Combination therapy of CD47 blockers and anti-BCMA / anti-CD3 bispecific antibodies

Abstract

The present invention provides regimens and methods for administering a combination therapy in combination with a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody. The regimens and methods may further comprise additional therapeutic agents.

Description

Background Art

[0001] Cancer cells are targeted for destruction by antibodies that bind to cancer cell antigens, and this is achieved by recruiting and activating macrophages in a manner in which the Fc receptor binds to the Fc portion of the antibody. The binding between CD47 on cancer cells and SIRPα on macrophages transmits a "don't eat me" signal, which enables many tumor cells to escape macrophage destruction. It has been demonstrated that inhibiting the CD47 / SIRPα interaction (CD47 blockade) will allow macrophages to "see" and destroy target CD47 + cancer cells. The use of SIRPα for treating cancer by CD47 blockade is described in WO 2010 / 130053 (incorporated herein by reference). International Patent Application Publication No. WO 2014 / 094122 (incorporated herein in its entirety by reference) describes a protein drug that inhibits the interaction between CD47 and SIRPα. This CD47-blocking drug is in the form of a specific region of human SIRPα that incorporates its extracellular domain, which is linked to a particularly useful form of the IgG-based Fc region. In this form, the SIRPαFc drug pair exhibits a significant effect on the viability of cancer cells presenting the CD47 + phenotype.

[0002] Another therapeutic approach for targeting cancer cells for destruction is bispecific antibodies directed against T cell antigens and tumor cell antigens (such as B cell maturation antigen). Bispecific antibodies that bind simultaneously to T cell and tumor cell antigens can cause T cell activation, proliferation, and tumor cell death. The simultaneous binding of bispecific antibodies to CD3 on T cells and the target antigen on tumor cells brings T cells into close proximity to target tumor cells, thereby causing T cell-mediated tumor cell killing.

[0003] B cell maturation antigen (BCMA, CD269, or TNFRSF17) is a member of the tumor necrosis factor receptor (TNFR) superfamily. BCMA was identified in malignant human T-cell lymphomas with a t(4;16) translocation. The gene is selectively expressed in the B-cell lineage, with highest expression in plasmablasts and plasma cells (antibody-secreting cells). BCMA binds two ligands, B cell-activating factor (BAFF) (also known as B-lymphocyte stimulator (BLyS) and APRIL-related leukocyte-expressed ligand (TALL-1)) and a proliferation-inducing ligand (APRIL), with affinities of 1 μM and 16 nM, respectively. Binding of APRIL or BAFF to BCMA promotes signal transduction cascades involving NF-κB, Elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, which results in signals for cell survival and proliferation. BCMA is also expressed on malignant B cells and in several B-lymphocyte-related cancers, including multiple myeloma, plasmacytoma, Hodgkin's lymphoma, and chronic lymphocytic leukemia. In autoimmune diseases involving plasmablasts, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, antibody-producing cells expressing BCMA secrete autoantibodies that attack the self. BCMA can also exist in a soluble form (soluble BCMA or sBCMA) in the peripheral blood of patients with multiple myeloma (MM), which can lead to failure of BCMA-specific therapies. Several BCMA-specific therapies are currently under development. Exemplary anti-BCMA / anti-CD3 bispecific antibodies include AMG420 (Amgen), AMG701 (Amgen), CC-93269 (Bristol Myers Squibb), elranatamab (Pfizer), REGN5458 (Regeneron), REGN5459 (Regeneron), teclistamab (Janssen), and TNB-383B (TeneoBio).

[0004] MM is a hematologic B-cell malignancy characterized by the dysregulated proliferation of bone marrow (BM) plasma cells. Approximately 176,000 new cases and 117,000 deaths are attributed to MM globally each year (Sung H et al., CA Cancer J Clin. 2021;71(3):209-49). The American Cancer Society estimates that approximately 34,920 new MM cases will be diagnosed in the United States in 2021, and approximately 12,410 MM-related deaths will occur.

[0005] Despite recent advances in treatment, MM remains an incurable disease, and almost all patients, even those who initially respond to treatment, are expected to relapse. Even patients who undergo autologous stem cell transplantation (ASCT) have a median time to relapse of only 17.2 months (Jimenez-Zepeda et al., Bone Marrow Transplant. 2015;50(2):204-8). Similarly, for patients treated with combination regimens based on novel proteasome inhibitors (PIs) or immunomodulatory drugs (IMiDs) as first-line treatment, the median time to relapse is 16.4 months (Lopez A et al., Leuk Res Rep. 2015;4(2):64-9).

[0006] As the disease progresses and becomes refractory to various treatment modalities, MM patients typically receive multiple lines of treatment. Trials of BCMA-directed therapies in the relapsed / refractory multiple myeloma (RRMM) population have included heavily pre-treated patients.

[0007] The outcomes in the RRMM population are quite poor; for example, RRMM patients with poor responses to PI- or IMiD-based regimens have a median overall survival (OS) of 13 months (95% CI: 11, 15) (Kumar SK et al., Leukemia. 2017;31(11):2443-48). Updated and more effective therapies have substantially increased patient benefit; however, in this real-world scenario (N = 3449), the survival rate over the last 4 years is only 75% (Nandakumar B et al., Journal of Clinical Oncology. 2019;37(15_suppl):8039). The lack of effective and durable treatment options highlights the unmet medical need in the RRMM patient population.

[0008] In cancer drug development and treatment, CD47 blockade and anti-BCMA / anti-CD3 bispecific antibody approaches have shown great promise for various types of cancers, including B-cell lymphomas such as MM. However, improved dosing regimens and treatment methods are needed. SUMMARY OF THE INVENTION

[0009] Provided herein are combination therapies and related methods and compositions for treating cancer. In some embodiments, the combination therapies provided herein comprise a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody. In some embodiments, the CD47 blocker is an SIRPα-Fc fusion protein (such as TTI-622) and the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.

[0010] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody.

[0011] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody, wherein the CD47 blocker is the SIRPαFc fusion protein (TTI-622 / maplirpacept) comprising the amino acid sequence of SEQ ID NO: 7, and wherein the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab.

[0012] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor.

[0013] 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.

[0014] In some embodiments, the cancer is triple refractory multiple myeloma. In some embodiments, the individual's multiple myeloma is refractory to all three of the following types of multiple myeloma therapies: (1) a previous multiple myeloma therapy comprising a proteasome inhibitor, (2) a previous multiple myeloma therapy comprising an immunomodulatory agent, and (3) a previous multiple myeloma therapy comprising an anti-CD38 antibody.

[0015] In some embodiments, the cancer is double refractory multiple myeloma. In some embodiments, the individual's multiple myeloma is refractory to at least two of the following three types of multiple myeloma therapies: (1) a previous multiple myeloma therapy comprising a proteasome inhibitor, (2) a previous multiple myeloma therapy comprising an immunomodulatory agent, and (3) a previous multiple myeloma therapy comprising an anti-CD38 antibody.

[0016] In some embodiments, the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma and the individual has received a stem cell transplant. In some embodiments, the individual has received an autologous stem cell transplant. In some embodiments, the individual has received an autologous stem cell transplant or an allogeneic stem cell transplant. In some embodiments, the individual is minimal residual disease positive after the stem cell transplant.

[0017] In some embodiments, the cancer is multiple myeloma, where in some embodiments the individual has progressed or is intolerant to established multiple myeloma therapies. In some embodiments, the established multiple myeloma therapies include at least one drug selected from the group consisting of proteasome inhibitors, IMid drugs, and anti-CD38 antibodies.

[0018] In some embodiments, the cancer is multiple myeloma, where the individual has received at least four prior therapies, and the individual's multiple myeloma is refractory or recurrent to the following therapies: (1) prior multiple myeloma therapies including proteasome inhibitors, (2) prior multiple myeloma therapies including immunomodulators, and (3) prior multiple myeloma therapies including anti-CD38 monoclonal antibodies, and where the individual has shown disease progression in the last therapy. In one aspect of these embodiments, the individual has received a prior therapy with a BCMA-targeted ADC or BCMA-targeted CAR-T. In another aspect of these embodiments, the individual has not received a prior therapy with either a BCMA-targeted ADC or BCMA-targeted CAR-T.

[0019] In some embodiments, the cancer is multiple myeloma, the individual has received at least one, at least two, at least three, or at least four prior multiple myeloma therapies, and the individual's multiple myeloma is refractory or recurrent to the following therapies: (1) prior multiple myeloma therapies including proteasome inhibitors, (2) prior multiple myeloma therapies including immunomodulators, and (3) prior multiple myeloma therapies including anti-CD38 antibodies, and the individual has shown disease progression in the last multiple myeloma therapy. In one aspect of this embodiment, the individual has received at least three prior multiple myeloma therapies. In another aspect of this embodiment, the individual has received at least four prior multiple myeloma therapies.

[0020] In some embodiments, the prior multiple myeloma therapies received by the individual include BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the prior multiple myeloma therapies received by the individual include BCMA-directed therapy.

[0021] In some embodiments, the prior multiple myeloma therapies received by the individual do not include BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the prior multiple myeloma therapies received by the individual do not include BCMA-directed therapy.

[0022] In some embodiments, the cancer is multiple myeloma and the individual has received at least one or at least two prior multiple myeloma therapies, and the individual's multiple myeloma is refractory or relapsed to the following therapies: (1) prior multiple myeloma therapies including proteasome inhibitors and (2) prior multiple myeloma therapies including immunomodulatory agents. In some embodiments, the individual has shown disease progression in the last multiple myeloma therapy.

[0023] In some embodiments, the cancer is multiple myeloma and the individual has not received any prior multiple myeloma therapies. In some embodiments, after the diagnosis of multiple myeloma, the individual has not received any prior multiple myeloma therapies. In some embodiments, the individual is not suitable for stem cell transplantation. In some embodiments, the cancer is multiple myeloma and the individual is not suitable for stem cell transplantation. In some embodiments, the individual is not suitable for autologous stem cell transplantation. In some embodiments, the individual is not suitable for allogeneic stem cell transplantation. In some embodiments, the individual is not suitable for autologous stem cell transplantation and is also not suitable for allogeneic stem cell transplantation.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Depicts an exemplary dosing regimen combining elotuzumab, carfilzomib, and dexamethasone. Each cycle is 28 days. The regimen includes Cycle 1 (C1), Cycles 2 - 6 (C2 - C6), and Cycle 7 and subsequent cycles (C7+). As Figure 1 shown, elotuzumab is administered on Days 1, 8, 15, and 22 of C1 - C6 and on Days 1 and 15 of C7 and subsequent cycles. Each elotuzumab dose is 44 mg or 76 mg. Carfilzomib is administered on Days 1, 8, and 15 of all cycles. The carfilzomib dose on Day 1 of Cycle 1 is 20 mg / m 2 ; the carfilzomib dose on all other days is 70 mg / m 2 . Dexamethasone is administered on Days 1, 8, 15, and 22 of all cycles. Each dexamethasone dose is 40 mg.

[0025] Figure 2 Schematic of the study design of Sections 2A and 2B depicting an exemplary dosing regimen combining elotuzumab and TTI - 622.

DETAILED DESCRIPTION

[0026] The present invention can be more readily understood by reference to the following detailed description of embodiments of the invention and the examples contained therein. It should be understood that the present invention is not limited to the specific manufacturing methods which may of course vary. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0027] The exemplary embodiments (E) of the present invention provided herein include:

[0028] E1. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody.

[0029] E2. The method of E1, wherein the CD47 blocker comprises a CD47-binding form of human SIRPα.

[0030] E3. The method of E2, wherein the CD47-binding form of human SIRPα is a CD47-binding fragment of human SIRPα.

[0031] E4. The method of E3, wherein the CD47-binding fragment of human SIRPα comprises the IgV domain of human SIRPα.

[0032] E5. The method of any one of E1 to E4, wherein the CD47 blocker comprises an Fc fusion protein comprising the IgV domain of human SIRPα variant 2 (SIRPα Fc fusion protein) linked to an antibody Fc region.

[0033] E6. The method of E5, wherein the SIRPα Fc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 1.

[0034] E7. The method of any one of E5 to E6, wherein the SIRPα Fc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 2.

[0035] E8. The method of any one of E5 to E7, wherein the SIRPα Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7.

[0036] E9. The method of any one of E5 to E8, wherein the SIRPα Fc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof having one, two, three, four or five amino acid substitutions compared to the sequence of SEQ ID NO: 1.

[0037] E10. A method according to any one of E1 to E9, wherein the anti-BCMA / anti-CD3 bispecific antibody comprises a first antigen-binding site that binds CD3 and a second antigen-binding site that binds BCMA, wherein the first antigen-binding site comprises VH and VL, wherein the second antigen-binding site comprises VH and VL, and wherein it has one or both of the following characteristics:

[0038] (a) The VH of the first antigen-binding site comprises heavy chain CDR (HCDR) 1 of one or more of SEQ ID NOs: 18, 33, and 34, HCDR2 of one or more of SEQ ID NOs: 19 and 35, and HCDR3 of SEQ ID NO: 20; and the VL of the first antigen-binding site comprises light chain CDR (LCDR) 1 of SEQ ID NO: 21, LCDR2 of SEQ ID NO: 22, and LCDR3 of SEQ ID NO: 23; and

[0039] (b) The VH of the second antigen-binding site comprises heavy chain CDR (HCDR) 1 of one or more of SEQ ID NOs: 10, 30, and 31, HCDR2 of one or more of SEQ ID NOs: 11 and 32, and HCDR3 of SEQ ID NO: 12; and the VL of the second antigen-binding site comprises light chain CDR (LCDR) 1 of SEQ ID NO: 13, LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15.

[0040] E11. A method according to E10, wherein the VH of the first antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24, the VL of the first antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25, the VH of the second antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16, and the VL of the second antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17.

[0041] E12. A method according to any one of E1 to E11, wherein the anti-BCMA / anti-CD3 bispecific antibody comprises a polypeptide comprising the sequence of SEQ ID NO: 26, a polypeptide comprising the sequence of SEQ ID NO: 27, a polypeptide comprising the sequence of SEQ ID NO: 28, and a polypeptide comprising the sequence of SEQ ID NO: 29.

[0042] E13. The method according to any one of E1 to E12, wherein the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab.

[0043] E14. The method according to E1 or any one of E10 to E13 appended to E1, wherein the CD47 blocker is an anti-CD47 or anti-SIRPα antibody.

[0044] E15. The method according to any one of E1 to E14, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, and the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first cycle.

[0045] E16. The method according to any one of E1 to E15, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, and the anti-BCMA / anti-CD3 bispecific antibody is administered (i) QW on days 1, 8, 15, and 22 of the first cycle, (ii) QW on days 2, 8, 15, and 22 of the first cycle, or (iii) Q2W on days 2 and 15 of the first cycle.

[0046] E17. The method according to any one of E1 to E16, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first cycle, and the anti-BCMA / anti-CD3 bispecific antibody is administered (i) QW on days 1, 8, 15, and 22 of the first cycle, (ii) QW on days 2, 8, 15, and 22 of the first cycle, or (iii) Q2W on days 2 and 15 of the first cycle.

[0047] E18. The method according to any one of E1 to E17, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, and the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first to sixth cycles and Q2W on days 1 and 15 of the seventh cycle.

[0048] E19. A method according to any one of E1 to E18, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least 7 cycles, each cycle being 28 days, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from the following: (i) QW on days 1, 8, 15, and 22 of the first to sixth cycles; (ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1, 8, 15, and 22 of the second to sixth cycles; and (iii) Q2W on days 2 and 15 of the first cycle, Q2W on days 1 and 15 of the second to sixth cycles, and Q2W on days 1 and 15 of the seventh cycle.

[0049] E20. A method according to any one of E1 to E19, having one or both of the following features:

[0050] (A) The CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least 6 cycles, each cycle being 28 days, wherein the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first to sixth cycles, and the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from the following: (i) QW on days 1, 8, 15, and 22 of the first to sixth cycles; (ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1, 8, 15, and 22 of the second to sixth cycles; and (iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second to sixth cycles; or

[0051] (B) The CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least 7 cycles, each cycle being 28 days, wherein the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first to sixth cycles, and the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from the following: (i) QW on days 1, 8, 15, and 22 of the first to sixth cycles; (ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1, 8, 15, and 22 of the second to sixth cycles; and (iii) Q2W on days 2 and 15 of the first cycle, Q2W on days 1 and 15 of the second to sixth cycles, and the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered Q2W on days 1 and 15 of the seventh cycle.

[0052] E21. A method according to any one of E1 to E20, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least a first cycle, wherein each cycle is 28 days, and wherein the CD47 blocker is administered QW at a dose of 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the first cycle.

[0053] E22. A method according to any one of E1 to E21, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least a first cycle, wherein each cycle is 28 days, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered according to a regimen selected from: (i) QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the first cycle, (ii) QW at a dose of 44 mg or 76 mg on days 2, 8, 15, and 22 of the first cycle, and (iii) Q2W at a dose of 44 mg or 76 mg on days 2 and 15 of the first cycle.

[0054] E23. A method according to any one of E1 to E22, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least a first cycle, wherein each cycle is 28 days, and wherein the CD47 blocker is administered QW at a dose of 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the first cycle, and the anti-BCMA / anti-CD3 bispecific antibody is administered according to a regimen selected from: (i) QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the first cycle, (ii) QW at a dose of 44 mg or 76 mg on days 2, 8, 15, and 22 of the first cycle, and (iii) Q2W at a dose of 44 mg or 76 mg on days 2 and 15 of the first cycle.

[0055] E24. A method according to any one of E15 to E23, wherein if at least a partial response (PR) or better is demonstrated in the disease response after at least six cycles and the response persists for at least two months, the dosing interval of one or both of the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody is changed from QW to Q2W.

[0056] E25. A method according to any one of E1 to E24, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to a patient for at least 7 cycles, wherein each cycle is 28 days, and wherein the CD47 blocker is administered QW at a dose of 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the first to sixth cycles and Q2W at a dose of 8 mg / kg or 16 mg / kg on days 1 and 15 of the seventh cycle.

[0057] E26. The method according to any one of E1 to E25, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, each cycle being 28 days, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from the following: (i) QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the first to sixth cycles; (ii) at a dose of 44 mg or 76 mg on days 2, 8, 15, and 22 of the first cycle and QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the second to sixth cycles; and (iii) Q2W at a dose of 44 mg or 76 mg on days 2 and 15 of the first cycle, Q2W at a dose of 44 mg or 76 mg on days 1 and 15 of the second to sixth cycles, and Q2W at a dose of 44 mg or 76 mg on days 1 and 15 of the seventh cycle.

[0058] E27. The method according to any one of E1 to E26, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, each cycle being 28 days, and wherein the CD47 blocker is administered QW at a dose of 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the first to sixth cycles and Q2W at a dose of 8 mg / kg or 16 mg / kg on days 1 and 15 of the seventh cycle, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from the following: (i) QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the first to sixth cycles; (ii) at a dose of 44 mg or 76 mg on days 2, 8, 15, and 22 of the first cycle and QW at a dose of 44 mg or 76 mg on days 1, 8, 15, and 22 of the second to sixth cycles; and (iii) Q2W at a dose of 44 mg or 76 mg on days 2 and 15 of the first cycle, Q2W at a dose of 44 mg or 76 mg on days 1 and 15 of the second to sixth cycles, and Q2W at a dose of 44 mg or 76 mg on days 1 and 15 of the seventh cycle.

[0059] E28. The method according to any one of E1 to E27, wherein the CD47 blocker is administered to the patient as a single therapy at least one dose before the first cycle.

[0060] E29. A method according to any one of E1 - E28, wherein the CD47 blocker is administered to the patient for at least a priming period and a first cycle, wherein the priming period is before the first cycle, wherein the priming period comprises at least 28 or 35 days, and wherein the CD47 blocker is administered as a single therapy QW on days 1, 8, 15, and 22 of the priming period.

[0061] E30. A method according to any one of E28 and E29, wherein the CD47 blocker is administered as a single therapy at a dose comprising 8 mg / kg or 16 mg / kg.

[0062] E31. A method according to any one of E1 - E30, wherein before the first cycle, a first initial dose and a second initial dose of the anti - BCMA / anti - CD3 bispecific antibody are administered to the patient.

[0063] E32. A method according to any one of E1 - E30, wherein the anti - BCMA / anti - CD3 bispecific antibody is administered to the patient for at least a priming period and a first cycle, wherein the priming period is before the first cycle, wherein the priming period comprises 7 days, and wherein the anti - BCMA / anti - CD3 bispecific antibody is administered as a first initial dose and a second initial dose on days 1 and 4 of the priming period.

[0064] E33. A method according to any one of E1 - E31, wherein the CD47 blocker and the anti - BCMA / anti - CD3 bispecific antibody are administered to the patient for at least a priming period and a first cycle, wherein the priming period is before the first cycle, wherein the priming period comprises 35 days, wherein the CD47 blocker is administered on days 1, 8, 15, and 22 of the priming period, and wherein the anti - BCMA / anti - CD3 bispecific antibody is administered as a first initial dose and a second initial dose on days 29 and 32 of the priming period.

[0065] E34. A method according to any one of E31 - E33, wherein the first initial dose of the anti - BCMA / anti - CD3 bispecific antibody comprises 12 mg and the second initial dose of the anti - BCMA / anti - CD3 bispecific antibody comprises 32 mg.

[0066] E35. A method according to any one of E18 - E20 and E24 - E27, and further wherein the CD47 blocker and the anti - BCMA / anti - CD3 bispecific antibody are administered Q2W on days 1 and 15 of the eighth and additional cycles until disease progression.

[0067] E36. The method as in E35, wherein the CD47 blocker is administered Q2W at a dose of 8 mg / kg or 16 mg / kg, and the anti-BCMA / anti-CD3 bispecific antibody is administered Q2W at a dose of 44 mg or 76 mg on days 1 and 15 of the eighth and additional cycles.

[0068] E37. The method as in any one of E1-E36, wherein the CD47 blocker is administered intravenously and / or the anti-BCMA / anti-CD3 bispecific antibody is administered subcutaneously.

[0069] E38. A method for treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody, wherein the CD47 blocker is the SIRPαFc fusion protein (TTI-622 / emapalumab) comprising the amino acid sequence of SEQ ID NO: 7, and wherein the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab.

[0070] E39. The method as in E38, wherein TTI-622 and elotuzumab are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein TTI-622 is administered QW at a dose of 8 mg / kg or 16 mg / kg on days 1, 8, 15 and 22 of the first cycle, and elotuzumab is administered according to a regimen selected from: (i) QW at a dose of 44 mg or 76 mg on days 1, 8, 15 and 22 of the first cycle, (ii) QW at a dose of 44 mg or 76 mg on days 2, 8, 15 and 22 of the first cycle, and (iii) Q2W at a dose of 44 mg or 76 mg on days 2 and 15 of the first cycle.

[0071] E40. A method as in E38 or E39, wherein TTI-622 and elotuzumab are administered to the patient for at least 7 cycles, each cycle being 28 days, wherein TTI-622 is administered QW at a dose of including 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the first to sixth cycles and Q2W at a dose of including 8 mg / kg or 16 mg / kg on days 1 and 15 of the seventh cycle, and wherein elotuzumab is administered in a regimen selected from the following in the first to sixth cycles: (i) QW at a dose of including 44 mg or 76 mg on days 1, 8, 15, and 22 of the first to sixth cycles, (ii) QW at a dose of including 44 mg or 76 mg on days 2, 8, 15, and 22 of the first cycle and QW at a dose of including 44 mg or 76 mg on days 1, 8, 15, and 22 of the second to sixth cycles, and (iii) Q2W at a dose of including 44 mg or 76 mg on days 2 and 15 of the first cycle and Q2W at a dose of including 44 mg or 76 mg on days 1 and 15 of the second to sixth cycles and Q2W at a dose of including 44 mg or 76 mg on days 1 and 15 of the seventh cycle.

[0072] E41. A method as in any one of E1 to E40, wherein (i) the CD47 blocker is administered to the patient at least 60 minutes before the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient on the day the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient, or (ii) the CD47 blocker is administered to the patient approximately 24 hours before the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient.

[0073] E42. A method as in any one of E1 to E41, wherein at least one dose of premedication is administered to the patient before each dose of the CD47 blocker and / or before the first initial dose, second initial dose, and / or first treatment dose of the anti-BCMA / anti-CD3 bispecific antibody.

[0074] E43. A method as in any one of E1 to E42, wherein one or more additional therapeutic agents are administered to the patient.

[0075] E44. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor.

[0076] E45. The method according to E44, wherein the anti-BCMA / anti-CD3 bispecific antibody and the proteasome inhibitor are administered to a patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered QW on days 1, 8, 15, and 22 of the first cycle, and the proteasome inhibitor is administered QW on days 1, 8, and 15 of the first cycle.

[0077] E46. The method according to E44 or E45, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered at a dose comprising 44 mg or 76 mg.

[0078] E47. The method according to any one of E44 to E46, wherein the proteasome inhibitor is administered at a dose comprising 20 mg / m 2 or 70 mg / m 2 of the dose.

[0079] E48. The method according to any one of E44 to E47, which further comprises administering dexamethasone to the patient.

[0080] E49. The method according to E48, wherein the anti-BCMA / anti-CD3 bispecific antibody and the proteasome inhibitor are administered to a patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered QW on days 1, 8, 15, and 22 of the first cycle, the proteasome inhibitor is administered QW on days 1, 8, and 15 of the first cycle, and the dexamethasone is administered QW on days 1, 8, 15, and 22 of the first cycle.

[0081] E50. The method according to E48 or E49, wherein the dexamethasone is administered at a dose of 40 mg.

[0082] E51. The method according to any one of E44 to E50, wherein one or both of the anti-BCMA / anti-CD3 bispecific antibodies is elotuzumab and the proteasome inhibitor is carfilzomib.

[0083] E52. The method according to any one of E45 to E51, wherein before the first cycle, a first initial dose and a second initial dose of the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient.

[0084] E53. The method according to any one of E45 to E52, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient for at least one induction cycle and a first cycle, wherein the induction cycle is before the first cycle, wherein the induction cycle comprises 7 or 14 days, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered as a first initial dose and a second initial dose on days 1 and 4 of the induction cycle.

[0085] E54. A method according to any one of E44 to E53, wherein one or more additional therapeutic agents are administered to the patient.

[0086] E55. A method according to any one of E1 to E54, wherein the cancer is a blood cancer or a solid tumor cancer.

[0087] E56. A method according to any one of E1 to E55, wherein the cancer is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and p53-mutated AML, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative disorders / tumors (MPDs), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndromes, lymphoma, T-cell lymphoma, Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell follicular lymphoma, large cell follicular lymphoma, myeloma, multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, light chain myeloma or Bence-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma or epithelioid sarcoma, optionally wherein the cancer is recurrent or refractory.

[0088] E57. A method according to any one of E1 to E56, wherein the cancer is relapsed or refractory (R / R) multiple myeloma (MM).

[0089] E58. A method according to any one of E1 to E57, wherein the patient has been previously treated with 1 to 3 lines of therapy.

[0090] E59. A method according to any one of E1 to E58, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered at least until disease progression.

[0091] E60. A method according to any one of E1 to E43, wherein the patient has CD47-positive cancer cells.

[0092] E61. A CD47 blocker or an anti-BCMA / anti-CD3 bispecific antibody for treating a patient according to a method of any one of E1 to E43 or E55 to E60 appended to any one of E1 to E43.

[0093] E62. Use of a CD47 blocker or an anti-BCMA / anti-CD3 bispecific antibody for manufacturing a medicament for treating a patient according to a method of any one of E

[0094] E63. A kit comprising one or both of a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody and instructions for a method according to any one of E1 to E43, and optionally further comprising one or more additional therapeutic agents for a method according to any one of E1 to E43 or any one of E55 to E60 attached to any one of E1 to E43.

[0095] E64. An anti-BCMA / anti-CD3 bispecific antibody or a proteasome inhibitor for treating a patient according to a method according to any one of E44 to E54 or any one of E55 to E60 attached to any one of E44 to E54.

[0096] E65. Use of an anti-BCMA / anti-CD3 bispecific antibody or a proteasome inhibitor for manufacturing a medicament for treating a patient according to a method according to any one of E44 to E54 or any one of E55 to E60 attached to any one of E44 to E54.

[0097] E66. A kit comprising one or both of an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor and instructions for a method according to any one of E44 to E54 or any one of E55 to E60 attached to any one of E44 to E54, and optionally further comprising one or more additional therapeutic agents for a method according to any one of E44 to E54 or any one of E55 to E60 attached to any one of E44 to E54.

[0098] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter in any way.

[0099] All references cited herein (including patent applications, patent publications, UniProtKB accession numbers) are incorporated herein by reference as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0100] The techniques and procedures described or mentioned herein are well known and are generally carried out by those skilled in the art using conventional methods. For example, widely used methods are described in the following references: Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F.M. Ausubel, et al. eds., (2003)), series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R.I. Freshney eds. (1987)), Oligonucleotide Synthesis (M.J. Gait eds., 1984), Methods in Molecular Biology, Humana Press, Cell Biology: A Laboratory Notebook (J.E. Cellis, eds., 1998) Academic Press, Animal Cell Culture (R.I. Freshney eds.), 1987), Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press, Cell and Tissue Culture Laboratory Procedures (A. Doyle, J.B. Griffiths and D.G. Newell, eds., 1993-8) J.Wiley and Sons, Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.), Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis, et al. eds., 1994), Current Protocols in Immunology (J.E. Coligan, et al. eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (C.A. Janeway & P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (D. Catty. eds., IRL Press, 1988 - 1989), Monoclonal Antibodies: A Practical Approach (P. Shepherd & C. Dean eds., Oxford University Press, 2000), Using Antibodies: A Laboratory Manual (E. Harlow & D. Lane (Cold Spring Harbor Laboratory Press, 1999)); and their updated versions.

[0101]

Definition

[0102] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings as commonly understood by one of ordinary skill in the art.

[0103] As used herein, unless otherwise indicated, the singular forms “a,” “an,” and “the” include plural referents. For example, “an” antibody includes one or more antibodies.

[0104] If aspects or embodiments of the present invention are described from the perspective of a Markush group or other grouping of alternatives, the present invention covers not only the entire group as listed as a whole, but also each member of the group individually and all possible subgroups of the main group, as well as the main group lacking one or more of the members. The present invention also contemplates the express exclusion of one or more of any of the claimed members of the present invention.

[0105] Any instance following the term "such as" ("e.g." or "for example") is not intended to be exclusive or limiting.

[0106] As used herein, when used to modify a parameter defined by a numerical value (such as the dose of an SIRPαFc fusion protein), the term "about" means that the parameter can vary by up to 10% below or above the specified numerical value of the parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

[0107] The term "identity" or "identical to" refers to the overall correlation between polymeric molecules, such as the correlation between nucleic acid molecules (such as DNA molecules or RNA molecules) or polypeptide molecules. "Identity" measures the percentage of identical matches between two or more sequences, where gap alignments are resolved by a specific mathematical model (such as an algorithm) of a computer program, which is well known in the art.

[0108] The term "treating" ("treating", "treat" or "treatment") refers to any type of treatment, such as alleviating, reducing the disease, disorder or condition of a patient or any tissue damage associated with the disease or slowing its progression. In some embodiments, the disease, disorder or condition is cancer.

[0109] The term "therapeutically effective amount" refers to the amount of an active ingredient that induces a biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human, and the biological or medical response may include one or more of the following: (1) preventing a disease; for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or shown the pathology or symptomatology of the disease; (2) inhibiting a disease; for example, inhibiting a disease, disorder or condition in an individual who is experiencing or showing the pathology or symptomatology of the disease, disorder or condition (i.e., preventing or slowing the further development of the pathology or symptomatology); and (3) improving a disease; for example, improving a disease, disorder or condition in an individual who is experiencing or showing the pathology or symptomatology of the disease, disorder or condition (i.e., reversing the pathology or symptomatology).

[0110] The term "CD47" + "(or CD47+) is used to refer to the cell phenotype to which an SIRPα fusion protein or other CD47 binder binds. A CD47 antibody can be used as an affinity ligand to identify CD47 by flow cytometry. +Cells. Appropriately labeled CD47 antibodies for this use are commercially available (e.g., the antibody product of clone B6H12 is available from Santa Cruz Biotechnology). Cells for examining the CD47 phenotype can include standard tumor biopsy samples, particularly blood samples taken from individuals suspected of carrying endogenous CD47 + cancer cells. CD47 disease cell lines that are of particular interest as targets for SIRPα fusion protein therapy are those cells that “overexpress” CD47. These CD47 + cells are typically disease cells and present CD47 on their surface at a density that exceeds the normal CD47 density of a given type of cell. CD47 overexpression will vary among different cell types but is intended herein to mean any CD47 level greater than the CD47 level measurable in corresponding cells having the normal CD47 phenotype of that cell type, such level being determined, for example, by flow cytometry as exemplified herein or by immunostaining or by gene expression analysis or the like.

[0111] “Antibody” refers to an immunoglobulin molecule capable of specifically binding to a target (e.g., polypeptide, carbohydrate, polynucleotide, lipid, etc.) via at least one antigen-binding site located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” can encompass any type of antibody (e.g., monospecific, bispecific) and includes a portion of a full antibody that retains the ability to bind to a given antigen (e.g., “antigen-binding fragment”) and any other modified configuration of an immunoglobulin molecule that includes an antigen-binding site. Exemplary antibodies include (i) the variable regions of the light chain, heavy chain, or both and (ii) the constant regions of the heavy chain that include three contiguous immunoglobulin domains (CH1, CH2, and CH3) and the light chain that includes a single immunoglobulin domain (CL). “Bispecific antibody” refers to a molecule that has binding specificity for at least two different epitopes. In some embodiments, a bispecific antibody can bind two different antigens simultaneously. In other embodiments, the two different epitopes can reside on the same antigen. In certain embodiments, a bispecific antibody is capable of binding two antigens expressed on two different cells simultaneously.

[0112] The "variable region" of an antibody refers to the variable region of the light chain of the antibody or the variable region of the heavy chain of the antibody (alone or in combination). As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs, also referred to as hypervariable regions), and contribute to the formation of the antigen-binding site of the antibody. If variants of a target variable region are desired, particularly amino acid residue substitutions outside the CDR regions (i.e., in the framework regions), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the target variable region with the variable regions of other antibodies that contain CDR1 and CDR2 sequences of the same canonical class as the target variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[0113] Antibodies produced by host cells can undergo post-translational cleavage of one or more, particularly one or two, amino acids at the C-terminus of the heavy chain. Thus, an antibody produced by a host cell expressing a particular nucleic acid molecule encoding a full-length heavy chain can contain the full-length heavy chain, or it can contain a cleaved variant of the full-length heavy chain. This can particularly be the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, according to the Kabat EU index number). Thus, the C-terminal lysine or C-terminal glycine and lysine of the antibody or SIRPα Fc region provided herein can be present or absent.

[0114] Elranatamab is a BCMA×CD3 bispecific antibody. Elranatamab is described, for example, in U.S. Patent No. 9,969,809 (incorporated herein by reference). The selected sequences of elranatamab are shown in Table 1 herein. Elranatamab is also referred to as PF-06863135 and these terms are used interchangeably herein.

[0115]

CD47 Blocker

[0116] The dosing regimens and methods provided herein include a CD47 blocker. As used herein, a CD47 blocker can be any molecule that interferes with and inhibits or blocks signal transduction when CD47 interacts with SIRPα presented on macrophages.

[0117] In some embodiments, the CD47-binding form of human SIRPα is a CD47 blocker for the regimens and methods provided herein. These molecules are based on the extracellular region of human SIRPα. It includes at least one region of the extracellular region sufficient to confer effective CD47-binding affinity and specificity. The so-called "soluble" forms of SIRPα lacking the membrane-anchoring component are described in the literature and include those mentioned in WO 2010 / 070047 (Novartis), WO2013 / 109752 (Stanford), and WO2014 / 094122 (Trillium), each of which is incorporated herein by reference in its entirety.

[0118] In some embodiments, the soluble form of SIRPα is an Fc fusion. More specifically, the agent suitably comprises a human SIRPα protein in a form directly or indirectly fused to an antibody constant region or Fc (fragment crystallizable). Unless otherwise specified, the term "human SIRPα" as used herein refers to the wild-type, endogenous, mature form of human SIRPα. In humans, the SIRPα protein is found in two main forms. One form, the variant 1 or V1 form, has the amino acid sequence as set forth in NCBI RefSeq NP_542970.1 (residues 27-504 constitute the mature form). The other form, the variant 2 or V2 form, differs by 13 amino acids and has the amino acid sequence stated in GenBanks as CAA71403.1 (residues 30-504 constitute the mature form). These two forms of SIRPα constitute approximately 80% of the SIRPα forms present in humans, and both are encompassed by the term "human SIRPα" herein. The term "human SIRPα" also encompasses its minor forms that are endogenous to humans and have the same property of triggering signal transduction via CD47 when binding to CD47. The present invention is directed to pharmaceutical combinations most particularly comprising the human SIRP variant 2 form or V2.

[0119] In the regimens and methods provided herein, useful SIRPα Fc fusion proteins include one of the three so-called immunoglobulin (Ig) domains within the extracellular region of human SIRPα. More specifically, the SIRPα Fc protein of the present invention incorporates residues 32-137 of human SIRPα (106-mer), which constitutes and defines the IgV domain of the V2 form according to the current nomenclature. As shown below, this SIRPα sequence is referred to herein as SEQ ID NO: 1.

[0120] [SEQ ID NO: 1]

[0121]

[0122] In some embodiments, the SIRPαFc fusion protein incorporates the IgV domain defined by SEQ ID NO: 1, and additional flanking residues adjacent within the SIRPα sequence. The IgV domain of this form, represented by residues 31-148 of the V2 form of human SIRPα, is an 118-mer having SEQ ID NO: 2 as shown below:

[0123] [SEQ ID NO: 2]

[0124]

[0125] The SIRPα fusion proteins of the invention may also incorporate an Fc region having effector functions. Fc refers to the "fragment crystallizable" and represents the constant region of an antibody mainly comprising the CH2 and CH3 domains of the heavy chain constant region and components within the hinge region. Suitable Fc components include those having effector functions. An Fc component "having effector functions" is an Fc component having at least some effector functions, such as at least some contribution to antibody-dependent cytotoxicity or some ability to fix complement. In addition, the Fc will bind to at least an Fc receptor. These properties can be revealed using assays established for this purpose. Functional assays include standard chromium release assays that detect target cell lysis. By this definition, the Fc region of wild-type IgG1 or IgG4 has effector functions, while an Fc region of human IgG4 that has been mutated to eliminate effector functions (such as by incorporating a series of alterations including deletions of Pro233, Val234, Ala235, and Gly236 (EU)) can be considered to not have effector functions. In some embodiments, the Fc is a human antibody based on the IG1 isotype. The Fc regions of these antibodies are readily identifiable to those skilled in the art. In an embodiment, the Fc region comprises the lower hinge-CH2-CH3 domains.

[0126] In a particular embodiment, the Fc region is based on the amino acid sequence of human IgG1 as described in UniProtKB / Swiss-Prot P01857 (residues 104-330) and has the amino acid sequence shown below and referred to herein as SEQ ID NO: 3:

[0127] [SEQ ID NO: 3]

[0128]

[0129] Thus, in some embodiments, the Fc region has the wild-type or consensus sequence of an IgG1 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein is derived from any IgG1 antibody having a canonical effector-active constant region. The sequences of such Fc regions can correspond to the Fc regions of any of the following IgG1 sequences (all cited from GenBank), for example: BAG65283 (residues 242-473), BAC04226.1 (residues 247-478), BAC05014.1 (residues 240-471), CAC20454.1 (residues 99-320), BAC05016.1 (residues 238-469), BAC85350.1 (residues 243-474), BAC85529.1 (residues 244-475), and BAC85429.1 (residues 238-469).

[0130] In other embodiments, the Fc region has the sequence of a wild-type human IgG4 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein is derived from any IgG4 antibody having a constant region with effector activity that is naturally occurring but significantly less effective than the IgG1 Fc region. The sequences of such Fc regions can correspond to the Fc regions of any of the following IgG4 sequences: P01861 (residues 99-327) from UniProtKB / Swiss-Prot and CAC20457.1 (residues 99-327) from GenBank.

[0131] In some embodiments, the Fc region is based on the amino acid sequence of human IgG4 (residues 99-327) as set forth in P01861 in UniProtKB / Swiss-Prot and has the amino acid sequence shown below and referred to herein as SEQ ID NO: 4:

[0132] [SEQ ID NO: 4]

[0133]

[0134] In some embodiments, the Fc region incorporates one or more alterations, typically no more than about 10 such alterations, for example up to 1, 2, 3, 4, 5, or 6 such alterations, including amino acid substitutions that affect certain Fc properties. In one particular embodiment, the Fc region incorporates an alteration at position 228 (EU numbering), where the serine at that position is replaced by proline (S 228 P), thereby stabilizing the disulfide bond within the Fc dimer. Other alterations within the Fc region can include substitutions that alter glycosylation, such as replacing Asn with glycine or alanine 297 ; alterations that increase the half-life, such as T 252 L, T253 S and T 256 F; and many others. Particularly useful are those alterations that enhance Fc properties and at the same time remain silent in terms of conformation (e.g., maintaining Fc receptor binding). In another embodiment, the Fc region is modified to increase its biological half-life. A variety of ways are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as set forth in U.S. Patent No. 6,277,375.

[0135] In a particular embodiment, and where the Fc moiety is an IgG4 Fc, the Fc incorporates at least 228 the S

[0136] [SEQ ID NO: 5]

[0137]

[0138] Thus, the CD47 blockers used in the compositions and methods provided herein are, in some embodiments, SIRP fusion proteins that are useful for inhibiting human SIRPα and human CD47 binding, and thus for inhibiting or reducing signal transduction mediated by SIRPα-bound CD47, the fusion protein comprising a human SIRPα moiety and an Fc moiety fused thereto, wherein the SIRPα moiety comprises the single IgV domain of human SIRPαV2 and an Fc moiety comprising a human IgG Fc domain having effector function, or consists of the foregoing.

[0139] In one embodiment, the fusion protein comprises a SIRPα moiety comprising at least residues 32-137 of the V2 form of wild-type human SIRPα (i.e., SEQ ID NO: 1). In a preferred embodiment, the SIRPα moiety comprises residues 31-148 of the V2 form of human SIRPα, i.e., SEQ ID NO: 2. In one embodiment, the Fc moiety is the Fc moiety of human IgG1 designated P01857 and, in a particular embodiment, has an amino acid sequence incorporating its lower hinge-CH2-CH3 region, i.e., SEQ ID NO: 3. In another embodiment, the Fc moiety is the Fc moiety of human IgG4 designated P01861 and, in a particular embodiment, has an amino acid sequence incorporating its lower hinge-CH2-CH3 region and the mutation S228P, i.e., SEQ ID NO: 5.

[0140] In some embodiments, the SIRPαFc fusion protein is provided and used in a secreted dimeric fusion form, wherein the fusion protein incorporates the SIRPα component having SEQ ID NO: 1 and preferably SEQ ID NO: 2 and an Fc region having effector function and having SEQ ID NO: 3 fused thereto. When the SIRPα component is SEQ ID NO: 2 and the Fc region is SEQ ID NO: 3, the fusion protein comprises SEQ ID NO: 6 as shown below:

[0141] [SEQ ID NO: 6]

[0142]

[0143] The SIRPαFc fusion protein of SEQ ID NO: 6 is also referred to as TTI-621 or ontorpacept. TTI-621 / ontorpacept comprises a dimer of the protein of SEQ ID NO: 6.

[0144] In alternative embodiments, the Fc component of the fusion protein is based on IgG4 and preferably incorporates an S 228 P-mutated IgG4. In the case where the fusion protein incorporates the SIRPα IgV domain of the preferred SEQ ID NO: 2 and the IgG4 Fc region is SEQ ID NO: 5, the fusion protein comprises SEQ ID NO: 7 as shown below:

[0145] [SEQ ID NO: 7]

[0146]

[0147] The SIRPαFc fusion protein of SEQ ID NO: 7 is also referred to as TTI-622 and mapracorat. TTI-622 / mapracorat comprises a dimer of the protein of SEQ ID NO: 7.

[0148] In one embodiment of the dosing regimens or methods provided herein, the SIRPαFc fusion protein comprises the sequence of the polypeptide comprising SEQ ID NO: 2 as the SIRPα component of the fusion protein. In one embodiment, the SIRPαFc fusion protein comprises the polypeptide of SEQ ID NO: 6 or SEQ ID NO: 7.

[0149] As described in the literature, the SIRPα sequence incorporated within the SIRPαFc fusion protein can be variable. This can eliminate glycosylation sites in the protein, such as at position 89 and other sites. Other useful substitutions within SIRPα include one or more of the following: L4V / I, V6I / L, A21V, V27I / L, I31T / S / F, E47V / L, K53R, E54Q, H56P / R, S66T / G, K68R, V92I, F94V / L, V63I, and / or F103V.

[0150] In the SIRPαFc fusion protein, the SIRPα component and the Fc component are directly or indirectly fused to provide a single-chain polypeptide that may ultimately result in a dimer, where the single-chain polypeptides in the dimer are coupled via interchain disulfide bonds formed within the Fc region. The nature of the fusion region is not important. The fusion can occur directly between the two components, where the SIRP component forms the N-terminus of the fusion and the Fc component forms the C-terminus. Alternatively, the fusion can occur indirectly via a linker comprising one or more amino acids, which are desirably genetically encoded amino acids, such as two, three, four, five, six, seven, eight, nine, ten amino acids, or any number of amino acids between 5 and 100 (e.g., between 5 and 50, 5 and 30, or 5 and 20 amino acids). The linker can comprise a peptide encoded by DNA that constitutes a restriction site (such as BamHI, ClaI, EcoRI, HindIII, PstI, SalI, and XhoI sites and the like).

[0151] The linker amino acids generally and desirably have a certain flexibility to allow the Fc and SIRP components to adopt their active conformations. Residues that allow this flexibility are typically Gly, Asn, and Ser, and thus any combination of these residues (and especially Gly and Ser) within the linker can substantially provide the desired linking effect. In one example, such a linker is based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser [SEQ ID NO: 8]) that can be repeated as (G4S)n, where n is 1, 2, 3, or greater, or is based on (Gly)n, (Ser)n, (Ser-Gly)n, or (Gly-Ser)n and the like. In another embodiment, the linker is GTELSVRAKPS [SEQ ID NO: 9]. This sequence constitutes the SIRPα sequence that flanks the IgV domain on the C-terminus (it should be understood that when coupled with the above IgV minimal sequence, this flanking sequence can be considered a linker or a different form of the IgV domain). It is only necessary that the fusion region or linker allows the components to adopt their active conformations, and this can be achieved by any form of linker available in the art.

[0152] In some embodiments, the SIRPαFc fusion protein (e.g., TTI-622) can be administered by the methods and regimens provided herein, at a dosage range of 0.1 to 50 mg / kg of the individual body weight. For example, the SIRPαFc fusion protein dosage can be 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg or 50 mg / kg. The SIRPαFc fusion protein dosage can also include, for example, 2 to 40 mg / kg, 4 to 40 mg / kg, 5 to 50 mg / kg, 8 to 50 mg / kg, 8 to 40 mg / kg, 8 to 30 mg / kg, 8 to 28 mg / kg, 10 to 50 mg / kg, 10 to 40 mg / kg, 10 to 30 mg / kg, 10 to 25 or 10 to 20 mg / kg. These dosages of the SIRPαFc fusion protein can be administered to the individual at the following frequencies, for example: once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), twice a month, once a month, once every two months or once every three months. These dosing frequencies can be part of a dosing cycle (e.g., a 14-day, 21-day or 28-day cycle).

[0153] In some embodiments, the SIRPαFc fusion proteins provided herein (e.g., TTI-622) are administered at a "uniform" (also referred to as "fixed") dose - i.e., the dose is based on the number of patients and the dose does not depend on the patient's mass. In some embodiments, the SIRPαFc fusion protein (e.g., TTI-622) is administered at a fixed dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg or 3600 mg. The fixed dose of the SIRPαFc fusion protein can be administered according to various regimens. In some embodiments, the dose is administered to the patient once a week (QW), every 2 weeks (Q2W), every 3 weeks (Q3W) or every 4 weeks (Q4W).

[0154] In some embodiments, the SIRPαFc fusion protein is administered at a dose between (a) a lower level of 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150 or 2200 mg and (b) a higher level of 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550 or 3600 mg, wherein the lower level is a value less than the higher level.

[0155] Other types of CD47 blockers can be used in the methods and combinations of the present invention to replace or supplement SIRPα-based drugs. These other agents include, in particular, anti-CD47 antibodies that bind to CD47 and antagonize the interaction with SIRPα. By blocking this interaction and due to the Fc region of the antibody, the effect of the anti-CD47 antibody can be similar to that of an SIRPα-based Fc fusion drug. Examples of anti-CD47 antibodies are described in the literature, such as US2008 / 0107654 (Chugai), WO2009 / 091601 (Stanford), WO2013 / 119714 (InhibRx), WO2016 / 109415 (Celgene) and WO2016 / 081423 (Janssen). Since these antibodies bind to red blood cells, dosing regimens that take this into account have been developed and are described in WO2014 / 149477. Properties of useful anti-CD47 antibodies include the ability to bind to CD47 in a manner that ultimately inhibits SIRPα signaling, i.e., as an antagonist. In some other embodiments, anti-SIRPα antibodies can also be used as CD47 blockers.

[0156] In some embodiments, the method further comprises administering to the individual at least one dose of premedication prior to each dose of the CD47 blocker. The premedication can include acetaminophen (or an equivalent, such as paracetamol) and / or an antihistamine (such as diphenhydramine (or an equivalent)). In some embodiments, diphenhydramine is administered orally or intravenously at a dose of 25 mg. In some embodiments, the premedication dosing can be the same or different prior to each dose of the CD47 blocker.

[0157]

Anti-BCMA / anti-CD3 bispecific antibody

[0158] The dosing regimens and methods provided herein include an anti-BCMA / anti-CD3 bispecific antibody. As used herein, an anti-BCMA / anti-CD3 bispecific antibody can be any molecule capable of binding simultaneously to BCMA (e.g., on B cells) and CD3 (e.g., on T cells). The anti-BCMA / anti-CD3 bispecific antibody is also referred to herein as a "BCMA×CD3" or "BCMA" bispecific antibody.

[0159] B cell maturation antigen (BCMA, also known as TNFRSF17 and CD269) is a candidate for bispecific antibody-based immunotherapy. BCMA expression is upregulated during the maturation of B cells into plasmablasts and plasma cells, but is not expressed on naive B cells, hematopoietic stem cells, or normal tissues (such as the heart, lung, kidney, or tonsils). In multiple myeloma, BCMA expression has been identified in every disease stage and in patients with different cytogenetic risks. Additionally, BCMA expression is not affected by treatment with autologous stem cell transplantation (ASCT) or chemotherapy. In vivo, anti-BCMA bispecific antibodies have demonstrated induction of T cell activation, reduction of tumor burden, and extension of survival.

[0160] Examples of anti-BCMA / anti-CD3 bispecific antibodies that can be used in the combination therapies of the invention include (but are not limited to) AMG 420 (BCMA×CD3 bispecific T cell engager, Amgen), AMG 701 (BCMA×CD3 Amgen), CC-93269 (BCMA×CD3 bispecific antibody, Celgene), teclistamab (JNJ-64007957-Jansen), elranatamab (BCMA×CD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio / AbbVie), linvoseltamab (REGN5458 - BCMA×CD3 bispecific antibody, Regeneron), alnuctamab (CC-93269 - BMS), AFM26 (BCMA×CD16 tetravalent bispecific antibody, Affimed GmbH), HPN217 (BCMA×ALB×CD3 trispecific, Harpoon Therapeutics).

[0161] In some aspects, the anti-BCMA / anti-CD3 bispecific antibody comprises a first antigen-binding site and a second antigen-binding site, wherein the first antigen-binding site specifically binds CD3 and wherein the second antigen-binding site specifically binds BCMA.

[0162] In some aspects, the anti-BCMA / anti-CD3 bispecific antibody can have any feature or characteristic of any BCMA bispecific antibody provided in WO2016 / 166629, which is incorporated herein by reference for all purposes.

[0163] In some aspects, the first antigen-binding site specifically binds to CD3. For example, information about CD3 is provided via UniProtKB#P07766. In some aspects, the first antigen-binding site comprises three CDRs of a heavy-chain variable region (VH) containing the amino acid sequence shown in SEQ ID NO: 24 and / or three CDRs of a light-chain variable region (VL) containing the amino acid sequence shown in SEQ ID NO: 25. In some aspects, the VH comprises a VH CDR1 containing the sequence shown in one or more of SEQ ID NOs: 18, 33, and 34, a VH CDR2 containing the sequence shown in one or more of SEQ ID NOs: 19 and 35, a VH CDR3 containing the sequence shown in SEQ ID NO: 20, and / or the VL comprises a VL CDR1 containing the sequence shown in SEQ ID NO: 21, a VL CDR2 containing the sequence shown in SEQ ID NO: 22, a VL CDR3 containing the sequence shown in SEQ ID NO: 23. In some aspects, the VH comprises the sequence shown in SEQ ID NO: 24, and / or the VL comprises the sequence shown in SEQ ID NO: 25. In some aspects, the bispecific antibody comprises a first heavy chain and a first light chain containing the first antigen-binding site, wherein the first heavy chain comprises the amino acid sequence shown in SEQ ID NO: 28, and / or the first light chain comprises the amino acid sequence shown in SEQ ID NO: 29.

[0164] In some aspects, the second antigen-binding site specifically binds to BCMA. For example, information about BCMA is provided via UniProtKB ID#Q02223. In some aspects, the antigen-binding site comprises three CDRs of a heavy-chain variable region (VH) containing the amino acid sequence shown in SEQ ID NO: 16 and / or three CDRs of a light-chain variable region (VL) containing the amino acid sequence shown in SEQ ID NO: 17. In some aspects, the VH comprises a VH CDR1 containing the sequence shown in one or more of SEQ ID NOs: 10, 30, and 31, a VH CDR2 containing the sequence shown in one or more of SEQ ID NOs: 11 and 32, a VH CDR3 containing the sequence shown in SEQ ID NO: 12, and / or the VL comprises a VL CDR1 containing the sequence shown in SEQ ID NO: 13, a VL CDR2 containing the sequence shown in SEQ ID NO: 14, a VL CDR3 containing the sequence shown in SEQ ID NO: 15. In some aspects, the VH comprises the sequence shown in SEQ ID NO: 16, and / or the VL comprises the sequence shown in SEQ ID NO: 17. In some aspects, the bispecific antibody comprises a second heavy chain and a second light chain containing the second antigen-binding site, wherein the second heavy chain comprises the amino acid sequence shown in SEQ ID NO: 26, and / or the second light chain comprises the amino acid sequence shown in SEQ ID NO: 27.

[0165] In some embodiments, the VH of the first antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24, the VL of the first antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25, the VH of the second antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16, and the VL of the second antigen-binding site comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17.

[0166] In some aspects, the BCMA bispecific antibody is elotuzumab. Elotuzumab is a heterodimeric humanized full-length bispecific antibody that includes a B-cell maturation antigen (BCMA) binding arm and a cluster of differentiation (CD3) binding arm paired via hinge mutation technology. It utilizes a modified human IgG2Da fragment crystallizable (Fc) region. Elotuzumab is described, for example, in U.S. Patent No. 9,969,809, which is incorporated herein by reference for all purposes. The sequence of elotuzumab is shown in Table 1. SEQ ID NOs: 18-25, 28, 29, and 33-35 are the sequences of the CD3 arm of elotuzumab, and SEQ ID NOs: 10-17, 26, 27, and 30-32 are the sequences of the BCMA arm of elotuzumab.

[0167] In some embodiments, the dose of elotuzumab can be selected from one of the following: 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 44 mg, 76 mg, 116 mg, and 152 mg.

[0168] In some embodiments, the methods or regimens of administration of the anti-BCMA / anti-CD3 bispecific antibodies provided herein can include one, two, or more initial doses. The initial dose can be used to initially sensitize the immune system at a lower dose, thereby reducing the rate, duration, and grade of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In some embodiments, the first initial dose can be 4 mg to 32 mg and the second initial dose can be 12 mg to 44 mg. Exemplary initial doses of elotuzumab are a first dose of 12 mg and a second dose of 32 mg. An exemplary initial dose regimen is to administer the first initial dose (e.g., 12 mg) on Day 1, the second initial dose (e.g., 32 mg) on Day 4, and then the therapeutic dose. In some embodiments, the therapeutic dose (e.g., 44 mg or 76 mg) is administered on Day 8 (i.e., 1 week after the first initial dose). In some embodiments, the therapeutic dose is 32 mg to 76 mg. The therapeutic dose can be selected from 44 mg or 76 mg. In some embodiments, the first initial dose is 12 mg, the second initial dose is 32 mg, and the therapeutic dose is 44 mg or 76 mg.

[0169] In some embodiments, the anti-BCMA / anti-CD3 bispecific antibody can be administered once a week (Q1W or QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W) according to the methods and regimens provided herein. In some embodiments, the antibody is administered QW or Q2W. In some embodiments, if the individual has received treatment for at least six months and the disease response shows at least a partial response (PR) or better and the response has persisted for at least two months, the dosing interval can be changed from QW to Q2W at the same dose level / dose (e.g., 76 mg QW to 76 mg Q2W or 44 mg QW to 44 mg Q2W). These dosing frequencies can be part of a dosing cycle (e.g., a 14-day, 21-day, or 28-day cycle).

[0170] In some embodiments, the method further includes administering to the individual at least one dose of premedication prior to each of a single initial dose, a first initial dose, a second initial dose, and / or a first treatment dose of the anti-BCMA / anti-CD3 bispecific antibody administered to the individual. In some embodiments, premedication is administered prior to the first and second initial doses and the first treatment dose. The premedication can be acetaminophen (or an equivalent, e.g., paracetamol), diphenhydramine (or an equivalent), and / or dexamethasone (or an equivalent). In some embodiments, dexamethasone is administered orally or intravenously at a dexamethasone dose of about 10 mg to about 40 mg per day, such as 20 mg. In some embodiments, acetaminophen is administered at a dose of 650 mg or paracetamol is administered at a dose of 500 mg. In some embodiments, diphenhydramine is administered orally or intravenously at a dose of 25 mg. In some embodiments, the premedication dosing can be the same or different when the individual undergoes initial administration, first treatment, and subsequent administration of the bispecific antibody.

[0171]

Anti-BCMA / anti-CD3 Bispecific Antibody and Proteasome Inhibitor Combination Therapy

[0172] The present disclosure provides a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor. In some embodiments, the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab and the proteasome inhibitor is carfilzomib. In some embodiments, the combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor also includes dexamethasone.

[0173] Carfilzomib is a second-generation proteasome inhibitor that irreversibly binds and potentially improves resistance while reducing off-target toxicity. Glucocorticoids (e.g., dexamethasone) are the mainstay in the treatment of multiple myeloma in newly diagnosed and relapsed / refractory settings.

[0174] Carfilzomib was first approved in the United States in 2012, based on the response rate of monotherapy reported in a single-arm, multicenter study conducted in patients who had received at least 2 prior lines of therapy, had responded to at least 1 prior line of therapy, and were refractory to their most recent therapy. Patients received 20 mg / m per dose in Cycle 1 2 of carfilzomib and 27 mg / m in subsequent cycles 2 . In the first and second cycles, 4 mg of PO or IV dexamethasone was administered prior to the carfilzomib dose. A total of 266 patients were enrolled. The objective response rate (ORR), as determined by independent review committee (IRC) assessment using International Myeloma Working Group (IMWG) criteria, was 23.7% (95% CI: 18.7 - 29.4).

[0175] Multiple myeloma cells are highly dependent on proteasome activity due to the high turnover of their abnormal immunoglobulins. Carfilzomib is a standard-of-care proteasome inhibitor that has shown significant activity in MM, initially used as monotherapy and more recently with enhanced activity when used in combination with drugs involved in the immune system, including immunomodulatory drugs (IMiDs) and CD38-targeting antibodies. Carfilzomib has been shown to activate apoptosis, autophagy, and directly inhibit myeloma cell proliferation and survival. In vitro studies have demonstrated the potential immunogenic role of proteasome inhibition in triggering an anti-myeloma immune response. Without wishing to be bound by theory, it is hypothesized that the combination of carfilzomib, which induces immunogenic cell death, and elotuzumab, which induces T cell-mediated tumor lysis, may enhance the activation of MM cell immune surveillance via distinct and complementary mechanisms.

[0176] In some embodiments, a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may comprise any of the therapeutic molecules, dosage amounts, and dosage frequencies as set forth in Example 1.

[0177] In some embodiments, a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may include a dosing regimen of elotuzumab 44 mg QW and carfilzomib 70 mg / m 2 QW.

[0178] In some embodiments, a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may include a dosing regimen of elotuzumab 44 mg Q2W and carfilzomib 70 mg / m 2 QW.

[0179] In some embodiments, the combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may include elotuzumab 76 mg QW and carfilzomib 70 mg / m 2 QW dosing schedule.

[0180] In some embodiments, the combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may include elotuzumab 76 mg Q2W and carfilzomib 70 mg / m 2 QW dosing schedule.

[0181]

CD47 Blocker and Anti-BCMA / anti-CD3 Bispecific Antibody Combination Therapy

[0182] The present disclosure provides a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody. In some embodiments, the CD47 blocker is a SIRPα-Fc fusion protein (such as TTI-622) and the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab.

[0183] The inhibitory, anti-phagocytic "don't eat me" signal mediated by CD47 on tumor cells and membrane-bound SIRPα on macrophages is used to evade innate immune surveillance of cancer. The CD47 blocker (such as PF-07901801 (TTI-622) (SIRPα fusion)) interacts with its ligand CD47, and the Fc region binds to the Fcγ receptor on macrophages. This blocks the CD47 anti-phagocytic signal, thereby activating macrophages and causing tumor cell phagocytosis. After phagocytosis, tumor cell antigens are processed by macrophages and presented as MHC peptide complexes to T cells, thereby causing T cell activation and tumor cell destruction. Thus, it is hypothesized that the combination of an anti-BCMA / anti-CD3 bispecific antibody (such as elotuzumab) and a CD47 blocker [such as PF-07901801 (TTI-622)] that engage the adaptive immune system via CD3 on T cells and BCMA on MM cells may enhance the engagement of the immune cell repertoire, thereby promoting subsequent lysis / killing of BCMA-expressing MM cells and control.

[0184] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may comprise any of the therapeutic molecules, dose amounts, and dose frequencies set forth in Example 1.

[0185] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing schedule of elotuzumab 44 mg QW and PF-07901801 8 mg / kg QW.

[0186] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 44 mg QW and PF-07901801 16 mg / kg QW.

[0187] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 44 mg Q2W and PF-07901801 8 mg / kg QW.

[0188] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 44 mg Q2W and PF-07901801 16 mg / kg QW.

[0189] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 76 mg QW and PF-07901801 8 mg / kg QW.

[0190] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 76 mg QW and PF-07901801 16 mg / kg QW.

[0191] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 76 mg Q2W and PF-07901801 8 mg / kg QW.

[0192] In some embodiments, the combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody may include a dosing regimen of elranatamab 76 mg Q2W and PF-07901801 16 mg / kg QW.

[0193] The SIRPαFc protein provided herein shows negligible binding to red blood cells. Thus, when administering the SIRPαFc fusion protein provided herein, there is no need to consider RBC "drop". Relative to other CD47 blocking agents that bind to RBCs, it is estimated that the SIRPαFc fusion of the present invention can be effective at a dose less than half the dose required for a drug that binds to RBCs (such as a CD47 antibody). Additionally, the SIRPαFc fusion protein provided herein is a specific antagonist of SIRPα-mediated signaling, which shows negligible CD47 agonistic effect when binding to CD47. Thus, when establishing a medically useful unit dosage regimen, there is no need to consider any stimulation induced by the drug.

[0194] The dosage regimens and methods provided herein can be used to treat various cancer cells. These cancer cells particularly include CD47 + cancer cells, including liquid (blood) and solid tumors. The dosage regimens and methods provided herein can be used to treat solid tumors to reduce their size, number, or growth rate and control the growth of cancer stem cells. These solid tumors include CD47 in the bladder, brain, breast, lung, colon, ovary, prostate, liver, and other tissues + tumors. In one embodiment, the dosage regimens and methods provided herein can be used to inhibit the growth or proliferation of blood cancers. As used herein, "blood cancer" refers to cancers of the blood and particularly includes leukemia, lymphoma, and myeloma. "Leukemia" refers to cancers of the blood in which too many white blood cells are produced that cannot effectively fight infection, thereby crowding out other parts that make up the blood (such as platelets and red blood cells). It should be understood that cases of leukemia are classified as acute or chronic. Some forms of leukemia can be (for example) acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / tumors (MPDS); and myelodysplastic syndromes. "Lymphoma" can particularly refer to Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell). Myeloma can refer to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence Jones myeloma. In certain embodiments, the dosage regimens and methods provided herein can be used to treat T cell lymphoma, which is a highly heterogeneous group of lymphoid malignancies that are divided into cutaneous and peripheral TCLs, which are themselves divided into nodular or extranodal types. CTCL originates from skin-homing T cells and includes mycosis fungoides, Sezary syndrome, primary cutaneous T cell lymphoproliferative disorders, and anaplastic large cell lymphoma. A common feature of TCLs is an aggressive course and poor response to therapy, with the exception of ALK and ALCL.

[0195] In some other embodiments, the hematologic cancers treated using the dosing regimens and methods are preferably selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndromes, preferably CD47 of human acute myeloid leukemia + leukemia.

[0196] In other embodiments, the hematologic cancers treated using the dosing regimens or methods provided herein are CD47 of Hodgkin lymphoma, indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma (small cell and large cell), multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence Jones myeloma, and leiomyosarcoma + lymphoma or myeloma.

[0197] In some embodiments, the cancers treated using the dosing regimens or methods provided herein are recurrent and / or refractory (R / R). In some embodiments, the individuals treated using the dosing regimens or methods provided herein have been previously treated with 1 to 3 lines of cancer therapy.

[0198] 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.

[0199] In some embodiments, the cancer is triple refractory multiple myeloma. In some embodiments, the multiple myeloma of the individual is refractory to the following three types of multiple myeloma therapies: (1) previous multiple myeloma therapy including a proteasome inhibitor, (2) previous multiple myeloma therapy including an immunomodulatory agent, and (3) previous multiple myeloma therapy including an anti-CD38 antibody.

[0200] In some embodiments, the cancer is double refractory multiple myeloma. In some embodiments, the multiple myeloma of the individual is refractory to at least two of the following three types of multiple myeloma therapies: (1) previous multiple myeloma therapy including a proteasome inhibitor, (2) previous multiple myeloma therapy including an immunomodulatory agent, and (3) previous multiple myeloma therapy including an anti-CD38 antibody.

[0201] In some embodiments, the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma and the individual has received a stem cell transplant. In some embodiments, the individual has received an autologous stem cell transplant. In some embodiments, the individual has received an autologous stem cell transplant or an allogeneic stem cell transplant. In some embodiments, the individual is minimal residual disease positive after stem cell transplant.

[0202] In some embodiments, the cancer is multiple myeloma, wherein in some embodiments the individual has progressed or is intolerant to established multiple myeloma therapies. In some embodiments, the established multiple myeloma therapies include at least one drug selected from the group consisting of proteasome inhibitors, IMid drugs, and anti-CD38 antibodies.

[0203] In some embodiments, the cancer is multiple myeloma, wherein the individual has received at least four prior therapies, and the individual's multiple myeloma is refractory or recurrent to the following therapies: (1) prior multiple myeloma therapies including proteasome inhibitors, (2) prior multiple myeloma therapies including immunomodulators, and (3) prior multiple myeloma therapies including anti-CD38 monoclonal antibodies, and wherein the individual has shown disease progression in the last therapy. In one aspect of these embodiments, the individual has received prior therapy with a BCMA-targeted ADC or BCMA-targeted CAR-T. In another aspect of these embodiments, the individual has not received prior therapy with either a BCMA-targeted ADC or BCMA-targeted CAR-T.

[0204] In some embodiments, the cancer is multiple myeloma, the individual has received at least one, at least two, at least three, or at least four prior multiple myeloma therapies, and the individual's multiple myeloma is refractory or recurrent to the following therapies: (1) prior multiple myeloma therapies including proteasome inhibitors, (2) prior multiple myeloma therapies including immunomodulators, and (3) prior multiple myeloma therapies including anti-CD38 antibodies, and the individual has shown disease progression in the last multiple myeloma therapy. In one aspect of this embodiment, the individual has received at least three prior multiple myeloma therapies. In another aspect of this embodiment, the individual has received at least four prior multiple myeloma therapies.

[0205] In some embodiments, the prior multiple myeloma therapies received by the individual include BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the prior multiple myeloma therapies received by the individual include BCMA-directed therapy.

[0206] In some embodiments, the prior multiple myeloma therapies received by the individual do not include BCMA-directed ADC therapy or BCMA-directed CAR-T cell therapy. In some embodiments, the prior multiple myeloma therapies received by the individual do not include BCMA-directed therapy.

[0207] In some embodiments, the cancer is multiple myeloma and the individual has received at least one or at least two prior multiple myeloma therapies, and the individual's multiple myeloma is refractory or relapsed to the following therapies: (1) prior multiple myeloma therapy including a proteasome inhibitor and (2) prior multiple myeloma therapy including an immunomodulatory agent. In some embodiments, the individual has shown disease progression in the last multiple myeloma therapy.

[0208] In some embodiments, the cancer is multiple myeloma and the individual has not received any prior multiple myeloma therapy. In some embodiments, after the diagnosis of multiple myeloma, the individual has not received any prior multiple myeloma therapy. In some embodiments, the individual is not suitable for stem cell transplantation. In some embodiments, the cancer is multiple myeloma and the individual is not suitable for stem cell transplantation. In some embodiments, the individual is not suitable for autologous stem cell transplantation. In some embodiments, the individual is not suitable for allogeneic stem cell transplantation. In some embodiments, the individual is not suitable for autologous stem cell transplantation and is also not suitable for allogeneic stem cell transplantation.

[0209] The CD47 blockers and anti-BCMA / anti-CD3 bispecific antibodies provided herein can be administered to an individual via any of the established routes for protein delivery, particularly intravenous, intradermal, and subcutaneous injection or infusion or by oral or nasal administration. In some embodiments, the CD47 blocker (e.g., SIRPαFc fusion protein TTI-622) is administered intravenously. In some embodiments, the anti-BCMA / anti-CD3 bispecific antibody (e.g., elranatamab) is administered subcutaneously.

[0210] In embodiments referring to the methods of treatment as set forth herein, such embodiments are also further embodiments for such treatment or alternatively for manufacturing a medicament for such treatment.

[0211] Incorporated herein by reference for all purposes is the content of U.S. Provisional Patent Application No. 63 / 386,732, filed on December 9, 2022.

[0212] The following examples provided for implementing specific aspects of the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0213] The foregoing description and the following examples detail certain specific embodiments of the present invention and set forth the best mode contemplated by the inventors. However, it should be understood that, however detailed the foregoing may appear in text, the present invention may be practiced in many ways and the present invention should be construed in accordance with the appended claims and any equivalents thereof.

[0214] Although the disclosed teachings have been described with reference to various applications, methods, kits, and compositions, it should be understood that various changes and modifications can be made without departing from the teachings herein and the disclosure claimed below. The following examples are provided to better illustrate the claimed disclosure and are not intended to limit the scope of the teachings presented herein. Although the teachings of the present invention have been described in accordance with these exemplary embodiments, those skilled in the art will readily understand that many changes and modifications can be made to these exemplary embodiments without undue experimentation. All such changes and modifications are within the scope of the teachings of the present invention.

[0215]

Sequence

[0216] The sequences provided herein are summarized in Table 1 below.

[0217]

Table 1

[0218]

[0219]

[0220]

[0221]

[0222]

Examples

[0223] To better understand the present invention, the following examples are presented. These examples are for illustrative purposes only and should not be considered as limiting the scope of the present invention in any way.

[0224]

Example 1

[0225] This is a Phase 1b, open-label, prospective, multi-center, non-randomized study to evaluate the safety, efficacy, PK, and pharmacokinetics of the combination of elotuzumab with carfilzomib + dexamethasone (Part 1) and the combination of elotuzumab with PF-07901801 (TTI-622) monotherapy (Part 2) in participants with relapsed / refractory (R / R) multiple myeloma (MM) (RRMM). Study endpoints were evaluated using a dose-escalation approach.

[0226] · Part 1: Dose escalation will evaluate the tolerability and safety of the combination of elotuzumab with carfilzomib and dexamethasone to determine the RP2D of the combination.

[0227] · Part 2A: Dose escalation will evaluate the tolerability, safety, PK, PD, and preliminary activity of PF-07901801 (TTI-622) monotherapy and the combination of PF-07901801 (TTI-622) and enfortumab vedotin. Based on all data, two combination dose levels of PF-07901801 and enfortumab vedotin will be selected for further evaluation in Part 2B.

[0228] · Part 2B: Randomized dose optimization will evaluate the tolerability, safety, PK, PD, and activity of the combination of enfortumab vedotin and PF-07901801 (TTI-622) to determine the RP2D of this combination.

[0229]

Part 1: Enfortumab vedotin and carfilzomib / dexamethasone

[0230]

Dose escalation design

[0231] The number of participants to be recruited will depend on the number of dose levels evaluated and the number of participants treated at each dose level. Approximately 3 - 6 dose-limiting toxicity (DLT) evaluable participants will be treated at each dose level of the combination therapy, and at least 6 DLT evaluable participants will be treated at the recommended phase 2 dose (RP2D) level of the enfortumab vedotin combination.

[0232] Before moving to the next dose level, once the DLT evaluable participants have completed the DLT observation period [from cycle 0 day 1 (C0D1) to the end of cycle 1], the safety data will be evaluated by the Dose Level Review Committee.

[0233] The target DLT rate is ≤30% and the Bayesian Logistic Regression Model (BLRM) approach will guide the dose escalation / de-escalation decisions to recommend the RP2D of enfortumab vedotin + carfilzomib and dexamethasone (Part 1). However, other available evidence (such as safety data outside the DLT window, clinical activity, pharmacokinetics (PK), and pharmacodynamics data) will also be evaluated to determine the tolerability profile and escalation decisions. The dose escalation decisions and RP2D will be determined by the investigator and the sponsor in a Dose Level Review Meeting (DLRM).

[0234]

Administration

[0235] The participants in Part 1 will be treated with the following:

[0236] · Enfortumab vedotin, 44 or 76 mg QW, over a 28-day cycle

[0237] · Administer 20 mg / m² on cycle 1 day 1 (C1D1)2 Ixazomib, and if tolerated, 70 mg / m² may be given starting on cycle 1 day 8 (C1D8). 2 And then all subsequent doses are administered on days 1, 8, and 15 of a 28-day cycle, and 40 mg of dexamethasone is administered orally (PO) or intravenously (IV) once weekly (QW) during the 28-day cycle. The ixazomib dose may be modified according to institutional guidelines for blood or other toxicities. Generally, dose modifications of ixazomib will follow the applicable product prescribing information (e.g., see Kyprolis (ixazomib) USPI). According to the product prescribing information, the ixazomib dose levels are 70 mg, 56 mg, 45 mg, and 36 mg.

[0238] If the participant has been treated for at least 6 months (6 cycles) and the disease response shows at least a partial response (PR) or better and the response has lasted at least 2 months, the dose interval is changed from QW to once every 2 weeks (Q2W) at the same enfortumab vedotin dose level (e.g., changing enfortumab vedotin from 76 mg QW to 76 mg Q2W or from 44 mg QW to 44 mg Q2W). If the dose interval is changed, each cycle should remain the same length (i.e., a 28-day cycle). The dose interval of ixazomib + dexamethasone remains unchanged.

[0239] Before cycle 1 of part 1, the participant may receive an initial dose of enfortumab vedotin as part of a lead-in 14-day initial dose cycle [also known as cycle 0 (C0); day 1 of cycle 1 is after day 14 of cycle 0]. In the 14-day initial dose cycle, enfortumab vedotin is administered at increasing doses over several days of the 14-day cycle. For example, enfortumab vedotin may be administered on days 1, 4, and 8 of the initial dose cycle, more specifically, enfortumab vedotin may be administered at a dose of 12 mg on day 1 of the 14-day initial dose cycle, 32 mg on day 4, and 44 mg or 76 mg on day 8.

[0240] The agents in part 1 may be administered according to the following dosing sequence. First, the participant may receive premedication (dexamethasone) for approximately 0.5 hour to 4 hours. Next, ixazomib is infused for approximately 30 minutes. Next, enfortumab vedotin is administered after at least 60 minutes.

[0241]

Part 2: Enfortumab Vedotin and PF-07901801 (TTI-622)

[0242]

Dose Escalation and Optimization Design

[0243] For dose escalation (Part 2A), approximately 3 to 6 DLT - evaluable participants will be treated at each dose level of the combination therapy. The actual number of participants to be enrolled will depend on the number of dose levels evaluated and the number of participants treated at each dose level. It is estimated that up to approximately 24 DLT - evaluable participants will be enrolled and treated in the Part 2A dose escalation.

[0244] In Part 2B, participants will be randomized into one of two cohorts to evaluate the safety, tolerability, and anti - myeloma activity of the PF - 07901801 + elotuzumab combination to determine the optimal combination dose for further clinical development. For Part 2B (randomized dose optimization), approximately 30 participants will be randomized at a 1:1 ratio to Dose Level A (DLA) and Dose Level B (DLB). The actual number of participants to be enrolled will depend on the tolerability of 3 to 6 initial DLT - evaluable participants. It is estimated that up to approximately 30 participants will be enrolled and treated in the Part 2B dose optimization.

[0245] Dose Level 1 (DL1) will be evaluated, and then Dose Level 2 (DL2) will be evaluated if DL1 is considered tolerable. Randomization in Part 2B will only start after DL2 is considered tolerable. The first (approximate) 6 participants enrolled in DLA and DLB are planned for DLT evaluation. Once the first 6 DLT - evaluable participants have completed the DLT observation period [from C0D1 to the end of Cycle 1], safety data will be evaluated by the Dose Level Review Committee. If both DLA and DLB are tolerable, randomization will be expanded to approximately 15 participants in total at each dose level. If one or both of DLA and DLB are not tolerable, additional dose levels (DL) may be added and a protocol amendment issued. If DL2 is not tolerable, DL1 will be further evaluated using at least 6 DLT - evaluable participants.

[0246] The target DLT rate for Part 2 is ≤30% and the tolerance evaluation is guided by the Bayesian optimal interval design (BOIN) approach to recommend dose escalation / de - escalation (DL1 to DL2 to Part 2B) and dose expansion (DLA and DLB to all 15 participants). The isotonic estimate of the toxicity rate according to the BOIN approach will guide the determination of the RP2D of elotuzumab + PF - 07901801 (TTI - 622). However, other available evidence (such as safety data outside the DLT window, clinical activity, PK, and pharmacodynamic data) will also be evaluated to determine the tolerance profile. Dose escalation decisions and the RP2D will be determined by the investigator and the sponsor in a Dose Level Review Meeting (DLRM).

[0247]

Administration

[0248]

Part 2A

[0249] Treat participants in Part 2A (dose escalation) using one of the following regimens:

[0250] · PF-07901801 (TTI-622) (8 mg / kg or 16 mg / kg) and enfortumab vedotin (44 mg or 76 mg), QW, over a 28-day cycle. For cycles 1 - 6, PF-07901801 and enfortumab vedotin are administered on days 1, 8, 15, and 22 of each cycle. For cycles 7 and subsequent cycles, PF-07901801 and enfortumab vedotin are administered on days 1 and 15 of each cycle.

[0251] · PF-07901801 (TTI-622) (8 mg / kg or 16 mg / kg) and enfortumab vedotin (44 mg or 76 mg), over a 28-day cycle. For cycle 1, PF-07901801 is administered on days 1, 8, 15, and 22, and enfortumab vedotin is administered on days 2 and 15. For cycles 2 - 6, PF-07901801 is administered on days 1, 8, 15, and 22, and enfortumab vedotin is administered on days 1 and 15 of each cycle. For cycles 7 and subsequent cycles, PF-07901801 and enfortumab vedotin are administered on days 1 and 15 of each cycle.

[0252] · PF-07901801 (TTI-622) (8 mg / kg or 16 mg / kg) and enfortumab vedotin (76 mg), QW, over a 28-day cycle. For cycle 1, PF-07901801 is administered on days 1, 8, 15, and 22, and enfortumab vedotin is administered on days 2, 8, 15, and 22. For cycles 2 - 6, PF-07901801 and enfortumab vedotin are administered on days 1, 8, 15, and 22 of each cycle. For cycles 7 and subsequent cycles, PF-07901801 and enfortumab vedotin are administered on days 1 and 15 of each cycle.

[0253] Prior to cycle 1 of Part 2A, participants may receive PF-07901801 (TTI-622) monotherapy and an initial dose of enfortumab vedotin as part of a lead-in cycle [also referred to as part of cycle 0 (C0)]. The duration of an exemplary lead-in cycle is 35 days, and PF-07901801 (e.g., at a dose of 8 mg / kg or 16 mg / kg) is administered on days 1, 8, 15, and 22 of the lead-in cycle as monotherapy, and the initial dose of enfortumab vedotin (e.g., a first dose of 12 mg and a second dose of 32 mg) is administered on days 29 and 32 of the lead-in cycle.

[0254] During the induction period, if signs / symptoms of clinical or biochemical progression are observed during Cycle 0 based on the investigator's judgment, participants receiving PF-07901801 (TTI-622) monotherapy (QW) may initiate initial treatment with elotuzumab (12 and 32 mg), followed by the full dose of 44 mg or 76 mg elotuzumab at any time according to the required schedule. During Cycle 0, elotuzumab can be initiated without progression confirmed according to the International Myeloma Working Group (IMWG) criteria.

[0255] If participants have received treatment for at least 6 months (6 cycles) and the disease response demonstrates at least PR or better and the response has persisted for at least 2 months, the dosing intervals of elotuzumab and PF-07901801 (TTI-622) are changed from QW to Q2W at the same elotuzumab dose level (e.g., elotuzumab changes from 44 mg QW to 44 mg Q2W) and the same PF-07901801 (TTI-622) dose level. If the dosing interval is changed, the duration of each cycle should be kept the same (i.e., 28-day cycle).

[0256] The agents in Part 2A can be administered according to the following dosing sequence. First, participants may receive premedication (antihistamine, acetaminophen) for up to 4 hours. Next, PF-07901801 (TTI-622) is infused for approximately 60 minutes. Next, elotuzumab is administered at least 60 minutes later. During this period, participants receive premedication (antihistamine, acetaminophen, dexamethasone). Next, participants receive elotuzumab.

[0257]

Part 2B

[0258] Participants in Part 2B (randomized dose optimization) are treated with a combination dose level selected from Part 2A at the Dose Level Review Meeting (DLRM).

[0259] Before Day 1 of Cycle 1 (e.g., 7 days and 4 days prior respectively), participants in Part 2B may receive the first and second initial doses of elotuzumab at 12 mg and 32 mg respectively. Optionally, before Part 2B, participants may receive PF-07901801 (TTI-622) monotherapy and the initial dose of elotuzumab as part of the induction period [also known as Cycle 0 (C0)], as described above for Part 2A. Optionally, before Part 2B, participants may receive the initial dose of elotuzumab as part of the induction period [also known as Cycle 0 (C0)], but not PF-07901801 (TTI-622).

[0260] If the participant has been treated according to the 76 mg QW elotuzumab schedule for at least 6 months (6 cycles) and the disease response demonstrates at least PR or better and the response has lasted for at least 2 months, then the dosing interval of elotuzumab and PF-07901801 is changed from QW to Q2W at the same elotuzumab dose level (e.g., elotuzumab changes from 76 mg QW to 76 mg Q2W) and the same PF-07901801 dose level. If the dosing interval is changed, each cycle should maintain the same duration (i.e., 28-day cycle).

[0261] In addition, if the participant has been treated according to the 76 mg Q2W elotuzumab schedule for at least 6 months (6 cycles) and the disease response demonstrates at least PR or better and the response has lasted for at least 2 months, then the dosing interval of PF-07901801 is changed from QW to Q2W at the same PF-07901801 dose level. If the dosing interval is changed, each cycle should maintain the same duration (i.e., 28-day cycle).

[0262] Figure 2 is a schematic diagram depicting aspects of Part 2A and Part 2B.

[0263] For Part 2A and Part 2B, on the days of administering PF-07901801 (TTI-622) and elotuzumab, PF-07901801 is administered before elotuzumab, and at least 60 minutes must have elapsed since the completion of the PF-07901801 infusion before starting the elotuzumab injection. PF-07901801 is administered by a 60-minute infusion.

[0264]

Study Population - Exemplary Inclusion Criteria

[0265] · Part 1: Received at least 1 but no more than 3 previous lines of treatment for multiple myeloma (induction therapy and subsequent stem cell transplantation and consolidation / maintenance therapy will be considered as 1 line of treatment).

[0266] · Part 2: Received at least 3 previous lines of treatment for multiple myeloma and is refractory to treatment with at least one IMiD, one PI, and one anti-CD38 antibody.

[0267]

Study Population - Exemplary Exclusion Criteria

[0268] · Part 1: Previous treatment with any anti-BCMA directed therapy (including bispecific antibodies, CAR-T, and ADC)

[0269] · Part 2: Previous treatment with any anti-BCMA directed therapy, excluding CAR-T

[0270] · Part 2: Treatment with a prior CD47-SIRPα-directed therapy.

Claims

1. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody.

2. The method according to claim 1, wherein the CD47 blocker comprises a CD47-binding form of human SIRPα.

3. The method according to any one of claims 1-2, wherein the CD47 blocker comprises an Fc fusion protein comprising the IgV domain of human SIRPα variant 2 attached to the antibody Fc region (SIRPα Fc fusion protein).

4. The method according to claim 3, wherein the SIRPα Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO:

7.

5. The method according to any one of claims 1-4, wherein the anti-BCMA / anti-CD3 bispecific antibody comprises: a first antigen-binding site that binds CD3, and a second antigen-binding site that binds BCMA, wherein the first antigen-binding site comprises VH and VL, wherein the second antigen-binding site comprises VH and VL, and wherein it has one or both of the following characteristics: (a) The VH of the first antigen-binding site comprises: the heavy chain CDR (HCDR) 1 of one or more of SEQ ID NO: 18, 33 and 34, the HCDR2 of one or more of SEQ ID NO: 19 and 35, and the HCDR3 of SEQ ID NO: 20; and the VL of the first antigen-binding site comprises: the light chain CDR (LCDR) 1 of SEQ ID NO: 21, the LCDR2 of SEQ ID NO: 22, and the LCDR3 of SEQ ID NO: 23; and (b) The VH of the second antigen-binding site comprises: the heavy chain CDR (HCDR) 1 of one or more of SEQ ID NO: 10, 30 and 31, the HCDR2 of one or more of SEQ ID NO: 11 and 32, and the HCDR3 of SEQ ID NO: 12; and the VL of the second antigen-binding site comprises: the light chain CDR (LCDR) 1 of SEQ ID NO: 13, the LCDR2 of SEQ ID NO: 14, and the LCDR3 of SEQ ID NO:

15.

6. The method according to any one of claims 1-5, wherein the anti-BCMA / anti-CD3 bispecific antibody comprises: a polypeptide containing the sequence of SEQ ID NO: 26, a polypeptide containing the sequence of SEQ ID NO: 27, a polypeptide containing the sequence of SEQ ID NO: 28, and a polypeptide containing the sequence of SEQ ID NO:

29.

7. The method according to any one of claims 1-6, wherein the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.

8. The method according to any one of claims 1-7, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle. Each cycle is 28 days, wherein the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first cycle.

9. The method according to any one of claims 1 to 8, wherein the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered according to the following regimen: (i) QW on days 1, 8, 15, and 22 of the first cycle, (ii) QW on days 2, 8, 15, and 22 of the first cycle, or (iii) Q2W on days 2 and 15 of the first cycle.

10. The method according to any one of claims 1 to 9, wherein it has one or both of the following characteristics: (A) The CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 6 cycles, wherein each cycle is 28 days, wherein the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first to sixth cycles, the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from: (i) QW on days 1, 8, 15, and 22 of the first to sixth cycles, (ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1, 8, 15, and 22 of the second to sixth cycles, and (iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second to sixth cycles; or (B) The CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the CD47 blocker is administered QW on days 1, 8, 15, and 22 of the first to sixth cycles, the anti-BCMA / anti-CD3 bispecific antibody is administered in the first to sixth cycles according to a regimen selected from: (i) QW on days 1, 8, 15, and 22 of the first to sixth cycles, (ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1, 8, 15, and 22 of the second to sixth cycles, and (iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second to sixth cycles, and the CD47 blocker and the anti-BCMA / anti-CD3 bispecific antibody are administered QW on days 1 and 15 of the seventh cycle.

11. The method according to any one of claims 1 to 10, wherein the CD47 blocker is administered to the patient for at least a lead-in cycle and a first cycle, wherein the lead-in cycle is before the first cycle, wherein the lead-in cycle comprises at least 28 or 35 days, and wherein the CD47 blocker is administered as a single therapy QW on days 1, 8, 15, and 22 of the lead-in cycle.

12. The method according to any one of claims 1 to 11, wherein prior to the first cycle, a first initial dose and a second initial dose of the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient.

13. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody, wherein the CD47 blocker is the SIRPαFc fusion protein (TTI-622) comprising the amino acid sequence of SEQ ID NO: 7, and wherein the anti-BCMA / anti-CD3 bispecific antibody is elotuzumab.

14. The method according to any one of claims 1 to 13, wherein the cancer is a blood cancer or a solid tumor cancer.

15. The method according to any one of claims 1 to 14, wherein the cancer is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and p53-mutated AML, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative disorders / tumors (MPDs), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndromes, lymphoma, T-cell lymphoma, Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell follicular lymphoma, large cell follicular lymphoma, myeloma, multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, light chain myeloma or Bence-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma or epithelioid sarcoma, optionally wherein the cancer is recurrent or refractory.

16. The method according to any one of claims 1 to 15, wherein the cancer is relapsed or refractory (R / R) multiple myeloma (MM).

17. The method according to any one of claims 1 to 16, wherein the patient has previously been treated with 1 to 3 lines of therapy.

18. The method according to any one of claims 1 to 17, wherein the patient has CD47-positive cancer cells.

19. A CD47 blocker or an anti-BCMA / anti-CD3 bispecific antibody for use in treating a patient according to any one of claims 1 to 18.

20. A kit comprising one or both of a CD47 blocker and an anti-BCMA / anti-CD3 bispecific antibody and instructions for use in the method according to any one of claims 1 to 19.

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