inhibitors such as temsirolimus, ji Dali plug (gedatolisib); src/abl inhibitors such as wave Su Tini; cyclin Dependent Kinase (CDK) inhibitors such as palbociclib (Pabociclib), PF-06873600, abeli (abemaciclib) and ribociclib (ribociclib); erb inhibitors such as dactinib (dacominib); PARP inhibitors such as talazapanib, olapanib, ruapab, nilaparib; SMO inhibitors such as glas gilb (glasdegib), PF-5274857; EGFR T790M inhibitors, such as PF-06747775; EZH2 inhibitors or other epigenetic modifiers such as PF-06821497; PRMT5, such as PF-06939999 inhibitors; TGFR r1 inhibitors such as PF-06952229; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

Treatment of

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

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

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

The therapeutic agents in the combination therapies of the invention may be administered by any suitable enteral route of administration or parenteral route of administration. The term "enteral route of administration" refers to administration via any portion of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal and rectal, or intragastric routes. By "parenteral route of administration" is meant a route of administration other than the enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous, or topical administration. The therapeutic agents of the present disclosure may be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. Suitable routes and methods of administration may vary depending on a variety of factors, such as the specific therapeutic agent being used, the desired rate of absorption, the specific formulation or dosage form being used, the type or severity of the condition being treated, the site of specific action, and the condition of the patient. Examples of parenteral routes of administration also include intraosseous and intrapleural.

Oral administration of solid dosage forms of therapeutic agents may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one therapeutic agent. In another aspect, oral administration may be in the form of a powder or granule. In another aspect, the oral dosage form is sublingual administration, such as, for example, a lozenge. In such solid dosage forms, the therapeutic agent 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 forms may also comprise buffering agents or may be prepared with enteric coatings.

In another aspect, oral administration of the therapeutic agent may be 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 include adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening), and/or perfuming agents.

In some aspects, the therapeutic agent is administered in a parenteral dosage form. "parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusions. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to known techniques using suitable dispersing, wetting and/or suspending agents and include depot formulations.

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

Other carrier materials and modes of administration known in the pharmaceutical arts may also be used with the therapeutic agent. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. The formulation of drugs is discussed, for example, in the following documents: 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 (3.sup.rd Ed.), american Pharmaceutical Association, washington,1999.

The dosage regimen (also referred to herein as the administration regimen) selected for the combination therapy of the invention may depend on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissues or organs in the subject being treated. Preferably, the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient while consistent with acceptable levels of side effects. Thus, the amount and frequency of administration of each therapeutic or chemotherapeutic agent in a combination will depend in part on the particular therapeutic agent, the severity of the cancer being treated, and the patient characteristics. Guidance in selecting appropriate doses of antibodies, cytokines and small molecules is available. See, e.g., wawrzynczak (1996) anti-body Therapy, biology Scientific pub.ltd, oxfordshire, UK; kresina (ed.) (1991) Monoclonal Antibodies, cytokines and Arthritis, marcel Dekker, new York, NY; bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, marcel Dekker, new York, N.Y.; baert et al (2003) New Engl. J. Med.348:601-608; milgrom et al (1999) New Engl. J. Med.341:1966-1973; slamon et al (2001) New Engl. J. Med.344:783-792; beninaminovitz et al (2000) New Engl. J. Med.342:613-619; ghosh et al (2003) New Engl. J. Med.348:24-32; lipsky et al (2000) New Engl. J. Med.343:1594-1602; physics 'Desk Reference 2003 (Physics' Desk Reference,57th Ed); medical Economics Company; ISBN 1563634457;57th edition (November 2002). The clinician may make a determination of the appropriate dosage regimen, for example, using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and the determination will depend on, for example, the patient's clinical history (e.g., previous therapies), the type and stage of cancer to be treated, and biomarkers of response to one or more therapeutic agents in the combination therapy.

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

In some aspects, the therapeutic agents in the combination therapies of the invention may be administered to a subject at the following doses: about 1mg/kg to about 1000mg/kg, about 2mg/kg to about 900mg/kg, about 3mg/kg to about 800mg/kg, about 4mg/kg to about 700mg/kg, about 5mg/kg to about 600mg/kg, about 6mg/kg to about 550mg/kg, about 7mg/kg to about 500mg/kg, about 8mg/kg to about 450mg/kg, about 9mg/kg to about 400mg/kg, about 5mg/kg to about 200mg/kg, about 2mg/kg to about 150mg/kg, about 5mg/kg to about 100mg/kg, about 10mg/kg to about 100mg/kg, or about 10mg/kg to about 60mg/kg.

In some aspects, the therapeutic agents in the combination therapies of the invention may be administered to a 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, 0.2mg/kg, 1.0mg/kg, 2.0mg/kg, 3.0mg/kg, 5.0mg/kg, 10mg/kg, 25mg/kg, 50mg/kg body weight or more. See, for example, yang et al (2003) New Engl. J. Med.349:427-434; herod et al (2002) New Engl. J. Med.346:1692-1698; liu et al (1999) J.Neurol. Neurosurg. Psych.67:451-456; portielji et al (20003) Cancer immunol. Immunother.52:133-144.

In some aspects, a fixed dose of the therapeutic agent of about or at least about: 0.05 μg, 0.2 μg, 0.5 μg, 1 μg, 10 μg, 100 μg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 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 more. The fixed dose may be administered at the following intervals: such as daily, every other day, three times a week, or once a week, once two weeks, once three weeks, once a month, once every 2 months, once every 3 months, once every 4 months, etc.

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

In some aspects, the therapeutic agents in the combination therapies of the invention may be administered to a subject in an oral, IV or SC dose in the following manner: at least once daily, once a day, twice a day, three times a day, four times a day, every two days, every three days, once a week, every two weeks, 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 methods of treatment described herein may continue as long as the clinician supervising patient care considers the method of treatment to be effective. Non-limiting parameters indicating the effectiveness of the treatment method include any one or more of the following: tumor shrinkage (expressed by weight and/or volume); the number of individual tumor colonies is reduced; tumor elimination; progression free survival. The change in tumor size may be determined by any suitable method, such as imaging. Various diagnostic imaging modalities well known in the art may be employed, such as computed tomography (CT scan), dual energy CDT, positron emission tomography, ultrasound, CAT scan, and MRI. In some aspects, the combination therapies of the invention are used to treat a sufficiently large tumor that can be found by palpation or by imaging techniques well known in the art (such as MRI, ultrasound, or CAT scan).

Exemplary lengths of time associated with a therapy procedure include about one week; about two weeks; about three weeks; about four weeks; about five weeks; about six weeks; about seven weeks; about eight weeks; about nine weeks; about ten weeks; about ten weeks; about twelve weeks; about thirteen weeks; about ten weeks; about fifteen weeks; about sixteen weeks; about seventeen weeks; about eighteen weeks; about nineteen weeks; about twenty weeks; about twenty weeks; about twenty-two weeks; about twenty-three weeks; about twenty four weeks; about seven months; about eight months; about nine months; about ten months; about eleven months; about twelve months; about thirteen months; about fourteen months; about fifteen months; about sixteen months; about seventeen months; about eighteen months; about nineteen months; about twenty months; about twenty-one months; about twenty-two months; about twenty-three months; about twenty-four months; about thirty months; about three years; about four years and about five years.

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

In some aspects, the condition is cancer, including but not limited to malignant epithelial tumors, lymphomas, leukemias, myelomas, blastomas, and sarcomas. In some aspects, the cancer may include cancer-related diseases, including B-cell-related cancers and/or cancer-related diseases, including but not limited to multiple myeloma, malignant plasma cell neoplasm, lymphoma, hodgkin's lymphoma, nodular lymphocytic dominant Hodgkin's lymphoma, kahler's disease and myelogenous leukemia, plasma cell leukemia, plasmacytoma, unidentified Monoclonal Gammaglobulosis (MGUS), smoldering myeloma, light chain amyloidosis, osteosclerotic myeloma, B-cell lymphocytic leukemia, hairy cell leukemia, B-cell non-hodgkin's lymphoma (NHL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL), chronic Myelogenous Leukemia (CML), follicular lymphoma, burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myelogenous leukemia, megaloblastic, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymus) 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/tissue cell-enriched large B cell lymphoma, primary central nervous system lymphoma, primary diffuse large B cell lymphoma of the skin (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, ALK positive large B-cell lymphoma, plasmablasts lymphoma, large B-cell lymphoma occurring in HHV 8-associated multicenter Castleman disease, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and burkitt's lymphoma, unclassified B-cell lymphoma between diffuse large B-cell lymphoma and classical hodgkin's lymphoma, and other B-cell-associated lymphomas.

In some aspects, the cancer is gastric cancer, small intestine cancer, head and neck cancer (e.g., squamous cell head and neck cancer), thymus cancer, epithelial cancer, salivary cancer, liver cancer, cholangiocarcinoma, neuroendocrine tumor, gastric cancer, thyroid cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), mesothelioma, ovarian cancer, breast cancer, prostate cancer, renal cancer, esophageal cancer, pancreatic cancer, glioma, renal cancer (e.g., renal cell carcinoma), bladder cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, penile cancer, testicular cancer, anal cancer, choriocarcinoma, colon cancer, colorectal cancer, oral cancer, skin cancer, merkel cells, malignant epithelial tumors, glioblastoma, brain tumor, bone cancer, eye cancer, melanoma, or cancer with high microsatellite instability (MSI-H).

The combination therapy of the invention may be used to remove tumors before or after surgery and may be used before, during or after radiation therapy.

In some aspects, the combination therapies of the invention are administered to a patient who has not been previously treated with a therapeutic or chemotherapeutic drug, i.e., who has never received treatment. In other aspects, the combination therapies of the invention are administered to a patient who fails to achieve a sustained response after prior therapy with a therapeutic or chemotherapeutic agent, i.e., who has undergone treatment. In some aspects, the subject has received prior therapy to treat the tumor, and the tumor is recurrent or refractory.

The invention provided herein encompasses combination therapies with additive efficacy or additive therapeutic effects while reducing or avoiding undesirable or adverse effects. The invention also encompasses synergistic combinations wherein the therapeutic effect is greater than the additive while reducing or avoiding undesired or adverse effects. In certain aspects, the methods and compositions provided herein allow for the treatment or prevention of diseases and conditions, wherein lower and/or less frequent doses of at least one therapeutic agent in combination therapy may result in enhanced anti-tumor responses, thereby improving treatment to at least one of: i) Reducing the incidence of undesired or adverse effects caused by the administration of the therapeutic agent alone, while maintaining at least the therapeutic efficacy of the treatment; ii) increase patient compliance, and iii) increase the efficacy of anti-tumor therapy.

Kit for detecting a substance in a sample

The therapeutic agents of the combination therapies of the invention may conveniently be combined in a kit suitable for co-administration of the compositions.

In one aspect, a kit comprises at least a first container and a second container, and a package insert. 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 of the combination therapy. The package insert/label contains instructions for using the therapeutic agent to treat the cancer and/or cancer-related disease patient. The first and second containers may be constructed 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 useful for administering therapeutic agents, such as diluents, filters, IV bags and lines, needles and syringes.

Clinical study

Phase 1, open label, multi-dose, multi-center, dose escalation, safety, pharmacokinetic (PK) and pharmacodynamic studies (NCT 03269136) of PF-06863135 in adult patients with advanced multiple myeloma for which standard therapy is relapsed or refractory continue. This is a two-part study that evaluates the safety and tolerability of increasing the PF-06863135 dose level in part 1 and confirms the recommended phase 2 dose (RP 2D) 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 may be performed on PF-06863135 in combination with any of the therapeutic agents disclosed herein: PF-06863135 in combination with an anti-PD-1/PD-L1 antibody (e.g., saran Li Shan anti/PF-06801591); PF-06863135 in combination with an immunomodulatory agent (e.g., thalidomide, lenalidomide, pomalidomide, ifenprodil Bei Du, and aplite); PF-06863135 in combination with a gamma secretase inhibitor (e.g., nirogachtat); PF-06863135 in combination with other therapeutic agents, such as biologic therapeutic agents (e.g., CD38 antibody darimumab, darimumab and hyaluronidase and isatuximab, and SLAMF7 antibody erltuzumab), chemotherapeutic agents (e.g., melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin and dandamustine), proteasome inhibitors (e.g., bortezomib, carfilzomib and ezetimibe), corticosteroids (e.g., dexamethasone and prednisone), histone Deacetylase (HDAC) inhibitors (e.g., pan Nuosi he), and nuclear output inhibitors (e.g., stuff Li Nisuo).

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

General procedure

The following documents describe standard methods in molecular biology: sambrook, fritsch and Maniatis (1982&1989 2nd Edition,2001 3rd Edition) Molecular Cloning, ALaboratory 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, calif.). Standard methods are 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 (cologan, et al (2000) Current Protocols in Protein Science, vol.1, john Wiley and Sons, inc., new York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., coligan, et al (2000) Current Protocols in Protein Science, vol.2, john Wiley and Sons, inc., new York; ausubel, et al (2001) Current Protocols in Molecular Biology, vol.3, john Wiley and Sons, inc., 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) BioDirector, piscataway, N.J., pp.384-391). The production, purification and fragmentation of polyclonal and monoclonal Antibodies is described (Coligan, et al (2001) Current Protcols in Immunology, vol.1, john Wiley and Sons, inc., new York; harlow and Lane (1999) Using Antibodies, cold Spring Harbor Laboratory Press, cold Spring Harbor, NY; harlow and Lane, supra.) Standard techniques for characterizing ligand/receptor interactions are available (see, e.g., coligan, et al (2001) Current Protocols in Immunology, vol.4, john Wiley, inc., new York).

Monoclonal, polyclonal and humanized antibodies can be prepared (see, e.g., shepherd and Dean (eds.) (2000) Monoclonal Antibodies, oxford Univ. Press, new York, N.Y., kontermann and Dubel (eds.) (2001) Antibody Engineering, springer-Verlag, new York; harlow and Lane (1988) Antibodies ALaboratory Manual, cold Spring Harbor Laboratory Press, cold Spring Harbor, N.Y., pp.139-243;Carpenter,et al (2000) J.Immunol.165:6205; he, et al (1998) J.Immunol.160:1029; tang et al (1999) J.biol.chem.274:27371-27378; baca et al (1997) J.biol.chem.272:10678-10684;Chothia et al (1989) Nature 342:877-883;Foote and Winter (1992) J.mol.biol.224; U.S. patent No. 6,329,511).

An alternative to humanisation is to use a library of human antibodies displayed on Phage or in transgenic mice (Vaughan et al (1996) Nature Biotechnol.14:309-314; barbas (1995) Nature Medicine1:837-839; mendez et al (1997) Nature Genetics 15:146-156;Hoogenboom and Chames (2000) immunol.today 21:371-377; barbas et al (2001) pharmaceutical display: A Laboratory Manual, cold Spring Harbor Laboratory Press, cold Spring Harbor, new York; kay et al (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, academic Press, san Diego, calif. de Bruin et al (1999) Nature Biotechnol.17:397-399).

Purification of the antigen is not necessary for antibody production. Animals may be immunized with cells carrying an antigen of interest. Spleen cells can then be isolated from the immunized animal and fused with a myeloma cell line to produce hybridomas (see, e.g., meyaard et al (1997) Immunity 7:283-290; wright et al (2000) Immunity 13:233-242;Preston et al, supra; kaithamana et al (1999) j. Immunol. 163:5157-5164).

Antibodies can be conjugated, for example, with small drug molecules, enzymes, liposomes, polyethylene glycols (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 etal (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 Flow Cytometry, including Fluorescence Activated Cell Sorting (FACS), are available (see, e.g., owens, et al (1994) Flow Cytometry Principles for Clinical Laboratory Practice, john Wiley and Sons, hoboken, NJ; givan (2001) Flow Cytometry,2nd ed.; wiley-lists, hoboken, NJ; shape (2003) Practical Flow Cytometry, john Wiley and Sons, hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids (including nucleic acid primers and Probes, polypeptides and antibodies) for use as, for example, diagnostic reagents are available (Molecular Probesy (2003) catalyst, molecular Probes, inc., eugene, OR; sigma-Aldrich (2003) catalyst, st.louis, MO).

Standard methods of immune system Histology are described (see, e.g., muller-Harmelink (ed.) (1986) Human Thymus: histopathology and Pathology, springer Verlag, new York, N.Y.; 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, N.Y.).

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

Examples

Example 1: PD-1 induced in vitro study of CD8+ T cells co-cultured with MM.1S multiple myeloma cells treated with BCMA CD3 bispecific antibody

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

Using EasyStep human T cellsEnrichment kit (Stem Cell Technologies) negative selection was performed on cd3+ T cells from PBMC (Stem Cell Technologies). 10,000 luciferase-expressing target multiple myeloma MM.1S cells (MM.1S-Luc) were isolated from 50,000 CD3 ⁺ pan T cells were seeded together in a clear 96-well V-bottom plate. Cells were treated with 1nm BCMAxCD3 bispecific antibody and analyzed for PD-1 expression 3, 24, 48 and 72 hours after BCMAxCD3 bispecific addition. At the indicated time points, cells were collected from wells, washed with pbs+2% fbs, and stained with ZombieNIR Viability dye (Biolegend) in PBS for 20 min at room temperature, followed by staining with antibodies against human CD8 and PD-1 (Biolegend). Samples were analyzed using FlowJo flow cytometry analysis software. Dead cells were removed from the assay by gating on ZombieNIR negative populations. In CD8 ⁺ Samples were further gated on the positive population. PD-1 ⁺ The percentage of cells expressed as CD8 ⁺ PD-1 positive cells within the population. The results are summarized in fig. 1, and table 1 shows that treatment of BCMA-expressing mm.1s multiple myeloma cells with BCMAxCD3 bispecific antibodies induced PD-1 expression on cd8+ T cells.

TABLE 1 PD-1 cells% after bispecific treatment with BCMA CD3

Example 2: in vivo study of BCMAxCD3 bispecific antibodies in combination with anti-PD-1 antibodies in mm.1s-pdl1 in situ and in subcutaneous mouse models

This example demonstrates the combined efficacy of BCMAxCD3 bispecific and anti-PD-1 antibodies in (a) in situ mm.1s-Luc-PD-L1 and (B) mm.1s-PD-L1 multiple myeloma models as compared to BCMAxCD3 bispecific or anti-PD-1 antibodies alone.

A. In situ mouse model

Mm.1s-Luc multiple myeloma cells are engineered to express PD-L1 and are referred to as mm.1s-Luc-PD-L1. Preparation of MM.1S-Luc-PD-L1 cells as 5X 10 ⁶ Single cell suspension of individual cells for Intravenous (IV) inoculation to NSGIn mice.

Tumor growth was monitored by Intraperitoneal (IP) injection of DPBS containing fluorescein solution, by luminescence imaging, and imaged using a Perkin Elmer IVIS Spectrum camera system. At 19 days post tumor cell inoculation, animals were IV administered 2x10 ⁷ Individual expanded human T cells. Two days after T cell administration, a single dose (10 μg/kg) of BCMAxCD3 bispecific was administered as an IV bolus injection. anti-PD-1 antibodies were administered as 5/kg IP bolus injections twice a week for a total of 6 injections.

Tumor growth was monitored via imaging measurements collected twice weekly. Mice were imaged using a Perkin Elmer IVIS Spectrum camera system, where parameters were determined automatically and imaging time was 3 minutes maximum. Data were collected using the live Image software. A region of interest (ROI) was drawn around the whole body of the mouse, excluding the tail as much as possible. Background flux as measured on the anesthesia manifold was subtracted from each ROI. Tumor measurements are expressed as total flux expressed in photons per second (p/s). The study was terminated on day 40 post tumor inoculation. The results are summarized in fig. 2A and table 2 shows that treatment with BCMAxCD3 bispecific and anti-PD-1 antibodies was more effective than treatment with bispecific or antibodies alone.

TABLE 2 tumor measurements expressed as total flux p/s after treatment

B. Subcutaneous mouse model

Mm.1s multiple myeloma cells are engineered to express PD-L1 and are referred to as mm.1s-PD-L1. Preactivated and expanded T cells (20X 10) were administered on day 19 after Subcutaneous (SC) inoculation of MM.1S-PDL1 tumor cells ⁶ ). BCMAxCD3 bispecific (0.3 or 1/kg) or negative bispecific (1/kg) was administered IV on day 21 and Q7Dx3 was administered. anti-PD-1 mAb was administered twice weekly, starting on day 21, at 5/kg Intraperitoneal (IP). Tumor measurements were recorded 2 to 3 times per week using a digital caliper. N (at the beginning of the study) was 5-12 animals per group. The results are summarized in FIG. 2BAnd table 3 shows that treatment with BCMAxCD3 bispecific and anti-PD-1 antibodies is more effective than treatment with bispecific or antibodies alone.

TABLE 3 tumor measurements after treatment (tumor volume.+ -. SEM (mm) ³ ))。

Example 3: in vitro studies to detect cell surface BCMA expression in multiple myeloma cell lines treated with Gamma Secretase Inhibitors (GSI)

This example demonstrates the up-regulation of cell surface BCMA expression in multiple myeloma cell lines treated with GSI.

Multiple myeloma cells (mm.1 s, OPM2, H929, molp8, RPMI 8226) were seeded at 40,000 cells/well in 96-well U-bottom plates. Cells were incubated in the presence of RPMI (0.1% dmso) diluted with GSI for 24 hours. The following concentrations of GSI were tested: 1000nM, 500nM, 100nM, 50nM, 25nM, 10nM, 5nM, 2.5nM, 1nM, 0.1nM, 0.01nM. Cells were collected after 24 hours and washed with pbs+2% fbs followed by staining with ZombieNIR Viability fuel (Biolegend) at 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-BCMA PE labeled antibody (Biolegend) at 4 ℃ for 30 min. Cells were collected on a BD flow cytometer and analyzed using FlowJo flow cytometry analysis software. Dead cells were removed from the assay by gating on ZombieNIR negative populations. BCMA Mean Fluorescence Intensity (MFI) was plotted against GSI concentration to confirm EC50.

The results are summarized in fig. 3A-3E and table 4 shows that GSI treatment upregulates BCMA expression on the cell surfaces of the multiple myeloma cell lines mm.1s, OPM2, H929, molp8 and RPMI8226, respectively.

TABLE 4 mean fluorescence intensity.+ -. Standard deviation

Example 4: in vitro studies to detect cell surface BCMA expression in a time dependent manner in multiple myeloma cell lines treated with GSI

This example demonstrates 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 GSI removal from culture.

Multiple myeloma cells (mm.1 s, OPM2, H929, molp8, RPMI 8226) 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 cell surface BCMA expression at baseline, then assessed 3 hours, 6 hours, and 24 hours after GSI addition. After 24 hours incubation with GSI, cells were washed twice in PBS and re-plated in fresh 6-well plates. Cells were further collected for staining 3 hours, 6 hours and 24 hours after washing GSI. At the indicated time points, samples were stained with ZombieNIR Viability dye (Biolegend) at 1/500 dilution in PBS for 20 min at room temperature, washed with pbs+2% fbs, and further stained with pbs+2% fbs diluted with anti-BCMA PE-labeled antibody at 4 ℃ for 30 min. Samples were collected on a BD flow cytometer and analyzed using FlowJo software. Dead cells were removed from the assay by gating on ZombieNIR negative populations. BCMA MFI is plotted as a histogram.

The results are summarized in fig. 4A-4E and table 5 shows that GSI upregulates BCMA expression on the cell surface on each of mm.1s, OPM2, H929, molp8 and RPMI8226 cells in a time dependent manner and that upregulated surface BCMA expression does not persist after GSI removal from the culture.

TABLE 5 mean fluorescence intensity.+ -. Standard deviation

Example 5: in vitro study to detect soluble BCMA (sBCMA) levels in multiple myeloma cell lines treated with GSI

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

Multiple myeloma cells (mm.1 s, OPM2, H929, molp8, RPMI 8226) were seeded at 40,000 cells/well in 96-well U-bottom plates. Cells were incubated in the presence of RPMI medium (0.1% dmso) diluted with GSI for 24 hours. The following concentrations of GSI were tested: 1000nM, 500nM, 100nM, 50nM, 25nM, 10nM, 5nM, 2.5nM, 1nM, 0.1nM, 0.01nM. After 24 hours, the cell culture medium was collected and the concentration of sba in the supernatant was measured using human BCMA/TNFRSF17 DuoSet ELISA kit (R & D Systems) according to the manufacturer's instructions.

The results are summarized in fig. 5A-5E, and table 6 shows that GSI treatment blocked sBCMA shedding in multiple myeloma cell lines mm.1s, OPM2, H929, molp8, and RPMI8226, respectively.

TABLE 6 mean fluorescence intensity.+ -. Standard deviation

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

This example demonstrates that treatment with BCMAxCD3 bispecific antibody in combination with GSI shows enhanced cell killing in multiple myeloma cells cultured with human T cells as compared to BCMAxCD3 bispecific antibody alone.

Pair of cells from PBMC (Stem Cell Technologies) using EasyStep human T cell enrichment kit (Stem Cell Technologies)CD3 ⁺ T cells were negative selected. Multiple myeloma cells expressing luciferase (MM.1S-luc, OPM2-luc, H929-luc, molp8-luc, RPMI 8226-luc) were treated with 1. Mu.M GSI 10,000. After 24 hours, cells were incubated with 50,000 CD 3' s ⁺ pan T cells were seeded together in a clear 96-well V-bottom plate. Cells were further treated with a range of BCMAxCD3 bispecific antibody concentrations (with or without 1 μm GSI). The luciferase activity in the treated cells was analyzed 60 hours after treatment using a NeoLite kit (Perkin-Elmer) and was obtained on a victor x multi-mode plate reader (PerkinElmer). Cell viability was calculated by dividing the luciferase activity of the treated cells by the luciferase activity of the untreated control (no BCMAxCD3 bispecific antibody added).

The results are summarized in fig. 6A-6E and tables 7-8 show that treatment with GSI enhanced BCMAxCD3 bispecific antibody ("BCMAxCD 3" in tables 7 and 8) mediated cell killing in multiple myeloma cell lines (mm.1 s (21 x), OPM2 (21 x), H929, molp8, RPMI8226 (24 x), respectively) when cultured with human T cells.

TABLE 7 mean fluorescence intensity.+ -. Standard deviation

TABLE 8 mean fluorescence intensity.+ -. Standard deviation

Example 7: in vitro studies to detect cell surface BCMA expression in lymphoma cell lines treated with GSI

This example demonstrates the up-regulation of cell surface BCMA expression in lymphoma cells treated with GSI.

Lymphoma cells (Raji cell line) were seeded at 40,000 cells/well in 96-well U-bottom plates. Cells were incubated in the presence of RPMI medium (0.1% dmso) diluted with GSI for 24 hours. The following concentrations of GSI were tested: 1000nM, 500nM, 100nM, 50nM, 25nM, 10nM, 5nM, 2.5nM, 1nM, 0.1nM, 0.01nM. Cells were collected after 24 hours and washed with pbs+2% fbs followed by staining with ZombieNIR Viability fuel (Biolegend) at 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 labeled antibody (Biolegend) at 4 ℃ for 30 min. Cells were collected on a BD flow cytometer and analyzed using FlowJo flow cytometry analysis software. Dead cells were removed from the assay by gating on ZombieNIR negative populations. BCMA MFI was plotted against GSI concentration to confirm EC50.

The results are summarized in fig. 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 studies to detect cell surface BCMA expression in a time dependent manner in lymphoma cell lines treated with GSI

This example demonstrates 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 GSI removal from culture.

Lymphoma cells (Raji) were seeded at 800,000 cells/2 ml/well in 6-well plates with GSI diluted at 1 μm in RPMI medium (containing 0.1% dmso). Cells were collected to evaluate cell surface BCMA expression at baseline, then assessed 3 hours, 6 hours, and 24 hours after GSI addition. After 24 hours incubation with GSI, cells were washed twice in PBS and re-plated in fresh 6-well plates. Cells were further collected for staining 3 hours, 6 hours and 24 hours after washing GSI. At the indicated time points, samples were stained with ZombieNIR Viability dye (Biolegend) at 1/500 dilution in PBS for 20 min at room temperature, washed with pbs+2% fbs, and further stained with pbs+2% fbs diluted with anti-BCMA PE-labeled antibody at 4 ℃ for 30 min. Samples were collected on a BD flow cytometer and analyzed using FlowJo software. Dead cells were removed from the assay by gating on ZombieNIR negative populations. BCMA Mean Fluorescence Intensity (MFI) is plotted as a histogram.

The results are summarized in fig. 7B and table 10 shows that GSI upregulates cell surface BCMA expression on Raji cells in a time dependent manner and that upregulated surface BCMA expression does not persist after GSI removal from the culture.

TABLE 10 mean fluorescence intensity.+ -. Standard deviation

Example 9A BCMA CD3 bispecific antibodies combined with GSI in lymphoma cells

This example demonstrates that treatment with BCMAxCD 3-bispecific antibody in combination with GSI shows enhanced cell killing in low BCMA expressing lymphoma cells cultured with human T cells compared to BCMAxCD3 bispecific antibody alone.

CD3 from PBMC (Stem Cell Technologies) using the easyStep human T cell enrichment kit (Stem Cell Technologies) ⁺ T cells were negative selected. 10,000 target lymphoma cells expressing luciferase (Raji-luc) were treated with 1. Mu.M GSI. After 24 hours, cells were incubated with 50,000 CD 3' s ⁺ pan T cells were seeded together in a clear 96-well V-bottom plate. Cells were further treated with a range of BCMAxCD3 bispecific concentrations (with or without 1 μm GSI). The luciferase activity in the treated cells was analyzed 60 hours after treatment using a NeoLite kit (Perkin-Elmer) and was obtained on a victor x multi-mode plate reader (PerkinElmer). By introducing the treated cells Cell viability was calculated by dividing luciferase activity by that of untreated control (BCMAxCD 3 bispecific antibody not added).

The results are summarized in fig. 8 and table 11A shows that treatment with GSI enhanced BCMAxCD3 bispecific antibody mediated cell killing in lymphoma cell lines (Raji) when cultured with human T cells.

TABLE 11A cell viability.+ -. Standard deviation

Example 9B: gamma secretase inhibitor action increases in vitro cytotoxic effects of BCMAxCD3 bispecific antibody PF06863135 (elranatamab) on multiple myeloma cells in co-culture assays

This example demonstrates the combined benefit of treating multiple myeloma cells with GSI and BCMAxCD3 bispecific antibody PF06863135 (elranatamab) in an in vitro co-culture assay in Cytotoxic T Lymphocytes (CTLs) as compared to BCMAxCD3 antibody alone.

Multiple myeloma cell lines (H929-Luc, molp8-Luc, OPM2-Luc and RPMI 8226-Luc) expressing luciferase were subjected to a temperature of 37℃and 5% CO ₂ The cells were incubated with 1mM GSI for 24 hours or left untreated. Myeloma cells were then harvested and transferred to 96-well U-bottom plates at 10,000 cells/well and 50,000 cd3+ T cells/well, which were enriched from human PBMCs using a negative selection Pan T cell isolation kit (Miltenyi Biotec). At 37℃and 5% CO ₂ A series of dilutions of medium with or without 1mM GSI and BCMAxCD3 bispecific PF06863135 were further added to the wells before incubating the plates for 72 hours. 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 was calculated in the following mannerThe ratio is as follows: the luminescence signal value for each test well was divided by the average signal from the no antibody treatment control well and then multiplied by 100. EC was further calculated by four-parameter dose-response curve fitting of GraphPad Prism generated cell viability data with antibody dose concentration ₅₀ Values. Table 11B shows that treatment with GSI improved BCMAxCD3 antibody mediated killing of multiple myeloma cells (H929, molp8, OPM2 and RPMI 8226) treated in co-cultures with human T cells.

Table 11B. Killing of multiple myeloma cells mediated by the BCMA xCD3 bispecific antibody PF06863135

Example 10: first human phase 1 clinical study of BCMAxCD3 bispecific antibody elranatamab (PF-06863135).

This example illustrates a continuous phase 1 open-label multicenter clinical study of PF-06863135 (BCMAxCD 3 bispecific) as monotherapy and in combination with saran Li Shan antibody, lenalidomide or pomalidomide in adult patients with advanced multiple myeloma who have recurrent or refractory to standard therapy. The study was registered on a clinical tools. Gov, with the identifier NCT03269136, and was first released in 2017, month 8. The results of the study of trial part 1 and additional groups of the study are described in this example.

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

PF-06863135 first human clinical study treatment

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

In part 1 combination dose discovery, a fixed dose of PF06863135 is decided to be administered to a subject, wherein the maintenance dose is started one week after the pre-injection administration and the starting dose is one level below the single formulation RP2D and is stepped up to the RP2D dose or stepped down to the RP2D minus 2 level. Table 12A depicts potential fixed dose levels in a combination study of PF06863135 and a second therapeutic agent. For part 1C, the initial dose of lenalidomide was modified to 15QD orally on days 1-21 during the 28 day period starting 7 days after the pre-administration of PF 06863135.

Table 12A potential fixed dose levels for the combination study

Dosage level	Administration by pre-injection (mg)	Maintenance dose (mg)
			PR2D minus 2	24	32
RP2D minus 1	32	44
			RP2D dose	44	76

Part 1 of the study was a single formulation dose escalating arm of 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), the patient may be treated at a dose level selected from the aforementioned dose levels set forth in this paragraph, and below the MTD/MAD of Q2W administration (both IV and SC) to further support the recommended phase 2 dose (RP 2D) decision. For this study, the dose-limiting toxicity observation period was set to 21 days for Q1W administration and 28 days for Q2W administration. The treatment period (also referred to as cycle) for Q1W administration was 3 weeks, and Q2W administration was four weeks.

Clinical results of part 1 of the study. Up to 15 months 4 in 2020, a total of 23 patients participated in part 1 of the study and received treatment with PF-06863135 administered at 0.1 (n=2), 0.3 (n=3), 1 (n=4), 3 (n=5), 10 (n=6) μg/kg Intravenous (IV). By day 21 of 8 in 2020, a total of 30 patients participated in part 1 of the study and received treatment with PF-06863135 administered at 80 (n=6), 130 (n=4), 215 (n=4), 360 (n=4), 600 (n=6) and 1000 (n=6) μg/kg Subcutaneously (SC). Safety and efficacy data for 23 IV and 30 SC treated patients are available according to IMWG (international myeloma working group (International Myeloma Working Group)) standards.

Of the IV cohort patients, 2 patients (1 of 30 patients and 1 of 50 μg/kg cohort) experienced grade 3 febrile neutropenia and grade 1 electrocardiogram QT prolonged Dose Limiting Toxicity (DLT). No patient in the SC cohort experienced DLT. Cytokine Release Syndrome (CRS) is 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. Of all IV treated patients, 6 (26.1%) experienced a maximum grade 1 CRS, while 5 (21.7%) experienced a maximum grade 2 CRS. Each of the 11 CRS patients began to appear CRS within the first 2 days of dosing. Among 3 patients of 50 μg/kg, CRS also occurred in 1 patient after the second dose, 1 patient after the second and third doses, and 1 patient after the third and fourth doses.

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

TABLE 13 Cytokine Release Syndrome (CRS) in SC queues of sections 1 and 1.1 of the study

In the IV cohort, 2 patients obtained minimal responses at 3 μg/kg and 50 μg/kg IV, and 1 patient obtained complete responses at 50 μg/kg IV. Ten subjects in IV cohorts (0.3-50. Mu.g/kg) obtained the best response to disease stabilization.

In the SC cohort, the efficacy results are summarized in table 14 below.

TABLE 14 patient responses in SC cohorts for the study, part 1 and part 1.1

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

Part 1.1 of the study was an alternative maintenance dose escalation arm for the single formulation PF-06863135. If excessive toxicity occurs or a Maximum Tolerated Dose (MTD)/Maximum Administered Dose (MAD) dose level is reached that is earlier than expected in part 1 of the study described above, a pre-injection dose will be administered one week prior to day 1 of cycle 1, at which dose level the dose (maintenance dose) is administered, and for all subsequent dose levels in the dose escalation that part 1.1 may initiate. The pre-injection administration will be at a lower dose level than the maintenance dose.

Clinical results of section 1.1 of the study. By day 2 and 4 of 2021, a total of 20 patients participated in and were treated in part 1.1 of the study, with a 7 patient cohort receiving 600 μg/kg of priming followed by 1000 μg/kg of Q1W, and a 13 patient cohort receiving 600 μg/kg of priming followed by 1000 μg/kg of Q2W. The CRSs in these two queues are described in table 13. The introduction of the pre-injection administration reduced the mid-term duration of CRS by 50% from 4 days to 2 days. The frequency of dosing (Q1W v.q2w) in section 1.1 of the study had no effect on CRS. Patient responses for part 1.1 of the study are described in table 14.

Part 2A of the study was a single formulation PF-06863135 dose-extending arm. Based on single formulation dose escalation clinical data, part 2A of the study will select IV or SC administration, including priming and maintenance doses, as well as Q1W or Q2W administration. Specifically, SC were administered at dose levels of 215, 360, 600, or 1000 μg/kg at Q1W or Q2W, with no pre-injection administration, or at maintenance dose levels of 215, 360, 600, and 1000 μg/kg at Q1W and Q2W, with pre-injection administration administered on day 1 of the zeroth cycle having a dose level lower than the maintenance dose, hopefully RP2D for the phase 2A study.

Preliminary Pharmacokinetic (PK) analysis indicated that body weight was not a clinically relevant factor for PF-06863135 exposure. Thus, a fixed dose is suitable for administration of PF-06863135. Based on encouraging therapeutic and safety data obtained from the first part of the study, the promising RP2D of section 2A of the study may be a fixed dose equivalent of 1000 μg/kg (i.e., 76) of PF-06863135 in Q1W or Q2W. On day 1 of the zeroth cycle, a fixed dose equivalent of 600 μg/kg (i.e., 44) would likely be used as a priming dose. 44 is used as a pre-infusion administration and is designed to alleviate CRS symptoms of the latter 76 dose. According to the results of part 1 of the study, CRS occurred primarily after the initial dose. Subsequently, 44 (priming) and 76 (maintenance) were selected as single formulation RP2D doses. A single pre-infusion administration of 44SC of PF06863135 will be administered to the patient followed by a maintenance administration of 76Q1W SC or 76Q2W 7 days after the single pre-infusion administration.

Part 1B and part 2B of the study are combination therapies of PF-06863135 and Sashan Li Shan anti (PD-1 antibody). The treatment period was 28 days. Sartoriab will be administered at 300sc q4w starting on cycle 1 day 1. PF-06863135 will be administered at selected doses (Q1W or Q2W) SC or IV starting on day 1 of cycle 1, with or without priming one week prior to day 1 of cycle 1.

In section 1B, the dosage of PF-06863135 will be determined based on the results of sections 1 and 1.1 of the study, starting with RP2D as described in section 2A of the study above, or starting with MTD/MAD minus one level, whichever is lower. If the combination regimen is not well tolerated, PF-06863135 is degraded to lower dose levels to select the dose level of part 2B.

In section 2B, PF06863135 would be administered at a dosage level based on the results of section 1B.

Part 1C and part 2C of the study are combination therapies of PF-06863135 and lenalidomide. The treatment period was 28 days. Lenalidomide will be administered daily at 25 oral (PO) on days 1-21 starting on cycle 1, day 1, without dexamethasone. PF-06863135 will be administered at selected doses (Q1W or Q2W) SC or IV starting on day 1 of cycle 1, with or without priming one week prior to day 1 of cycle 1.

In section 1C, the dose of PF-06863135 will be determined based on the results of sections 1 and 1.1 of the study, and the initial schedule will begin with RP2D as described in section 2A of the study above, or with MTD/MAD, whichever is lower. If the combination regimen is not well tolerated, PF-06863135 is degraded to lower dose levels to select the dose level of part 2C. Subsequently, a decision was made to start with a dosage level of PF06863135 that was one level lower than the single formulation RP2D described in table 12A. The initial dose of lenalidomide was modified to 15QD oral days 1-21 during the 28 day period starting 7 days after the pre-administration of PF06863135.

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

Part 1D and part 2D of the study were combination therapies of PF06863135 and pomalidomide. The treatment period was 28 days. Pomalidomide will be administered daily at 4PO, without dexamethasone, starting on cycle 1, day 1, days 1-21. PF-06863135 will be administered at selected doses (Q1W or Q2W) SC or IV starting on day 1 of cycle 1, with or without priming one week prior to day 1 of cycle 1.

In section 1D, the dosage of PF-06863135 will be determined based on the results of sections 1 and 1.1 of the study, starting from RP2D as described in section 2A of the study above, or starting from MTD/MAD, whichever is lower. If the combination regimen is not well tolerated, PF06863135 is degraded to lower dose levels to select the dose level of the 2D part. Subsequently, a decision was made to start with a dosage level of PF06863135 that was one level lower than the single formulation RP2D described in table 12A.

In section 2D, PF-06863135 would be administered at a dosage level based on the results of section 1D.

The patient participated in the criteria. For all groups of studies described herein, patient participation criteria include that the patient must have progressed on or be intolerant to established therapies known to provide clinical benefit for multiple myeloma, including proteasome inhibitors, immunomodulatory imide drugs (imids), and anti-CD 38 mabs, if approved and available, in combination or in a single formulation, and that the patient must not be a candidate for a regimen known to provide clinical benefit in relapsed or refractory multiple myeloma based on the discretion of the researcher.

Primary and secondary objectives of this study included (1) assessing the primary clinical efficacy of PF-06863135RP2D, (2) further characterizing safety and tolerability, (3) assessing PK of PF-06863135 at RP2D, (4) assessing immunogenicity of PF-06863135, (5) characterizing the effect of PF-06863135 on systemic soluble immune factors, each of (1) to (5) being with respect to PF-06863135 as monotherapy and in combination with sara Li Shan antibody, lenalidomide or pomalidomide.

Example 11 phase 2 clinical study of bcmaxcd3 bispecific antibody PF-06863135 monotherapy in participants with multiple myeloma who are refractory to at least one proteasome inhibitor, one IMiD and one anti-CD 38 monoclonal antibody.

The study was an open-label multicenter non-randomized, phase 2 study to evaluate the efficacy and safety of PF-06863135 in refractory/relapsed multiple myeloma (RRMM) participants refractory to at least one Proteasome Inhibitor (PI), one IMiD, and one anti-CD 38 mAb. To determine the effect of previous BCMA-directed therapies on PF-06863135 monotherapy response, the study will recruit 2 independent and parallel cohorts, one cohort comprising participants who did not receive BCMA-directed therapies (cohort a; about 90 participants), and the other cohort comprising participants who received previous BCMA-directed ADC therapies or BCMA-directed CAR-T cell therapies, both of which had been approved or clinically studied (cohort B; about 60 participants). The primary goal of each independent queue was to determine the efficacy (i.e., ORR) of PF-06863135 as assessed by blind independent central reading (blinded independent central review, BICR), as defined by the International Myeloma Working Group (IMWG). The design of this study is shown in table 15 below.

Table 15 study treatment of phase 2 clinical study of bcmaxcd3 bispecific antibody PF-06863135 monotherapy

Administration: an initial dose of 44 of PF-06863135 will be administered to the participants in each cohort by subcutaneous injection (SC) on cycle 1, day 1 (C1D 1). Each treatment cycle was 28 days. 44 is used as a pre-injection administration and is intended to alleviate CRS symptoms, which are primarily intended after an initial dose. The pre-infusion administration was then modified to 12PF06863135 for administration at C1D1, followed by 32PF06863135 for administration at C1D 4. Starting on cycle 1, day 8, the dose of PF-06863135 should be increased to 76SC Q1W, as long as the participants meet all three criteria:

(1)ANC≥1.0×10 ⁹ /L；

(2) Platelet count is greater than or equal to 25X 10 ⁹ L; and

(3) Treatment-related non-hematologic toxicity returns to baseline or grade-1 severity (or grade-2 if the participants are not considered to be at safety risk) at the discretion of the investigator.

If the participants did not meet these criteria on cycle 1, day 8, the initial dosing of 76 should be deferred until these criteria are met. If participants received at least 6 cycles of Q1W dosing and a PR or better IMWG response was obtained and the response lasted at least 2 months, the dose interval should be changed from Q1W to Q2W, as lower dose intensities may be sufficient to maintain the response given the reduced disease burden of these participants. However, based on the medical judgment of the researcher, and after negotiating with the trial sponsor, the subject may continue to participate in the Q1W program. After changing to the Q2W interval, the dosing interval may be restored to Q1W at the discretion of the researcher.

For each of the study cohorts, treatment with PF-06863135 continued until disease progression, patient refusal (withdrawal of consent), or unacceptable toxicity occurred. The study will be completed when all participants discontinued study intervention and a total survival (OS) was followed for at least 2 years.

The main end point is: determination of total response Rate (ORR) by Blind Independent Center Read (BICR) according to International Myeloma Working Group (IMWG)

Secondary endpoint: (1) BICR and duration of response (DOR) derived by researchers from IMWG; (2) BICR and the Cumulative Complete Response Rate (CCRR) by researchers based on IMWG; (3) ORR derived by the investigator from IMWG; (4) BICR and cumulative complete response duration (docr) by researchers based on IMWG; (5) BICR and researchers derived Progression Free Survival (PFS) from IMWG; (6) total survival (OS); (7) BICR and Time To Response (TTR) derived by researchers based on IMWG; (8) Minimum Residual Disease (MRD) negative rate according to IMWG (central laboratory); (9) AE and laboratory abnormalities as graded by NCI common term standard of adverse events (CTCAE) v 5.0; (10) CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were evaluated for severity according to American society for transplantation and cell therapy (American Society for Transplantation and Cellular Therapy, ASCTT) standards. (11) Front and rear dose concentrations of PF-06863135, and (12) ADA and NAb for PF-06863135

Example 12A two-step ascending pre-injection dosing and longer dosing interval open-label multicenter study to evaluate elranatamab (PF-06863135) monotherapy in relapsed/refractory multiple myeloma participants

The purpose of this study was to evaluate the ratio of CRS grade 2 or higher when elranatamab was administered on a dosing regimen of 2 ascending pre-infusion dosing and precursor dosing. Furthermore, the study will evaluate the safety, tolerability, PK and primary anti-myeloma activity of elranatamab at doses above 76 at different dosing intervals (QW, Q2W and Q4W) in relapsed/refractory multiple myeloma (RRMM) participants. The 76QW full dose regimen of elranatamab for 6 cycles followed by Q2W (part 2) will also be evaluated. Period 1 begins on the day of administration of the first priming dose to the participants.

All doses of elranatamab were administered Subcutaneously (SC).

In the first cycle (C1) of elranatamab treatment, all participants for this study were evaluated for the following protocol:

C1D1: precursor administration +elranatamab12; C1D4: precursor administration +elranatamab32; C1D8: precursor administration +elranatamab76; C1D15 and C1D22: elranatamab76.

Precursor administration is required approximately 60 minutes prior to both the pre-infusion administration (C1D 1 and C1D 4) of elranatamab (C1D 8) and the first full dose. The precursor drug delivery to be used is: acetaminophen 650 (or paracetamol) 500, diphenhydramine 25 (oral or IV) and dexamethasone 20 (or equivalent) (oral or IV).

At and after cycle 2, the following will be evaluated:

part 1A in the dose level 1 cohort, will administer 116Q2W to participants in C2 to C6, optionally switching to 116Q4W for participants with PR or better IMWG responses for at least 2 cycles on Q2W. If dose level 1 is tolerable, in the dose level 2 cohort, 152Q2W will be administered to participants in C2 to C6, optionally transitioning to 152Q4W for participants with PR or better IMWG responses for at least 2 cycles on Q2W. For both dose level 1 and dose level 2, if after switching to the Q4W interval the participant subsequently begins to develop an increased disease burden but has not yet reached the level of PD according to the IMWG standard, the dosing interval should revert to Q2W (e.g., from 152Q4W to 152Q 2W) at the same dose level.

Once the potential MTD/RP2D is identified from section 1A, section 1B will begin and will become a dose expansion queue for the selected dose level.

Section 1C will only start if both dose level 1 and dose level 2 in section 1A are tolerated. Here, within C2 to C3, 116Q1W or 152Q1W will be administered to the participant. Within C4 to C6, 116 or 152Q2W will be administered for participants with PR or better IMWG responses at C2 and C3. At C7 and beyond, 116 or 152Q4W will be administered to participants with PR or better IMWG responses for at least 2 cycles on Q2W.

Part 2: 76Q1W will be applied from C2 to C6. For participants with PR or better IMWG responses for at least 2 cycles on Q1W, 76Q2W will be administered at C7 and later. If after switching to the Q2W interval the participant subsequently begins to develop an increased disease burden but has not yet reached the level of PD according to the IMWG standard, the dose interval should revert to Q1W at 76.

Example 13 an open label multicenter random phase 3 study to evaluate efficacy and safety of elranatamab (PF 06863135) and darlingumab in relapsed/refractory multiple myeloma (RRMM) participants

The objective of part 1 of this study was to evaluate DLT, safety and tolerability of elranatamab plus rammumab to select RP3D for combination therapy. The purpose of section 2 was to compare the efficacy of elranatamab (arm a) and elranatamab plus darlingmumab (arm B), each control: the combination therapy was darimumab plus pomalidomide plus dexamethasone (C-arm). The objective of part 1 of the study also included evaluating the ratio of CRS grade 2 and above when elranatamab alone or in combination was administered with 2 ascending pre-infusion and precursor administration. The study treatments are described in table 16. Each cycle was 28 days.

Table 16.Elranatamab and darimumab combination study treatment

elranatamab administration: in part 1, the dose level is reduced by 1, after the participant has been at 44QW until the end of cycle 6, for participants with PR or better IMWG responses for at least 2 cycles, 44Q2W should be administered thereafter. Similarly, in part 1 dose level 1, 76QW is converted to part 1 of 76Q2W, and similarly QW is converted to Q2W in part 2 a and B arms. Subsequently, if an increased disease burden is observed (the level of PD according to IMWG standard is not reached), the dosing interval should be restored to QW.

Darifenacin administration: the 1800, Q1W, then Q2W, then Q4W was subcutaneously injected according to the USPI dosing schedule for the FDA approved darimumab and hyaluronidase fihj products.

Precursor administration is required approximately 60 minutes prior to both the pre-infusion administration (C1D 1 and C4D 1) of elranatamab (C1D 8) and the first full dose. In addition to part 2C-arm, a precursor administration is also required 1-3 hours prior to each dose of darimumab, wherein the dexamethasone component of the treatment regimen should be administered prior to darimumab and used as a precursor administration. If elranatamab and darunamumab were to be administered on the same day, then only one precursor administration should be given on the day prior to administration of elranatamab and darunamumab. The precursor drug delivery to be used is: acetaminophen 650-1000 (OR paracetamol 500), diphenhydramine 25-50 (oral OR IV) OR dexamethasone 20 (OR equivalent) (oral OR IV).

EXAMPLE 14 random 2-arm 3 study in New Diagnosed Multiple Myeloma (NDMM) patients with Minimal Residual Disease (MRD) positivity after undergoing Autologous Stem Cell Transplantation (ASCT) with one elranatamab (PF-06863135) plus lenalidomide

The objectives of this study included comparing the efficacy of elranatamab plus lenalidomide combination therapy (arm a) with lenalidomide (arm B) and determining the safety and tolerability of elranatamab plus lenalidomide combination therapy. The participants in this study will be the lowest residual disease (MRD) positive newly diagnosed multiple myeloma participants after receiving autologous stem cell transplantation. Table 16 below describes the planned dosing regimen for each arm in the study.

Table 16 combination therapy of elanatamamab (elanatamamab) plus lenalidomide for MRD positive NDMM patients after ASCT study treatment

Precursor administration is required approximately 60 minutes prior to both the pre-infusion administration (C1D 1 and C1D 4) of elranatamab (C1D 8) and the first full dose. The precursor drug delivery to be used is: acetaminophen 650 (or paracetamol 500), diphenhydramine 25 (oral or IV) and dexamethasone 20 (or equivalent) (oral or IV).

EXAMPLE 15 random controlled 2-arm phase 3 study of one elranatamab (PF 06863135) and lenalidomide control in New Diagnosed Multiple Myeloma (NDMM) patients unsuitable for Stem cell transplantation (ASCT)

The objectives of this study included comparing the efficacy of elranatamab plus lenalidomide combination therapy (arm a) with the lenalidomide control arm, and determining the safety and tolerability of elranatamab. The participants in this study will be newly diagnosed multiple myeloma participants who are not suitable for stem cell transplantation. Table 17 below describes the planned dosing regimen for each arm in the study.

TABLE 17 combination therapy of elranatamab and lenalidomide for NDMM patients unsuitable for treatment in stem cell transplantation studies

EXAMPLE 16 open tag umbrella study of elranatamab (PF 06863135) in combination with other anti-cancer treatments in relapsed/refractory multiple myeloma (RRMM) participants

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

Table 18 combination therapy of elranatamab and other anti-cancer therapies for the study treatment of relapsed/refractory multiple myeloma (RRMM)

Sequence(s)

Table 19 lists the sequences of the BCMA CD3 bispecific antibody PF-06863135 and the PD-1 antibody Sashanlizumab, as well as the corresponding SEQ ID NOs as referred to herein. SEQ ID NOs 1 to 13 are the sequence of the CD3 arm of PF-06863135 and SEQ ID NOs 14 to 26 are the sequence of the BCMA arm of PF-06863135. SEQ ID NO 27 through 34 are the sequences of the PD-1 antibody, sashanlizumab.

Table 19PF-06863135 and Sashanlizumab sequences

Claims

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 immunomodulatory agent, or a Gamma Secretase Inhibitor (GSI).

2. The method or medicament of claim 1, wherein the BCMA bispecific therapeutic agent is PF-06863135, the anti-PD-1 antibody is sartorimab, the immunomodulatory agent is lenalidomide or pomalidomide, and/or the GSI is nirogachitat 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) About 16 to 80mg Q1 wsc or Q2 wsc;

(d) About 16 to 20, 40 to 44, or 76 to 80mg q1 wsc;

(e) About 16 to 20, 40 to 44, or 76 to 80mg q2 wsc;

(f) About 40mg Q1WSC or Q2 WSC;

(g) About 44mg Q1WSC or Q2 WSC;

(h) About 76mg Q1WSC or Q2 WSC;

(i) About 80mg of Q1WSC or Q2 WSC;

(j) About 44mg of the Q1W SC is administered for 1-4 weeks, or about 32mg of the Q1W SC is administered for 1-4 weeks, followed by about 76mg of the Q1W SC or the first therapeutic administration of the Q2W SC;

(k) About 40mg of Q1WSC is administered for 1-4 weeks followed by about 80mg of Q1WSC or Q2 WSC for the first therapeutic administration;

(l) About 44mg of the Q1W SC is administered for 1-4 weeks, or about 32mg of the Q1W SC is administered for 1-4 weeks, followed by about 76mg of the Q1W SC for 2-20, 21, 22, 23, 24, 25-46, 47, or 48 weeks of the first treatment, followed by about 76mg of the Q2W SC for the second treatment;

(m) about 40mg of q1w SC is administered for 1-4 weeks followed by about 80mg of q1w SC for a first therapeutic administration for 2 to 20, 21, 22, 23, 24, 25 to 46, 47 or 48 weeks followed by about 80mg of q2w SC for a second therapeutic administration;

(n) about 44mg of Q1W SC is administered for 1 week followed by about 76mg of Q1W SC or Q2W SC for the first therapeutic administration;

(o) about 32mg of Q1W SC is administered for 1 week followed by about 76mg of Q1W SC or Q2W SC for the first therapeutic administration;

(p) a pre-infusion administration of about 40mg Q1W SC for 1 week followed by a first therapeutic administration of about 80mg Q1W SC or Q2W SC;

(q) about 44mg of q1w SC administered for 1 week followed by about 76mg of q1w SC administered for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks followed by about 76mg of q2w SC administered for a second treatment;

(r) about 44mg of q1w SC administered for 1 week followed by about 76mg of q1w SC administered for 23 weeks for a first treatment followed by about 76mg of q2w SC administered for a second treatment;

(s) about 44mg of Q1W SC was administered for 1 week with a pre-infusion followed by about 76mg of Q1W SC for 24 weeks with a first treatment followed by about 76mg of Q2W for a second treatment

(t) about 32mg of q1w SC for 1 week followed by about 76mg of q1w SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks of first therapeutic administration followed by about 76mg of q2w SC for a second therapeutic administration;

(u) about 40mg of q1w SC for 1 week followed by about 80mg of q1w SC for 2 to 20, 21, 22, 23, 24, 25 to 46, 47, or 48 weeks of first therapeutic administration followed by about 80mg of q2w SC for a second therapeutic administration; or (b)

(v) About 40mg of Q1W SC was administered for 1 week followed by about 80mg of Q1W for 23 or 24 weeks of the first treatment followed by about 80mg of Q2W SC for the second treatment.

4. The method of claim 3, wherein PF06863135 is administered to the subject at the first therapeutic dose of about 76mg q1w SC and, after receiving such first therapeutic dose for at least 23 weeks, PF06863135 is administered to the subject at the second therapeutic dose of 76mg q2w or PF06863135 is continued to be administered to the subject at the first therapeutic dose.

5. A method of treating cancer in a subject comprising administering subcutaneously to the subject a first therapeutic administration of PF-06863135 for 23, 24, or 25 weeks followed by a second therapeutic administration, wherein

(a) The first therapeutic administration is about 4mg q1w and the second therapeutic administration is about 4mg q2w;

(b) The first therapeutic administration is about 12mg q1w and the second therapeutic administration is about 12mg q2w;

(c) The first therapeutic administration is about 24mg q1w and the second therapeutic administration is about 24mg q2w;

(d) The first therapeutic administration is about 32mg q1w and the second therapeutic administration is about 32mg q2w;

(e) The first therapeutic administration is about 44mg q1w and the second therapeutic administration is about 44mg q2w; or (b)

(f) The first therapeutic dose is about 76mg q1w and the second therapeutic dose is about 76mg q2w.

6. The method of claim 5, wherein if the amount of administration of the first therapeutic administration is 32mg or more, the method further comprises administering PF06863135 to the subject as a pre-infusion administration and administering the pre-infusion administration for one week, the first dose in the first therapeutic administration being administered within one week immediately after the one week of administering the pre-infusion administration, and wherein

(1) The pre-infusion administration is a single pre-infusion administration, and the single pre-infusion administration is about 24mg;

(2) The pre-administration comprises a first pre-administration of about 4mg and a second pre-administration of about 20mg, and the two pre-administration are administered at two different days and the first pre-administration is administered before the second pre-administration;

(3) The pre-administration comprises a first pre-administration of about 8mg and a second pre-administration of about 16mg, and the two pre-administration are administered at two different days and the first pre-administration is administered before the second pre-administration;

(4) The pre-administration comprises a first pre-administration of about 12mg and a second pre-administration of about 12mg, and the two pre-administration are administered at two different days and the first pre-administration is administered before the second pre-administration;

(5) The pre-administration comprises a first pre-administration of about 8mg and a second pre-administration of about 24mg, and the two pre-administration are administered at two different days and the first pre-administration is administered before the second pre-administration; or (b)

(6) The pre-administration comprises a first pre-administration of about 4mg and a second pre-administration of about 28mg, and the two pre-administration are administered at two different days and the first pre-administration is administered before the second pre-administration.

7. A method of treating cancer in a subject comprising administering PF-06863135 to the subject

(a) The first therapeutic administration of about 32mg to about 76mg of q1w SC begins at week 1; or (b)

(b) A pre-infusion administration during week 1 and a first therapeutic administration beginning at week 2, wherein the pre-infusion administration is (i) a first pre-infusion administration of about 4mg SC to about 32mg SC and a second pre-infusion administration of about 12mg SC to about 44mg SC, wherein the first pre-infusion administration and the second pre-infusion administration are administered sequentially at week 1, or (ii) a single pre-infusion administration of about 24mg to about 44mg SC, and wherein the first therapeutic administration is about 32mg to about 76mg Q1W SC or about 32mg to about 152mg Q2W SC, beginning at week 2, and wherein the administration of the first therapeutic administration is higher than the administration of each of the respective single pre-infusion administration, first pre-infusion administration, and second pre-infusion administration;

8. The method of claim 7, wherein a pre-infusion administration is administered to the subject, wherein the pre-infusion administration is a single pre-infusion administration of about 24mg SC, about 32mg SC, or about 44mg SC at week 1, or a pre-infusion administration is (i) a first pre-infusion administration of about 12mg SC and a second pre-infusion administration of about 32mg SC; (ii) About 4mg SC for a first pre-infusion administration and about 20mg for a second pre-infusion administration; (iii) About 8mg of the first pre-infusion administration and about 16mg of the second pre-infusion administration; (iv) About 12mg of the first pre-infusion administration and about 12mg of the second pre-infusion administration; or (v) about 8mg of the first pre-infusion and about 24mg of the second pre-infusion.

9. The method of claim 7 or 8, wherein the first therapeutic administration is about 32mg q1w SC or about 32mg q2w SC, about 44mg q1w SC or about 44mg q2w SC.

10. The method of claim 9, wherein the first therapeutic administration is administered to the subject until at least cycle 1 ends or until at least cycle 6 ends, wherein cycle 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 are the first cycle, second cycle, and subsequent cycles, respectively, when PF06863135 is administered to the subject.

11. The method of claim 10, further comprising administering PF06863135 to the subject after the subject is no longer in the first therapeutic administration with a second therapeutic administration of about 32mg to about 152mg q2w SC, about 32mg to about 152mg q3w SC, or about 32mg to about 152mg q4w SC, wherein the second therapeutic administration is administered less frequently than the corresponding first therapeutic administration, or the second therapeutic administration is administered less frequently than the first therapeutic administration.

12. The method of claim 10, wherein a second therapeutic administration of PF06863135 is administered to the subject in place of the first therapeutic administration or the administration of the first therapeutic administration to the subject may continue after the administration of the first therapeutic administration to the subject until at least the end of cycle 6, and wherein the second therapeutic administration is about 32mg to about 152mg q2w SC, about 32mg to about 152mg q3w SC, or about 32mg to about 152mg q4w SC, wherein the frequency of administration of the second therapeutic administration is less than the frequency of administration of the first therapeutic administration, or the amount of administration of the second therapeutic administration is less than the amount of administration of the first therapeutic administration.

13. The method of claim 7 or 8, wherein the first therapeutic administration is (i) about 76mg q1wsc, (ii) about 76mg q2 wsc, or (iii) about 76mg q1wsc for three weeks, followed by about 116mg q1wsc, or (iv) about 76mg q1wsc for three weeks, followed by about 152mg q1 wsc.

14. The method of claim 13, wherein the first treatment is administered to the subject until at least cycle 1 ends, at least cycle 3 ends, or at least cycle 6 ends, wherein cycle 21 or 28 days, and 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 are the first cycle, second cycle, and subsequent cycles, respectively, when PF06863135 is administered to the subject.

15. The method of claim 14, further comprising administering PF06863135 to the subject after the subject is no longer in the first therapeutic administration with a second therapeutic administration of about 44mg to about 152mg q2w SC, about 44mg to about 152mg q3w SC, or about 44mg to about 152mg q4w SC, wherein the second therapeutic administration is administered less frequently than the first therapeutic administration, or the second therapeutic administration is administered less frequently than the first therapeutic administration.

16. The method of claim 14, wherein a second therapeutic administration of about 44mg to about 152mg q2w SC, about 44mg to about 152mg q3wsc, or about 44mg to about 152mg q4w SC is administered to the subject in place of the first therapeutic administration after the first therapeutic administration is administered to the subject until at least the end of cycle 6, or the administration of the first therapeutic administration to the subject may be continued, wherein the frequency of administration of the second therapeutic administration is less than the frequency of administration of the corresponding first therapeutic administration, or the amount of administration of the second therapeutic administration is less than the amount of administration of the first therapeutic administration.

17. The method of claim 15 or 16, wherein the first therapeutic administration is about 76mg q1w SC and the second therapeutic administration is about 44mg q2w SC, about 76mg q2w SC, about 116mg q2w SC, about 152mg q2w SC, about 44mg q3w SC, about 76mg q3w SC, about 116mg q3w SC, about 152mg q3w SC, about 44mg q4w SC, about 76mg q4w SC, about 116mg q4w SC, or about 152mg q4w SC.

18. The method of any one of claims 15 or 16, wherein the first therapeutic administration is about 76mg q2w SC and the second therapeutic administration is about 204 mg q2w SC, about 44mg q3w SC, about 76mg q3w SC, about 116mg q3w SC, about 152mg q3w SC, about 44mg q4w SC, about 76mg q4w SC, about 116mg q4wsc, or about 152mg q4w SC.

19. The method of any one of claims 7 to 18, wherein PF06863135 is administered to the subject in the first therapeutic administration until the end of cycle 1, followed by the second therapeutic administration, wherein cycle 1 starts on day 1 of week 1 or day 1 of week 2 or day 1 of week 3, and cycle 1, cycle 2, and subsequent cycles are the first, second, and subsequent cycles, respectively, when PF06863135 is administered to the subject.

20. The method of claim 19, wherein the second therapeutic administration is administered until at least the end of cycle 6, and thereafter a third therapeutic administration of about 76mg to about 152mg q3w SC or about 76mg to about 152mg q4w SC is administered to the subject in place of the second therapeutic administration, or the administration of the second therapeutic administration to the subject is continued.

21. The method of claim 20, wherein the second therapeutic administration is administered until the end of cycle 6, the first dose in the third therapeutic administration begins at cycle 7, and the third therapeutic administration is 116mg q4 wsc or 152mg q4 wsc.

22. The method of claim 20 or 21, wherein the first therapeutic administration is about 76mg q1w SC, the second therapeutic administration is about 116mg q2w SC, and the third therapeutic administration is about 116mg q4w SC.

23. The method of claim 20 or 21, wherein the first therapeutic administration is about 76mg q1w SC, the second therapeutic administration is about 152mg q2w SC, and the third therapeutic administration is about 152mg q4w SC.

24. A method of treating cancer comprising administering elranatamab (PF 06863135) to a subject according to a dosing schedule as shown below, and wherein the dosing schedule is described by a number of weeks, an amount of dosing, and a dosing frequency corresponding to each number of weeks:

(a)

(b)

(c)

(d)

(e)

number of weeks Dosage (mg) Frequency of administration 1 44;32;12 and 32; or A and B; weekly by week 2-25 32;44;76;116 or 152 Every two weeks 26 later 32;44;76;116 or 152 Every two weeks; every three weeks; or every four weeks

Or (f)

Number of weeks Dosage (mg) Frequency of administration 1 44;32;12 and 32; or A and B; weekly by week 2-26 32;44;76;116 or 152 Every two weeks 27 later 32;44;76;116 or 152 Every two weeks; every three weeks; or every four weeks

Wherein when the dose is 12mg plus 32mg during week 1, a dose of 12mg is administered on one day followed by a dose of 32mg 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 dose is Amg plus bmmg during week 1, a dose of Amg is administered on one day followed by a dose of bmmg on another day.

25. The method of claim 24, wherein elranatamab (PF 06863135) is administered to the subject according to a dosing schedule as shown below,

(a)

number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-24 76 Weekly by week After 25 times 76 Weekly; every two weeks; every three weeks; or every four weeks

(b)

Number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-25 76 Weekly by week 26 later 76 Weekly; every two weeks; every three weeks; or every four weeks

(c)

Number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-26 76 Weekly by week 27 later 76 Weekly; every two weeks; every three weeks; or every four weeks

(d)

Number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-24 76 Every two weeks After 25 times 76 Every two weeks; every three weeks; or every four weeks

(e)

Number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-25 76 Every two weeks 26 later 76 Every two weeks; every three weeks; or every four weeks

Or (f)

Number of weeks Dosage (mg) Frequency of administration 1 44 Weekly by week 2-26 76 Every two weeks 27 later 76 Every two weeks; every three weeks; or every four weeks

。

26. The method of claim 25, wherein PF06863135 is administered to the subject according to dosing schedules (a), (b) or (c), and the dosing frequency after week 25, after week 26 and after week 27 in dosing schedules (a), (b) and (c) is (i) weekly, (ii) biweekly, or (iii) weekly or biweekly, respectively.

27. The method of claim 24, wherein elranatamab (PF 06863135) is administered to the subject according to a dosing schedule as shown below,

(a)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-24 76 Weekly by week After 25 times 76 Weekly; every two weeks; every three weeks; or every four weeks

(b)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-25 76 Weekly by week 26 later 76 Weekly; every two weeks; every three weeks; or every four weeks

(c)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-26 76 Weekly by week 27 later 76 Weekly; every two weeks; every three weeks; or every four weeks

(d)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-24 76 Every two weeks After 25 times 76 Every two weeks; every three weeks; or every four weeks

(e)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-25 76 Every two weeks 26 later 76 Every two weeks; every three weeks; or every four weeks

Or (f)

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-26 76 Every two weeks 27 later 76 Every two weeks; every three weeks; or every four weeks

。

28. The method of claim 27, wherein PF06863135 is administered to the subject according to dosing schedules (a), (b) or (c), and the dosing frequency after week 25, after week 26 and after week 27 in dosing schedules (a), (b) and (c) is (i) weekly, (ii) biweekly, or (iii) weekly or biweekly, respectively.

29. The method of claim 24, wherein elranatamab (PF 06863135) is administered to the subject according to a dosing schedule as shown below,

(a)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-24 44 Weekly by week After 25 times 44 Weekly; every two weeks; every three weeks; or every four weeks

(b)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-25 44 Weekly by week 26 later 44 Weekly; every two weeks; every three weeks; or every four weeks

(c)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-26 44 Weekly by week 27 later 44 Weekly; every two weeks; every three weeks; or every four weeks

(d)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-24 44 Every two weeks After 25 times 44 Every two weeks; every three weeks; or every four weeks

(e)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-25 44 Every two weeks 26 later 44 Every two weeks; every three weeks; or every four weeks

Or (f)

Number of weeks Dosage (mg) Frequency of administration 1 32; or 12 plus 32 Weekly by week 2-26 44 Every two weeks 27 later 44 Every two weeks; every three weeks; or every four weeks

。

30. The method of claim 29, wherein PF06863135 is administered to the subject according to dosing schedules (a), (b) or (c), and the dosing frequency after week 25, after week 26 and after week 27 of dosing schedules (a), (b) and (c) is (i) weekly, (ii) biweekly, or (iii) weekly or biweekly, respectively.

31. The method of any one of claims 24 to 30, wherein the amount administered during week 1 and the frequency of administration together are referred to as a pre-infusion administration, and if only one dose of elranatamab is administered to the subject in a pre-infusion administration, such one dose is referred to as a single pre-infusion administration, and if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are referred to as a first pre-infusion administration and a second pre-infusion administration, respectively; the amounts and frequencies of administration during weeks 2-24, weeks 2-25 and weeks 2-26 of each of the administration schedules (a) and (d), (b) and (e) and (c) and (f), respectively, are collectively referred to as first treatment administration in each of the administration schedules, and the amounts and frequencies of administration during weeks 25 and thereafter, after week 26 and after week 27 of each of the administration schedules (a) and (d), (b) and (e) and (c) and (f), respectively, are collectively referred to as second treatment administration in each of the administration schedules.

32. The method of claim 31, wherein PF06863135 6 to 18 cycles of the second therapeutic administration are administered to the subject, after which a third therapeutic administration of PF06863135 is administered subcutaneously to the subject, wherein the third therapeutic administration is 32mg q2w, 32mg q4w, 44mg q2w, 44mg q4w, 76mg q2w, 76mg q4w, 116mg Q2W,116mg Q4W,152mg Q2W, or 152mg q4w, wherein cycles are 21 days or 28 days, cycle 1 beginning at week 1, week 2, day 1, or week 3, day 1.

33. The method of claim 32, wherein (i) the first therapeutic administration is 32mg Q1W, the second therapeutic administration is 32mg Q1W or 32mg Q2W, and the third therapeutic administration is 32mg Q2W or 32mg Q4W, (ii) the first therapeutic administration is 32mg Q1W, the second therapeutic administration is 32mg Q2W, and the third therapeutic administration is 32mg Q4W, (iii) the first therapeutic administration is 44mg Q1W, the second therapeutic administration is 44mg Q1W or 44mg Q2W, and the third therapeutic administration is 44mg Q2W or 44mg Q4W; (iv) The first therapeutic administration is 44mg q1w, the second therapeutic administration is 44mg q2w, and the third therapeutic administration is 44mg q4w; (v) The first therapeutic administration is 76mg of q1w, the second therapeutic administration is 76mg of q1w or 76mg of q2w, and the third therapeutic administration is 76mg of q2w or 76mg of q4w, (vi) the first therapeutic administration is 76mg of q1w, the second therapeutic administration is 76mg of q2w, and the third therapeutic administration is 76mg of q4w, (vii) the first therapeutic administration is 116mg of q1w, the second therapeutic administration is 116mg of q2w, and the third therapeutic administration is 116mg of q2w or 116mg of q4w; (viii) The first therapeutic administration is 116mg Q2W, the second therapeutic administration is 116mg Q2W, and the third therapeutic administration is 116mg Q4W, (ix) the first therapeutic administration is 152mg Q1W, the second therapeutic administration is 152mg Q1W or 152mg Q2W, and the third therapeutic administration is 152mg Q2W or 152mg Q4W, or (x) the first therapeutic administration is 152mg Q1W, the second therapeutic administration is 152Q2W, and the third therapeutic administration is 152mg Q4W.

34. A method of treating cancer comprising administering elranatamab (PF 06863135) to a subject according to a dosing schedule as shown below, and wherein the dosing schedule is described by a number of weeks, an amount of dosing, and a dosing frequency corresponding to each number of weeks:

Wherein when the dose is 12mg plus 32mg during week 1, a dose of 12mg is administered on one day followed by a dose of 32mg 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 dose of Amg is administered on one day followed by a dose of Bmg 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 dose and frequency of administration during week 1 are together referred to as a pre-infusion administration, and if only one dose of elranatamab is administered to the subject in a pre-infusion administration, such one dose is referred to as a single pre-infusion administration, if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are respectively referred to as a first pre-infusion administration and a second pre-infusion administration, the dose and frequency of administration during weeks 2-4 are together referred to as a first therapeutic administration, the dose and frequency of administration during weeks 5-24 are together referred to as a second therapeutic administration, and the dose and frequency of administration during weeks 25 and thereafter are together referred to as a third therapeutic administration.

38. A method of treating cancer comprising administering elranatamab (PF 06863135) to a subject according to a dosing schedule as shown below, and wherein the dosing schedule is described by a number of weeks, an amount of dosing, and a dosing frequency corresponding to each number of weeks:

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

Number of weeks Dosage (mg) Frequency of administration 1 12 and 32 Weekly by week 2-4 76 Weekly by week 2-12 152 Weekly by week 13-24 152 Weekly or biweekly After 25 times 152 Every two weeks; or every four weeks

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 dose amount during week 1 and the dosing frequency are together referred to as a pre-dose, and if only one dose of elranatamab is administered to the subject in a pre-dose, such one dose is referred to as a single pre-dose, if two doses of elranatamab are sequentially administered to the subject during week 1, the two doses are referred to as a first pre-dose and a second pre-dose, respectively, the dose amount during weeks 2-4 and the dosing frequency during weeks 5-12 are both together referred to as a first therapeutic dose, the dose amount during weeks 13-24 and the dosing frequency are together referred to as a second therapeutic dose, and the dosing amount during weeks 25 and the dosing frequency are together referred to as a third therapeutic dose.

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 to said subject sarlizumab.

46. The method of any one of claims 3 to 44, further comprising administering lenalidomide to the subject.

47. The method of any one of claims 3 to 44, further comprising administering darimumab to the subject.

48. The method of any one of claims 3 to 44, further comprising administering isatuximab to the subject.

49. The method of any one of claims 3 to 44, further comprising administering to the subject at least one dose of a precursor dose on the day of a single pre-injection administration, a first pre-injection administration, a second pre-injection administration, or a first dose of a first therapeutic administration of PF06863135 to the subject, wherein the precursor dose 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 radiation therapy to the subject.