JP2025540215A - Combination therapy of CD47 blocking agents and anti-BCMA/anti-CD3 bispecific antibodies - Google Patents

Abstract

Dosing regimens and methods are provided for administering combination therapies that combine a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody. The dosing regimens and methods may further include an additional therapeutic agent.
Figure 1

Description

Cancer cells are targeted for destruction by antibodies that bind to cancer cell antigens and through the recruitment and activation of macrophages via binding of Fc receptors to the Fc portion of the antibody. Binding between CD47 on cancer cells and SIRPα on macrophages transmits a "don't eat me" signal, allowing many tumor cells to avoid destruction by macrophages. Inhibition of the CD47/SIRPα interaction (CD47 blockade) has been shown to enable macrophages to "find" and destroy targeted CD47+ cancer cells. The use of SIRPα to treat cancer through CD47 blockade is described in WO 2010/130053, which is incorporated herein by reference. International Patent Application Publication No. WO 2014/094122, which is incorporated herein by reference in its entirety, describes protein drugs that inhibit the interaction between CD47 and SIRPα. This CD47 blocking agent is a form of human SIRPα that incorporates a specific region of its extracellular domain linked to a particularly useful form of the IgG-based Fc region. In this form, SIRPαFc agents exhibit dramatic effects on the viability of cancer cells that display a CD47+ phenotype.

Another therapeutic approach to targeting cancer cells for destruction is bispecific antibodies directed against both T cell antigens and tumor cell antigens (e.g., B cell maturation antigens). Bispecific antibodies that simultaneously bind to T cell and tumor cell antigens can result in T cell activation, proliferation, and tumor cell death. Simultaneous binding of a bispecific antibody to CD3 on T cells and a target antigen on tumor cells brings the T cells into close proximity with the target tumor cells, resulting in T cell-mediated killing of the tumor cells.

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

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

Despite recent advances in treatment, MM remains an incurable disease, and nearly all patients, even those who initially respond to treatment, are expected to relapse. Even in patients undergoing autologous stem cell transplantation (ASCT), the median time to relapse is only 17.2 months (Jimenez-Zepeda et al., Bone Marrow Transplant., 2015, 50(2):204-8). Similarly, in patients treated with novel proteasome inhibitor (PI)- or immunomodulatory drug (IMiD)-based combination regimens 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).

MM patients typically undergo multiple lines of treatment as their disease progresses and becomes refractory to various therapeutic approaches. Clinical trials treating patients with BCMA-directed therapies in the relapsed/refractory multiple myeloma (RRMM) population have included patients who have received extensive prior treatment.

Outcomes in the RRMM population are considerably poor. For example, patients with RRMM who have a poor response to PI-based 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). Although newer, more effective treatments have significantly increased patient benefit, in this real-world setting (N=3449), the most recent 4-year survival rate 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.

CD47 blockade and anti-BCMA/anti-CD3 bispecific antibody approaches in anti-cancer drug development and treatment show great promise for various types of cancer, including B-cell lymphomas such as MM. However, improved dosing regimens and treatment methods are needed.

Provided herein are combination therapies for the treatment of cancer, as well as related methods and compositions. In some embodiments, the combination therapies provided herein comprise a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody. In some embodiments, the CD47 blocking agent is a SIRPα-Fc fusion protein (e.g., TTI-622) and the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab.

In some embodiments, provided herein are methods of treating cancer in a patient, comprising administering to the patient a combination therapy comprising a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody.

In some embodiments, provided herein are methods of treating cancer in a patient, comprising administering to the patient a combination therapy comprising a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody, wherein the CD47 blocking agent is a SIRPαFc fusion protein (TTI-622/maprilpacept) comprising the amino acid sequence of SEQ ID NO: 7, and the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab.

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

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

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

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

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

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

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

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

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

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

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

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

FIG. 1 illustrates an exemplary dosing regimen combining erlanatamab, carfilzomib, and dexamethasone. Each cycle is 28 days long. The regimen includes cycle 1 (C1), cycles 2-6 (C2-C6), and cycles 7 and beyond (C7+). As shown in FIG. 1, erlanatamab is administered on days 1, 8, 15, and 22 of cycles C1-C6 and on days 1 and 15 of cycles C7 and beyond. Each erlanatamab 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/ ^m² , and the carfilzomib dose on all other days is 70 mg/ ^m² . Dexamethasone is administered on days 1, 8, 15, and 22 of all cycles. Each dexamethasone dose is 40 mg. FIG. 2 shows a schematic diagram of the study design for Parts 2A and 2B of an exemplary dosing regimen combining erlanatamab and TTI-622.

The present invention may be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included therein. It is to be understood that the present invention is not limited to specific methods of preparation, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

Exemplary embodiments (E) of the present invention provided herein include the following:

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

E2. The method of E1, wherein the CD47 blocking agent comprises a CD47-binding form of human SIRP alpha (SIRPα).

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

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

E5. The method of any one of E1 to E4, wherein the CD47 blocking agent comprises an Fc fusion protein comprising the IgV domain of human SIRPα variant 2 attached to an antibody Fc region (SIRPαFc fusion protein).

E6. The method of E5, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide having the amino acid sequence of SEQ ID NO: 1.

E7. The method of any one of E5 to E6, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide having the amino acid sequence of SEQ ID NO:2.

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

E9. The method of any one of E5 to E8, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide having the amino acid sequence of SEQ ID NO: 1, or a variant thereof having 1, 2, 3, 4, or 5 amino acid substitutions compared to the sequence of SEQ ID NO: 1.

E10. The anti-BCMA/anti-CD3 bispecific antibody comprises a first antigen-binding site that binds to CD3 and a second antigen-binding site that binds to BCMA, wherein the first antigen-binding site comprises a VH and a VL, and the second antigen-binding site comprises a VH and a VL;
a) a first antigen-binding site VH comprises a heavy chain CDR (HCDR)1 of one or more of SEQ ID NOs: 18, 33, and 34, a HCDR2 of one or more of SEQ ID NOs: 19 and 35, and a HCDR3 of SEQ ID NO: 20; and a first antigen-binding site VL comprises a light chain CDR (LCDR)1 of SEQ ID NO: 21, a LCDR2 of SEQ ID NO: 22, and a LCDR3 of SEQ ID NO: 23;
b) The method of any one of E1 to E9, wherein the second antigen-binding site VH comprises a heavy chain CDR (HCDR)1 of one or more of SEQ ID NOs: 10, 30, and 31, a HCDR2 of one or more of SEQ ID NOs: 11 and 32, and a HCDR3 of SEQ ID NO: 12; and the second antigen-binding site VL comprises one or both of a light chain CDR (LCDR)1 of SEQ ID NO: 13, a LCDR2 of SEQ ID NO: 14, and a LCDR3 of SEQ ID NO: 15.

E11. The method of E10, wherein the first antigen-binding site VH 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 first antigen-binding site VL 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 second antigen-binding site VH 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 second antigen-binding site VL 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.

E12. The method of 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.

E13. The method of any one of E1 to E12, wherein the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab.

E14. The method of any one of E1, or E10 to E13 if dependent on E1, wherein the CD47 blocking agent is an anti-CD47 or anti-SIRPα antibody.

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

E16. The method of any one of E1 to E15, wherein the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, each cycle being 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.

E17. The method of any one of E1 to E16, wherein the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, each cycle being 28 days, and wherein the CD47 blocking agent 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.

E18. The method of any one of E1 to E17, wherein the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least seven cycles, each cycle lasting 28 days, and the CD47 blocking agent is administered QW on days 1, 8, 15, and 22 of cycles 1 through 6 and Q2W on days 1 and 15 of cycle 7.

E19. The method of any one of E1 to E18, wherein the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least seven cycles, each cycle being 28 days, and the anti-BCMA/anti-CD3 bispecific antibody is administered in a regimen selected from the following in cycles 1 through 6: i) QW on days 1, 8, 15, and 22 of cycles 1 through 6; ii) QW on days 2, 8, 15, and 22 of cycle 1 and QW on days 1, 8, 15, and 22 of cycle 2 through 6; and iii) Q2W on days 2 and 15 of cycle 1 and Q2W on days 1 and 15 of cycles 2 through 6, and in cycle 7, Q2W on days 1 and 15.

E20.
A) the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least six cycles, each cycle being 28 days, wherein the CD47 blocking agent is administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, and the anti-BCMA/anti-CD3 bispecific antibody is administered in cycles 1 through 6 in a regimen selected from: i) QW on days 1, 8, 15, and 22 of cycles 1 through 6; ii) QW on days 2, 8, 15, and 22 of cycle 1 and QW on days 1, 8, 15, and 22 of cycles 2 through 6; and iii) Q2W on days 2 and 15 of cycle 1 and Q2W on days 1 and 15 of cycles 2 through 6; or
B) The CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, each cycle being 28 days, with the CD47 blocking agent administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, and the anti-BCMA/anti-CD3 bispecific antibody administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, i) QW on days 1, 8, 15, and 22 of cycles 1 through 6, ii) QW on days 2, 8, 15, and 22 of cycle 1, and ii) QW on days 2, 8, 15, and 22 of cycle 1. and iii) Q2W on days 1, 8, 15, and 22 of cycles 2 through 6; and iii) Q2W on days 2 and 15 of cycle 1 and Q2W on days 1 and 15 of cycles 2 through 6; and wherein one or both of the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered Q2W on days 1 and 15 of cycle 7.

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

E22. The method of any one of E1 to E21, wherein the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, each cycle being 28 days, and the anti-BCMA/anti-CD3 bispecific antibody is administered in a regimen selected from: i) doses comprising 44 mg or 76 mg QW on days 1, 8, 15, and 22 of the first cycle; ii) doses comprising 44 mg or 76 mg QW on days 2, 8, 15, and 22 of the first cycle; and iii) doses comprising 44 mg or 76 mg Q2W on days 2 and 15 of the first cycle.

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

E24. The method of any one of E15 to E23, wherein the dose interval of one or both of the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody is changed from QW to Q2W if, after at least six cycles, the disease response is at least a partial response (PR) or better and the response is sustained for at least two months.

E25. The method of any one of E1 to E24, wherein the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least seven cycles, each cycle being 28 days, and the CD47 blocking agent is administered at a dose comprising 8 mg/kg or 16 mg/kg QW on days 1, 8, 15, and 22 of cycles 1 through 6, and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of cycle 7.

E26. A CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody are administered to a patient for at least 7 cycles, each cycle being 28 days, and the anti-BCMA/anti-CD3 bispecific antibody is administered in the following doses in cycles 1 through 6: i) a dose containing 44 mg or 76 mg QW on days 1, 8, 15, and 22 of cycles 1 through 6; ii) a dose containing 44 mg or 76 mg QW on days 2, 8, 15, and 22 of cycle 1; and The method of any one of E1 to E25, wherein the method is administered in a regimen selected from: iii) a dose comprising 44 mg or 76 mg Q2W on days 1, 8, 15, and 22 of cycles 2 through 6; and iii) a dose comprising 44 mg or 76 mg Q2W on days 2 and 15 of cycle 1, 44 mg or 76 mg Q2W on days 1 and 15 of cycles 2 through 6, and 44 mg or 76 mg Q2W on days 1 and 15 of cycle 7.

E27. A CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody are administered to a patient for at least 7 cycles, each cycle being 28 days, with the CD47 blocking agent administered at a dose comprising 8 mg/kg or 16 mg/kg QW on days 1, 8, 15, and 22 of cycles 1 through 6 and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of cycle 7, and the anti-BCMA/anti-CD3 bispecific antibody administered in cycles 1 through 6 at: i) a dose comprising 44 mg or 76 mg QW on days 1, 8, 15, and 22 of cycles 1 through 6. The method of any one of E1 to E26, wherein the eye is administered a regimen selected from: ii) a dose comprising 44 mg or 76 mg QW on days 2, 8, 15, and 22 of the first cycle, and 44 mg or 76 mg QW on days 1, 8, 15, and 22 of cycles 2 through 6; and iii) a dose comprising 44 mg or 76 mg Q2W on days 2 and 15 of the first cycle, and 44 mg or 76 mg Q2W on days 1 and 15 of cycles 2 through 6, and 44 mg or 76 mg Q2W on days 1 and 15 of cycle 7.

E28. The method of any one of E1 to E27, wherein prior to the first cycle, the patient is administered at least one dose of a CD47 blocking agent as monotherapy.

E29. The method of any one of E1 to E28, wherein the CD47 blocking agent is administered to the patient for at least the induction cycle and the first cycle, the induction cycle preceding the first cycle, the induction cycle comprising at least 28 or 35 days, and the CD47 blocking agent is administered as monotherapy QW on days 1, 8, 15, and 22 of the induction cycle.

E30. The method of any one of E28 and E29, wherein the CD47 blocking agent is administered as monotherapy at a dose including 8 mg/kg or 16 mg/kg.

E31. The method of any one of E1 to E30, wherein the patient is administered a first priming dose and a second priming dose of an anti-BCMA/anti-CD3 bispecific antibody prior to the first cycle.

E32. The method of any one of E1 to E30, wherein the anti-BCMA/anti-CD3 bispecific antibody is administered to the patient for at least an induction cycle and a first cycle, the induction cycle preceding the first cycle, the induction cycle comprising 7 days, and the anti-BCMA/anti-CD3 bispecific antibody being administered as a first priming dose and a second priming dose on days 1 and 4 of the induction cycle.

E33. The method of any one of E1 to E31, wherein a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least an induction cycle and a first cycle, the induction cycle preceding the first cycle, the induction cycle comprising 35 days, the CD47 blocking agent being administered on days 1, 8, 15, and 22 of the induction cycle, and the anti-BCMA/anti-CD3 bispecific antibody being administered as a first and second priming dose on days 29 and 32 of the induction cycle.

E34. The method of any one of E31 to E33, wherein the first priming dose of the anti-BCMA/anti-CD3 bispecific antibody comprises 12 mg and the second priming dose of the anti-BCMA/anti-CD3 bispecific antibody comprises 32 mg.

E35. The method of any one of E18 to E20 and E24 to E27, further comprising administering a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody Q2W on days 1 and 15 of the eighth and additional cycles until disease progression.

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

E37. The method of any one of E1 to E36, wherein the CD47 blocking agent is administered intravenously and/or the anti-BCMA/anti-CD3 bispecific antibody is administered subcutaneously.

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

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

E40. TTI-622 and erlanatamab are administered to patients for at least 7 cycles, each cycle being 28 days, with TTI-622 administered at a dose including 8 mg/kg or 16 mg/kg QW on days 1, 8, 15, and 22 of cycles 1 through 6 and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of cycle 7, and erlanatamab administered at the following doses in cycles 1 through 6: i) 44 mg or 76 mg QW on days 1, 8, 15, and 22 of cycles 1 through 6; ii) 44 mg or 76 mg QW on days 1, 8, 15, and 22 of cycles 1 through 6; The method of E38 or E39, wherein 44 mg or 76 mg are administered in a regimen selected from: iii) a dose comprising 44 mg or 76 mg Q2W on days 2, 8, 15, and 22 of the first cycle, and 44 mg or 76 mg Q2W on days 1, 8, 15, and 22 of the second through sixth cycles; and iii) a dose comprising 44 mg or 76 mg Q2W on days 2 and 15 of the first cycle, and 44 mg or 76 mg Q2W on days 1 and 15 of the second through sixth cycles, and 44 mg or 76 mg Q2W on days 1 and 15 of the seventh cycle.

E41. The method of any one of E1 to E40, wherein i) the CD47 blocking agent is administered to the patient at least 60 minutes before administering the anti-BCMA/anti-CD3 bispecific antibody to the patient on the day both the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient, or ii) the CD47 blocking agent is administered to the patient about 24 hours before administering the anti-BCMA/anti-CD3 bispecific antibody to the patient.

E42. The method of any one of E1 to E41, wherein at least one dose of premedication is administered to the patient prior to each dose of the CD47 blocking agent and/or prior to the first priming dose, second priming dose, and/or first therapeutic dose of the anti-BCMA/anti-CD3 bispecific antibody.

E43. The method of any one of E1 to E42, wherein one or more additional therapeutic agents are administered to the patient.

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

E45. The method of E44, wherein an anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor are administered to the patient for at least a first cycle, each cycle being 28 days, and 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.

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

E47. The method of any one of E44 to E46, wherein the proteasome inhibitor is administered at a dose including 20 mg/ ^m2 or 70 mg/ ^m2 .

E48. The method of any one of E44 to E47, further comprising administering dexamethasone to the patient.

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

E50. The method of E48 or E49, wherein dexamethasone is administered at a dose of 40 mg.

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

E52. The method of any one of E45 to E51, wherein the patient is administered a first priming dose and a second priming dose of an anti-BCMA/anti-CD3 bispecific antibody prior to the first cycle.

E53. The method of any one of E45 to E52, wherein the anti-BCMA/anti-CD3 bispecific antibody is administered to the patient for at least an induction cycle and a first cycle, the induction cycle preceding the first cycle, the induction cycle comprising 7 or 14 days, and the anti-BCMA/anti-CD3 bispecific antibody is administered as a first priming dose and a second priming dose on days 1 and 4 of the induction cycle.

E54. The method of any one of E44 to E53, wherein one or more additional therapeutic agents are administered to the patient.

E55. The method of any one of E1 to E54, wherein the cancer is a blood cancer or a solid tumor cancer.

E56. Cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and p53-mutated AML, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myeloproliferative disorders/neoplasms (MPDS), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome, lymphoma, T-cell lymphoma, Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, The method of any one of E1 to E55, wherein the cancer is selected from the group consisting of lymphoma, small cell follicular lymphoma, large cell follicular lymphoma, myeloma, multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, light chain or Bence-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma, or epithelioid sarcoma, and the cancer may be relapsed or refractory.

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

E58. The method of any one of E1 to E57, wherein the patient has previously been treated with 1 to 3 lines of therapy.

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

E60. The method of any one of E1 to E43, wherein the patient has CD47-positive cancer cells.

E61. A CD47 blocking agent or anti-BCMA/anti-CD3 bispecific antibody for use in treating a patient according to any one of E1 to E43, or E55 to E60 if dependent on any one of E1 to E43.

E62. Use of a CD47 blocking agent or an anti-BCMA/anti-CD3 bispecific antibody in the manufacture of a medicament for use in treating a patient according to any one of E1 to E43, or, if dependent on any one of E1 to E43, E55 to E60.

E63. A kit comprising one or both of a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody and instructions for use according to the method of any one of E1 to E43, and optionally further comprising one or more additional therapeutic agents according to the method of any one of E1 to E43, or, if dependent on any one of E1 to E43, E55 to E60.

E64. An anti-BCMA/anti-CD3 bispecific antibody or proteasome inhibitor for use in treating a patient according to any one of E44 to E54, or E55 to E60 when dependent on any one of E44 to E54.

E65. Use of an anti-BCMA/anti-CD3 bispecific antibody or a proteasome inhibitor in the manufacture of a medicament for use in treating a patient according to any one of E44 to E54, or E55 to E60 when dependent on any one of E44 to E54.

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

The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

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

The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are described, for example, in 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 (edited by R.I. Freshney (1987)), Oligonucleotide Synthesis (edited by M.J. Gait, 1984), Methods in Molecular Biology, Humana Press, Cell Biology: A Laboratory Notebook (edited by J.E. Cellis, 1998), Academic Press, Animal Cell Culture (R.I. Freshney), 1987, Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998), Plenum Press, Cell and Tissue Culture Laboratory Procedures (eds. A. Doyle, J.B. Griffiths, and D.G. Newell, 1993-8), J. Wiley and Sons, Handbook of Experimental Immunology (eds. D. M. Weir and C. C. Blackwell), Gene Transfer Vectors for Mammalian Cells (eds. J. M. Miller and M. P. Calos, 1987), PCR: The Polymerase Chain Reaction (eds. Mullis et al., 1994), Current Protocols in Immunology (eds. J. E. Coligan et al., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (C.A. Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989), Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000), Using Antibodies: A Laboratory These methods are commonly used using conventional methods, such as those widely used in the Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)), The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995), and their latest versions.

Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those skilled in the art.

As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "an" antibody includes one or more antibodies.

When aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the invention encompasses not only the entire recited group 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 group members. The invention also contemplates the explicit exclusion of one or more of any of the group members in the claimed invention.

Any examples following the term "e.g.," or "for example," are not intended to be exhaustive or limiting.

As used herein, the term "about," when used to modify a parameter (e.g., a dose of a SIRPαFc fusion protein) that defines a numerical value, means that the parameter can vary by as much as 10% above and below the numerical value stated for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

The terms "identity" or "identical to" refer to the overall relatedness between polymers, such as nucleic acid molecules (e.g., DNA or RNA molecules) or polypeptide molecules. "Identity" is measured by the percent of identical matches between two or more sequences, using gap alignment, which is handled by specific mathematical models (e.g., algorithms) in computer programs that are well known in the art.

The terms "treating," "treat," or "treatment" refer to any type of treatment, for example, to alleviate, reduce, or slow the progression of a patient's disease, disorder, or condition, or any tissue damage associated with the disease. In some embodiments, the disease, disorder, or condition is cancer.

The term "therapeutically effective amount" refers to an amount of active ingredient that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, and may include one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., halting or slowing further development of the pathology or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

The term "CD47 ⁺ " (or CD47+) is used in reference to the phenotype of cells targeted for binding by a SIRP alpha fusion protein or other CD47-binding agent. Cells that are CD47 ⁺ can be identified by flow cytometry using a CD47 antibody as an affinity ligand. Appropriately labeled CD47 antibodies are commercially available for this use (e.g., the antibody product clone B6H12 is available from Santa Cruz Biotechnology). Cells examined for the CD47 phenotype can include standard tumor biopsy samples, particularly blood samples taken from subjects suspected of harboring endogenous CD47 ⁺ cancer cells. CD47 disease cells of particular interest as targets for therapy with SIRP alpha fusion proteins are those that "overexpress" CD47. These CD47 ⁺ cells are typically disease cells that display CD47 on their surface at a density that exceeds the normal CD47 density for a given cell type. CD47 overexpression varies among different cell types, but is intended herein to refer to any CD47 level determined, for example, by flow cytometry as exemplified herein, or by immunostaining or gene expression analysis, etc., that is higher than the level measurable in a cellular counterpart having a CD47 phenotype that is normal for that cell type.

"Antibody" refers to an immunoglobulin molecule capable of specifically binding to a target, such as a polypeptide, carbohydrate, polynucleotide, or lipid, through at least one antigen-binding site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses any type of antibody (e.g., monospecific, bispecific), including portions of an intact antibody (e.g., "antigen-binding fragments") that retain the ability to bind to a given antigen, as well as any other modified configuration of an immunoglobulin molecule that contains an antigen-binding site. An exemplary antibody comprises i) a light chain, a heavy chain, or both variable regions; and ii) a heavy chain constant region comprising three consecutive immunoglobulin domains (CH1, CH2, and CH3) and a light chain constant region (CL) comprising a single immunoglobulin domain. A "bispecific antibody" refers to a molecule with binding specificities for at least two different epitopes. In some embodiments, a bispecific antibody can simultaneously bind to two different antigens. In other embodiments, the two different epitopes may be present on the same antigen. In certain embodiments, bispecific antibodies can simultaneously bind to two antigens expressed on two distinct cells.

The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either 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 known as hypervariable regions, which contribute to the formation of the antigen-binding site of the antibody. When a variant of a subject variable region is desired, particularly one employing a substitution of amino acid residues 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 subject variable region with the variable regions of other antibodies containing CDR1 and CDR2 sequences in the same canonical class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

Antibodies produced by a host cell may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, upon expression of a particular nucleic acid molecule encoding a full-length heavy chain, the antibody produced by the host cell may comprise a full-length heavy chain or may comprise a truncated variant of the full-length heavy chain. This is particularly true when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to the Kabat EU index). Thus, the C-terminal lysine or C-terminal glycine and lysine of the antibodies or SIRPαFc regions provided herein may or may not be present.

Erlanatamab is a BCMAxCD3 bispecific antibody. Erlanatamab is described, for example, in U.S. Patent No. 9,969,809, which is incorporated by reference in its entirety. Selected sequences of erlanatamab are shown in Table 1 herein. Erlanatamab is also known as PF-06863135, and these terms are used interchangeably herein.

CD47 Blocking Agents The dosing regimens and methods provided herein include a CD47 blocking agent. As used herein, a CD47 blocking agent can be any molecule that interferes with, attenuates, or blocks signaling that occurs when CD47 interacts with SIRPα presented by macrophages.

In some embodiments, CD47-binding forms of human SIRPα are CD47 blocking agents for use in the regimens and methods provided herein. These molecules are based on the extracellular region of human SIRPα. They contain at least a region of the extracellular region sufficient to confer effective CD47 binding affinity and specificity. So-called "soluble" forms of SIRPα that lack the membrane anchor component have been described in the literature, including those referenced in WO 2010/070047 (Novartis), WO 2013/109752 (Stanford), and WO 2014/094122 (Trillium), each of which is incorporated by reference in its entirety.

In some embodiments, the soluble form of SIRPα is an Fc fusion. More specifically, the drug suitably comprises a human SIRPα protein fused directly or indirectly to an antibody constant region or Fc (crystallizable fragment). Unless otherwise noted, the term "human SIRPα" as used herein refers to the wild-type, endogenous, mature form of human SIRPα. In humans, SIRPα protein is found in two major forms. One form, the Variant 1 or V1 form, has the amino acid sequence assigned as NCBI RefSeq NP_542970.1 (residues 27-504 constitute the mature form). Another form, the Variant 2 or V2 form, differs by 13 amino acids and has the amino acid sequence assigned in GenBank as CAA71403.1 (residues 30-504 constitute the mature form). These two forms of SIRPα constitute approximately 80% of the forms of SIRPα present in humans, and both are encompassed herein by the term "human SIRPα." Also encompassed by the term "human SIRPα" is the minor form thereof that is endogenous to humans and has the same property of initiating signaling through CD47 upon binding. The present invention is most specifically directed to drug combinations that include the human SIRP variant 2 form, or V2.

In the dosing regimens and methods provided herein, useful SIRPαFc fusion proteins comprise one of the three so-called immunoglobulin (Ig) domains present within the extracellular region of human SIRPα. More specifically, the SIRPαFc proteins of the present invention incorporate residues 32-137 (106-mer) of human SIRPα, which constitute the V2 form of the IgV domain and define it according to current nomenclature. This SIRPα sequence, shown below, is referred to herein as SEQ ID NO:1.
EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA [SEQ ID NO: 1]

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

SIRPα fusion proteins of the present invention can also incorporate an Fc region having effector function. Fc refers to "fragment crystallizable" and refers to the constant region of an antibody, consisting primarily of the CH2 and CH3 domains of the heavy chain constant region and components within the hinge region. Suitable Fc components include those having effector function. An Fc component "having effector function" is an Fc component that has at least some effector function, such as at least some contribution to antibody-dependent cellular cytotoxicity or some ability to fix complement. The Fc also binds to at least an Fc receptor. These properties can be demonstrated using assays established for this purpose. Functional assays include standard chromium release assays to detect target cell lysis. According to this definition, a wild-type IgG1 or IgG4 Fc region has effector function, while a human IgG4 Fc region mutated to eliminate effector function, such as by incorporation of a series of modifications including Pro233, Val234, and Ala235 and deletion (EU) of Gly236, is considered to have no effector function. In some embodiments, the Fc is based on a human antibody of the IgG1 isotype. The Fc regions of these antibodies would be readily identifiable by one of skill in the art. In embodiments, the Fc region comprises the lower hinge-CH2-CH3 domain.

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

Thus, in some embodiments, the Fc region has either 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 with a typical effector-active constant region. Such an Fc region sequence can correspond, for example, to the Fc region of any of the following IgG1 sequences (all taken from GenBank): 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).

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 present but with effector activity that is significantly weaker in nature than that of the IgG1 Fc region. The sequence of such an Fc region can correspond, for example, to the Fc region of any of the following IgG4 sequences: P01861 (residues 99-327) from UniProtKB/Swiss-Prot and CAC20457.1 (residues 99-327) from GenBank.

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

In some embodiments, the Fc region incorporates one or more alterations, typically no more than about 10, e.g., up to 1, 2, 3, 4, 5, or 6, including amino acid substitutions that affect specific Fc properties. In one specific embodiment, the Fc region incorporates an alteration at position 228 (EU numbering), in which serine at this position is replaced with 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 the substitution of Asn ²⁹⁷ with glycine or alanine, alterations that enhance half-life, such as T ²⁵² L, T ²⁵³ S, and T ²⁵⁶ F, as taught in US Pat. No. 6,277,7375, as well as numerous others. Alterations that enhance Fc properties while remaining conformationally silent, e.g., retaining Fc receptor binding, are particularly useful. In another embodiment, the Fc region is modified to increase its biological half-life. Various approaches are possible. For example, as described in U.S. Patent No. 6,277,375, one or more of the following mutations can be introduced: T252L, T254S, T256F.

In a specific embodiment, when the Fc component is an IgG4 Fc, the Fc incorporates at least an S ²²⁸ P mutation and has the amino acid sequence set forth below and referred to herein as SEQ ID NO:5:
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 5]

Thus, in some embodiments, the CD47 blocking agent used in the regimens and methods provided herein is a SIRP fusion protein useful for inhibiting binding of human SIRPα to human CD47, thereby inhibiting or reducing signal transduction mediated through CD47 bound to SIRPα, a fusion protein comprising a human SIRPα component, and an Fc component fused thereto, wherein the SIRPα component comprises or consists of a single IgV domain of human SIRPα V2, and the Fc component contains a human IgG Fc domain having effector function.

In one embodiment, the fusion protein comprises a SIRPα component 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 component comprises residues 31-148 of the V2 form of human SIRPα, i.e., SEQ ID NO: 2. In one embodiment, the Fc component is the Fc component of human IgG1 designated P01857, which in a specific embodiment has the amino acid sequence incorporating the lower hinge-CH2-CH3 region thereof, i.e., SEQ ID NO: 3. In another embodiment, the Fc component is the Fc component of human IgG4 designated P01861, which in a specific embodiment has the amino acid sequence incorporating the lower hinge-CH2-CH3 region thereof and the S228P mutation, i.e., SEQ ID NO: 5.

In some embodiments, a SIRPαFc fusion protein is provided and used in a secreted dimeric fusion form, which fusion protein incorporates a SIRPα component having SEQ ID NO: 1 and preferably SEQ ID NO: 2, fused thereto, having an effector function and an Fc region having SEQ ID NO: 3. 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:
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISNITPADAGT YYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 6]

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

In an alternative embodiment, the Fc component of the fusion protein is based on IgG4, preferably IgG4 incorporating the ^S228P mutation. When the fusion protein incorporates the preferred SIRPα IgV domain of SEQ ID NO:2 and the IgG4 Fc region is SEQ ID NO:5, the fusion protein comprises SEQ ID NO:7, shown below:
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISNITPADAGT YYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 7]

The SIRPαFc fusion protein of SEQ ID NO:7 is also known as TTI-622 and Maprylpacept. TTI-622/Maprylpacept comprises a dimer of the protein of SEQ ID NO:7.

In one embodiment of the dosing regimen or method provided herein, the SIRPαFc fusion protein comprises a sequence that includes the polypeptide of 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.

As described in the literature, the SIRPα sequence incorporated into the SIRPαFc fusion protein can be varied. This can eliminate glycosylation sites in the protein, such as position 89 and elsewhere. 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.

In a SIRPαFc fusion protein, the SIRPα component and the Fc component are fused either directly or indirectly to provide a single-chain polypeptide, which may ultimately be produced as a dimer in which the single-chain polypeptides are coupled through an interchain disulfide bond formed within the Fc region. The nature of the fusion region is not important. The fusion can be direct between the two components, with the SIRP component constituting the N-terminus of the fusion and the Fc component constituting the C-terminus. Alternatively, the fusion can be indirect through a linker composed of one or more amino acids, preferably genetically encoded amino acids, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any number of amino acids from 5 to 100 amino acids, such as 5 to 50, 5 to 30, or 5 to 20 amino acids. The linker may include a peptide encoded by DNA that comprises restriction sites such as BamHI, ClaI, EcoRI, HindIII, PstI, SalI, and XhoI sites.

Linker amino acids typically desirably have some flexibility to allow the Fc and SIRP components to adopt their active conformations. Residues that allow such flexibility are typically Gly, Asn, and Ser, so virtually any combination of these residues (particularly Gly and Ser) within the linker is likely to 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]), which can be repeated as (G4S)n, where n is 1, 2, 3, or more, or based on (Gly)n, (Ser)n, (Ser-Gly)n, or (Gly-Ser)n, etc. In another embodiment, the linker is GTELSVRAKPS [SEQ ID NO: 9]. This sequence constitutes the SIRPα sequence adjacent to the C-terminal side of the IgV domain (it will be understood that this adjacent sequence can be considered either as a linker or a different form of IgV domain when coupled with the minimal IgV sequence described above). The fusion region or linker need only permit the components to adopt their active conformation, which can be achieved by any form of linker available in the art.

In some embodiments, a SIRPαFc fusion protein (e.g., TTI-622) may be administered in the methods and regimens provided herein at a dose ranging from 0.1 to 50 mg/kg of subject body weight. For example, the dose of a SIRPαFc fusion protein may 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, or 26 mg/kg. g, 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. Doses of SIRPαFc fusion proteins can also include, for example, 2-40 mg/kg, 4-40 mg/kg, 5-50 mg/kg, 8-50 mg/kg, 8-40 mg/kg, 8-30 mg/kg, 8-28 mg/kg, 10-50 mg/kg, 10-40 mg/kg, 10-30 mg/kg, 10-25 mg/kg, or 10-20 mg/kg. These doses of SIRPαFc fusion proteins can be administered to a subject, for example, once per 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, such as a 14-day, 21-day, or 28-day cycle.

In some embodiments, the SIRPαFc fusion proteins provided herein (e.g., TTI-622) are administered as a "flat" (also called "fixed") dose, i.e., the dose is per patient and is not dependent on the patient's weight. In some embodiments, a SIRPαFc fusion protein such as TTI-622 is administered in a concentration 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. Fixed dose SIRPαFc fusion proteins may be administered in a variety of regimens. In some embodiments, doses are administered to patients every week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

In some embodiments, the SIRPαFc fusion protein is a) 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, 145 a) a lower limit level of 0, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, or 2200 mg; and b) a lower limit level of 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, or 1200 mg. 0, 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, 26 It is administered at a dose between the upper level of 00, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, or 3600 mg, with the lower level being a value less than the upper level.

Instead of, or in addition to, SIRPα-based drugs, still other types of CD47 blocking agents can be used in the methods and combinations of the present invention. These other drugs include, in particular, anti-CD47 antibodies that bind to CD47 and antagonize its interaction with SIRPα. By blocking this interaction, and due to the antibody's Fc region, the effects of CD47 antibodies can be similar to those of SIRPα-based Fc fusion drugs. Examples of CD47 antibodies are described in literature, such as US 2008/0107654 (Chugai), WO 2009/091601 (Stanford), WO 2013/119714 (InhibRx), WO 2016/109415 (Celgene), and WO 2016/081423 (Janssen). Because these antibodies bind to red blood cells, dosing regimens that take this into account have been developed and are described in WO 2014/149477. Properties of useful anti-CD47 antibodies include their ability to bind to CD47 in a manner that ultimately inhibits signaling by SIRPα, i.e., as antagonists. In some other embodiments, anti-SIRPα antibodies may also be used as CD47 blocking agents.

In some embodiments, the method further includes administering to the subject at least one dose of premedication prior to each dose of the CD47 blocking agent. The premedication may 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 doses can be the same or different prior to each dose of the CD47 blocking agent.

Anti-BCMA/Anti-CD3 Bispecific Antibodies The dosing regimens and methods provided herein include anti-BCMA/anti-CD3 bispecific antibodies. As used herein, an anti-BCMA/anti-CD3 bispecific antibody can be any molecule capable of simultaneously binding to both BCMA (e.g., on B cells) and CD3 (e.g., on T cells). Anti-BCMA/anti-CD3 bispecific antibodies are also referred to herein as "BCMA x CD3" or "BCMA" bispecific antibodies.

B-cell maturation antigen (BCMA, also known as TNFRSF17 and CD269) is a candidate for bispecific antibody-based immunotherapy. BCMA expression is upregulated during B-cell maturation into plasmablasts and plasma cells, but 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 patients with different cytogenetic risks at different disease stages. Furthermore, BCMA expression was not affected by autologous stem cell transplantation (ASCT) or chemotherapy treatment. In vivo, bispecific antibodies against BCMA have been shown to induce T-cell activation, reduce tumor burden, and prolong survival.

Examples of anti-BCMA/anti-CD3 bispecific antibodies that may be useful in the combination therapy of the present invention include, but are not limited to, AMG 420 (BCMA x CD3 bispecific T cell engaging agent, BiTE®, Amgen), AMG 701 (BCMA x CD3 BiTE®, Amgen), CC-93269 (BCMA x CD3 bispecific antibody, Celgene), teclistamab (JNJ-64007957-Jansen), erlanatamab (BCMA x CD3 bispecific antibody, Pfizer), Inc.), TNB-383B (TeneoBio/AbbVie), rimbosertamab (REGN5458-BCMA x CD3 bispecific antibody, Regeneron), alnuctamab (CC-93269-BMS), AFM26 (BCMA x CD16 tetravalent bispecific antibody, Affimed GmbH), and HPN217 (BCMA x ALB x CD3 trispecific, Harpoon Therapeutics).

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 to CD3 and the second antigen-binding site specifically binds to BCMA.

In some aspects, the anti-BCMA/anti-CD3 bispecific antibody may have any of the features or characteristics of any of the BCMA bispecific antibodies provided in WO 2016/166629, which is incorporated by reference herein for all purposes.

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

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

In some embodiments, the first antigen-binding site VH 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 first antigen-binding site VL 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 second antigen-binding site VH 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 second antigen-binding site VL 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.

In some aspects, the BCMA bispecific antibody is erlanatamab. Erlanatamab is a heterodimeric humanized full-length bispecific antibody composed of one B-cell maturation antigen (BCMA)-binding arm and one cluster of differentiation (CD3)-binding arm paired through hinge mutation technology. They utilize an engineered human IgG2Da crystallizable fragment (Fc) region. Erlanatamab is described, for example, in U.S. Patent No. 9,969,809, which is incorporated herein for all purposes. The sequence of erlanatamab is shown in Table 1. SEQ ID NOS: 18-25, 28, 29, and 33-35 are the sequences of the CD3 arm of erlanatamab, and SEQ ID NOS: 10-17, 26, 27, and 30-32 are the sequences of the BCMA arm of erlanatamab.

In some embodiments, the dose of erlanatamab may be selected from one of 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 44 mg, 76 mg, 116 mg, and 152 mg.

In some embodiments, dosing methods or regimens provided herein involving anti-BCMA/anti-CD3 bispecific antibodies may include one, two, or more priming doses. Priming doses can be utilized to initially prime the immune system with lower doses, thus reducing the rate, duration, and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In some embodiments, the first priming dose may be 4 mg to 32 mg, and the second priming dose may be 12 mg to 44 mg. An exemplary priming dose of erlanatamab is a first dose of 12 mg and a second dose of 32 mg. An exemplary priming dose schedule is administering a first priming dose (e.g., 12 mg) on day 1, a second priming dose (e.g., 32 mg) on day 4, followed by a therapeutic dose. In some embodiments, the therapeutic dose (e.g., 44 mg or 76 mg) is on day 8 (i.e., one week after the first priming dose). In some embodiments, the therapeutic dose is between 32 mg and 76 mg. The therapeutic dose may be selected from 44 mg or 76 mg. In some embodiments, the first priming dose is 12 mg, the second priming dose is 32 mg, and the therapeutic dose is 44 mg or 76 mg.

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

In some embodiments, the method further includes administering at least one dose of premedication to the subject prior to administering to the subject each of the single priming dose, the first priming dose, the second priming dose, and/or the first therapeutic dose of the anti-BCMA/anti-CD3 bispecific antibody. In some embodiments, the premedication is administered before the first and second priming doses and the first therapeutic dose. The premedication can be acetaminophen (or an equivalent, such as paracetamol), diphenhydramine (or an equivalent), and/or dexamethasone (or an equivalent). In some embodiments, dexamethasone is administered orally or intravenously once daily at a dexamethasone dosage of about 10 mg to about 40 mg, 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 dosage of the premedication can be the same or different while the subject receives the priming dosage, the first therapeutic dosage, and the subsequent dosage of the bispecific antibody.

Combination Therapy of an Anti-BCMA/Anti-CD3 Bispecific Antibody and a Proteasome Inhibitor Provided herein are combination therapies containing an anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor. In some embodiments, the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab and the proteasome inhibitor is carfilzomib. In some embodiments, the combination therapy containing the anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor also includes dexamethasone.

Carfilzomib is a second-generation proteosome inhibitor that binds irreversibly while potentially ameliorating resistance and reducing the potential for off-target toxicity. Glucocorticoids, such as dexamethasone, are the backbone of multiple myeloma treatment in both the newly diagnosed and relapsed/refractory settings.

Carfilzomib was first approved in the United States in 2012 based on the monotherapy response rate reported in a single-arm, multicenter study conducted in patients who had responded to at least one prior line of therapy and were refractory to their most recent therapy, with at least two prior lines. Patients received carfilzomib at the respective doses of 20 mg/ ^m² in cycle 1 and 27 mg/ ^m² in subsequent cycles. Dexamethasone 4 mg PO or IV was administered prior to the carfilzomib dose in cycles 1 and 2. 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).

Multiple myeloma cells are highly dependent on proteasome activity due to their high turnover of abnormal immunoglobulins. Carfilzomib is a standard-of-care proteasome inhibitor that has demonstrated significant activity in MM, initially as monotherapy and more recently with enhanced activity in combination with immune system-engaging drugs, including immunomodulatory drugs (IMiDs) and CD38-targeting antibodies. Carfilzomib has demonstrated activation of apoptosis, autophagy, direct inhibition of myeloma cell proliferation, and survival. In vitro studies indicate a role for the immunogenic potential of proteasome inhibition in eliciting anti-myeloma immune responses. Without being bound by theory, it is hypothesized that the combination of carfilzomib, which induces immunogenic cell death, with erlanatamab, T cell-mediated tumor lysis, may enhance activation of immune surveillance of MM cells through distinct and complementary mechanisms.

In some embodiments, a combination therapy containing an anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor may include any of the therapeutic molecules, dosages, and dosing frequencies described in Example 1.

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

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

In some embodiments, a combination therapy containing an anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor may include a dosing regimen of erlanatamab 76 mg QW and carfilzomib 70 mg/m ² QW.

In some embodiments, a combination therapy containing an anti-BCMA/anti-CD3 bispecific antibody and a proteasome inhibitor may include a dosing regimen of erlanatamab 76 mg Q2W and carfilzomib 70 mg/m ² QW.

Combination Therapy of a CD47 Blocking Agent and an Anti-BCMA/Anti-CD3 Bispecific Antibody Provided herein are combination therapies containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody. In some embodiments, the CD47 blocking agent is a SIRPα-Fc fusion protein (e.g., TTI-622) and the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab.

The inhibitory, anti-phagocytic "don't eat me" signal mediated through CD47 on tumor cells to membrane-bound SIRPα on macrophages plays a role in evading cancer innate immune surveillance. CD47 blockers, such as PF-07901801 (TTI-622) (SIRPα-fusion), interact with its ligand CD47 while the Fc region binds to Fcγ receptors on macrophages. This blocks the anti-phagocytic signal of CD47, enabling macrophage activation and resulting in the phagocytosis of tumor cells. After phagocytosis, tumor cell antigens are processed and presented by macrophages as MHC-peptide complexes to T cells, leading to T cell activation and tumor cell destruction. Therefore, it is hypothesized that the combination of an anti-BCMA/anti-CD3 bispecific antibody (such as erlanatamab), which engages the adaptive immune system via CD3 on T cells and BCMA on MM cells, with a CD47 blocking agent (such as PF-07901801 (TTI-622)), may enhance engagement of the immune cell repertoire to facilitate subsequent lysis/killing and control of BCMA-expressing MM cells.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include any of the therapeutic molecules, dosages, and dosing frequencies described in Example 1.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 44 mg QW and PF-07901801 8 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 44 mg QW and PF-07901801 16 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 44 mg Q2W and PF-07901801 8 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 44 mg Q2W and PF-07901801 16 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 76 mg QW and PF-07901801 8 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 76 mg QW and PF-07901801 16 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 76 mg Q2W and PF-07901801 8 mg/kg QW.

In some embodiments, a combination therapy containing a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody may include a dosing regimen of erlanatamab 76 mg Q2W and PF-07901801 16 mg/kg QW.

The SIRPαFc proteins provided herein exhibit negligible binding to red blood cells. Therefore, RBC "plumbing" need not be a consideration when administering medication using the SIRPαFc fusion proteins provided herein. Compared to other CD47 blocking agents that are bound by RBCs, it is estimated that the SIRPαFc fusions of the present invention may be effective at doses that are less than half the dose required for RBC-bound drugs, such as CD47 antibodies. Furthermore, the SIRPαFc fusion proteins provided herein are dedicated antagonists of SIRPα-mediated signals and exhibit negligible CD47 agonism upon binding. Therefore, any drug-induced stimulation need not be considered when establishing a medically useful unit dosing regimen.

The dosing regimens and methods provided herein may be useful for treating a variety of cancer cells. These include, in particular, CD47 ⁺ cancer cells, including liquid (hematological) and solid tumors. Solid tumors can be treated with the dosing regimens and methods provided herein to reduce their size, number, or growth rate and to control the growth of cancer stem cells. Such solid tumors include CD47 ⁺ tumors in the bladder, brain, breast, lung, colon, ovary, prostate, liver, and other tissues. In one embodiment, the dosing regimens and methods provided herein can be used to inhibit the growth or proliferation of blood cancers. As used herein, "blood cancer" refers to cancer of the blood, including, among others, leukemia, lymphoma, and myeloma. "Leukemia" refers to a cancer of the blood in which too many white blood cells are produced that are ineffective at fighting infection, thus displacing other parts of the blood, such as platelets and red blood cells. It will be understood that leukemia cases are classified as acute or chronic. Specific forms of leukemia may be, by way of example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myeloproliferative disorders/neoplasms (MPDS), and myelodysplastic syndromes. "Lymphoma" may refer to Hodgkin's lymphoma (both indolent and aggressive non-Hodgkin's lymphoma), Burkitt's lymphoma, and follicular lymphoma (small cell and large cell), among others. Myeloma may refer to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma. In certain embodiments, the dosing regimens and methods provided herein are useful for treating T-cell lymphomas, which are a highly heterogeneous group of lymphoid malignancies divided into cutaneous and peripheral TCLs, which themselves can be divided into nodal or extranodal types. CTCLs are derived from skin-homing T cells and consist of mycosis fungoides, Sézary syndrome, primary cutaneous T-cell lymphoproliferative disorder, and anaplastic large cell lymphoma. Common features of TCLs, with the exception of ALK and ALCL, are an aggressive course and poor response to treatment.

In some other embodiments, the hematological cancer treated with the dosing regimens and methods is a CD47 ⁺ leukemia, preferably selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome, preferably human acute myeloid leukemia.

In other embodiments, the hematological cancer treated with the dosing regimens or methods provided herein is a CD47+ lymphoma or myeloma selected from Hodgkin's lymphoma (both indolent and aggressive non-Hodgkin's lymphoma), Burkitt's lymphoma, follicular lymphoma (small cell and large cell), multiple myeloma (MM), ^giant cell myeloma, heavy chain myeloma, light chain or Bence-Jones myeloma, and leimyosarcoma.

In some embodiments, the cancer being treated with the dosing regimens or methods provided herein is recurrent and/or refractory (R/R). In some embodiments, the subject being treated with the dosing regimens or methods provided herein has previously been treated with 1 to 3 lines of therapy for the cancer.

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

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

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

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

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

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

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

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

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

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

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

The CD47 blocking agents and anti-BCMA/anti-CD3 bispecific antibodies provided herein can be administered to a subject via any of the established routes for protein delivery, particularly intravenous, intradermal, and subcutaneous injection or infusion, or by oral or intranasal administration. In some embodiments, the CD47 blocking agent (e.g., SIRPαFc fusion protein TTI-622) is administered intravenously. In some embodiments, the anti-BCMA/anti-CD3 bispecific antibody (e.g., erlanatamab) is administered subcutaneously.

In embodiments herein referring to methods of treatment, such embodiments are also further embodiments for use in that treatment, or alternatively, for the manufacture of a medicament for use in that treatment.

The contents of U.S. Provisional Patent Application No. 63/386,732, filed December 9, 2022, are incorporated by reference herein for all purposes.

The following examples of specific embodiments for carrying out the present invention are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The foregoing description and the following examples detail certain specific embodiments of the present disclosure and set forth the best mode contemplated by the inventors. However, no matter how detailed the foregoing may appear on paper, it will be understood that the present disclosure can be embodied in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

While the disclosed teachings have been described in terms of 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 claimed disclosure below. The following examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented herein. While the teachings of the present invention have been described in terms of these exemplary embodiments, those skilled in the art will readily appreciate that numerous variations and modifications of these exemplary embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the present teachings.

Sequences The sequences provided herein are summarized in Table 1 below.

In order that the present invention may be better understood, the following examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

Example 1
This is a Phase 1b, open-label, prospective, multicenter, non-randomized study to evaluate the safety, efficacy, PK, and pharmacodynamics of carfilzomib plus dexamethasone in combination with erlanatamab (Part 1) and PF-07901801 (TTI-622) monotherapy in combination with erlanatamab (Part 2) in participants with relapsed/refractory (R/R) multiple myeloma (MM) (RRMM). Study endpoints will be assessed using a dose-escalation approach.
Part 1: Dose escalation will evaluate the tolerability and safety of carfilzomib and dexamethasone in combination with erlanatamab to determine the RP2D of the combination.
Part 2A: Dose escalation will evaluate the tolerability, safety, PK, PD, and preliminary activity of PF-07901801 (TTI-622) monotherapy and erlanatamab in combination with PF-07901801 (TTI-622). Based on the totality of the data, two combination dose levels of PF-07901801 and erlanatamab will be selected for further evaluation in Part 2B.
Part 2B: Randomized dose optimization will evaluate the tolerability, safety, PK, PD, and activity of PF-07901801 (TTI-622) in combination with erlanatamab to determine the RP2D of the combination.

Part 1: Erlanatamab and carfilzomib/dexamethasone dose-escalation design:
The number of participants enrolled 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 erlanatamab combination.

Before progressing to the next dose level, safety data will be reviewed by the Dose Level Review Committee after DLT-evaluable participants complete the DLT observation period [Cycle 0, Day 1 (C0D1) through the end of Cycle 1].

The target DLT rate is ≤30%, and dose escalation/deescalation decisions will be guided by a Bayesian logistic regression model (BLRM) approach to recommend a RP2D for erlanatamab plus carfilzomib and dexamethasone (Part 1). However, other available evidence, such as safety data beyond the DLT window, clinical activity, pharmacokinetic (PK), and pharmacodynamic data, will also be evaluated in determining the tolerability profile and escalation decisions. Dose escalation decisions and the RP2D will be determined by consensus between the investigator and the sponsor in a Dose Level Review Meeting (DLRM).

dosage:
Part 1 participants will be treated with:
Erlanatamab, 44 or 76 mg QW for 28-day cycles. Carfilzomib, 20 mg/ ^m2 IV on day 1 of cycle 1 (C1D1). If tolerated, 70 mg/ ^m2 may then be given starting on day 8 of cycle 1 (C1D8) and for all subsequent doses administered on days 1, 8, and 15 of 28-day cycles thereafter. Also, dexamethasone, 40 mg orally (PO) or intravenous (IV) infusion, once weekly (QW) for 28-day cycles. Carfilzomib dosing may be modified for hematologic or other toxicity according to institutional guidelines. In general, carfilzomib dose modifications follow the applicable product prescribing information (see, e.g., Kyprolis (carfilzomib) USPI). Carfilzomib dose levels are 70 mg, 56 mg, 45 mg, and 36 mg according to the product's prescribing information.

If participants have been treated for at least 6 months (6 cycles) and have demonstrated at least a partial response (PR) or better, and the response is sustained for at least 2 months, the dose interval will be changed from QW to Q2W at the same erlanatamab dose level (e.g., changing erlanatamab from 76 mg QW to 76 mg Q2W or 44 mg QW to 44 mg Q2W). If the dose interval is changed, the cycle length should remain the same (i.e., 28-day cycle). The dose interval for carfilzomib plus dexamethasone will remain the same.

Prior to Part 1 Cycle 1, participants may receive a priming dose of erlanatamab as part of an induction 14-day priming dose cycle (also referred to as Cycle 0 (C0) where Day 1 of Cycle 1 follows Day 14 of Cycle 0). In a 14-day priming dose cycle, erlanatamab is administered at escalating doses over multiple days of the 14-day cycle. For example, erlanatamab may be administered on days 1, 4, and 8 of the priming dose cycle; more specifically, erlanatamab may be administered at a dose of 12 mg on day 1 of the 14-day priming dose cycle, 32 mg on day 4, and 44 mg or 76 mg on day 8.

Part 1 medications may be administered according to the following dosing sequence: First, participants may receive premedication (dexamethasone) for approximately 0.5 to 4 hours. Next, carfilzomib will be infused over approximately 30 minutes. Then, after at least 60 minutes have passed, erlanatamab will be administered.

Part 2: Erlanatamab and PF-07901801 (TTI-622)
Dose escalation and optimization design:
In dose escalation (Part 2A), approximately 3-6 DLT-evaluable participants will be treated at each dose level of the combination therapy. The actual number of participants 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 Part 2A dose escalation.

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 + erlanatamab combination and determine the optimal combination dose for further clinical development. In Part 2B, randomized dose optimization, approximately 30 participants will be randomized 1:1 to dose level A (DLA) and dose level B (DLB). The actual number of participants enrolled will depend on the tolerability of the first 3-6 DLT-evaluable participants. It is estimated that up to approximately 30 participants will be enrolled and treated in Part 2B dose optimization.

Dose level 1 (DL1) will be evaluated, followed by dose level 2 (DL2) if DL1 is deemed tolerable. Randomization for Part 2B will begin only after DL2 is deemed tolerable. The first (approximately) six participants enrolled in DLA and DLB will be scheduled for DLT evaluation. After the first six DLT-evaluable participants complete the DLT observation period (from COD1 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 a total of approximately 15 participants for each dose level. If one or both of DLA and DLB are not tolerated, other dose levels (DL) may be added and a protocol amendment will be issued. If DL2 is not tolerated, DL1 will be further evaluated within a minimum of six DLT-evaluable participants.

The target DLT rate is ≤30% in Part 2, and tolerability assessment will be guided by a Bayesian optimal interval design (BOIN) approach to recommend dose escalation/deescalation (from DL1 to DL2 to Part 2B) and dose expansion (all 15 participants from DLA and DLB). Isotonic estimates of toxicity rates from the BOIN approach will guide the determination of the RP2D for erlanatamab + PF-07901801 (TTI-622). However, other available evidence, such as safety data beyond the DLT window, clinical activity, PK, and pharmacodynamic data, will also be evaluated in determining the tolerability profile. The dose escalation decision and RP2D will be determined by consensus between the investigator and the DLRM sponsor.

dosage:
Part 2A
Participants in Part 2A (dose escalation) will be treated using one of the following protocols:
PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and erlanatamab 44 mg or 76 mg QW over 28-day cycles. In cycles 1-6, both PF-07901801 and erlanatamab are administered on days 1, 8, 15, and 22 of each cycle. From cycle 7 onwards, both PF-07901801 and erlanatamab are administered on days 1 and 15 of each cycle.
PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and erlanatamab 44 mg or 76 mg over 28-day cycles. In cycle 1, PF-07901801 is administered on days 1, 8, 15, and 22, and erlanatamab is administered on days 2 and 15. In cycles 2-6, PF-07901801 is administered on days 1, 8, 15, and 22 of each cycle, and erlanatamab is administered on days 1 and 15 of each cycle. From cycle 7 onwards, both PF-07901801 and erlanatamab are administered on days 1 and 15 of each cycle.
PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and erlanatamab 76 mg QW over 28-day cycles. In cycle 1, PF-07901801 is administered on days 1, 8, 15, and 22, and erlanatamab is administered on days 2, 8, 15, and 22. In cycles 2-6, both PF-07901801 and erlanatamab are administered on days 1, 8, 15, and 22 of each cycle. From cycle 7 onwards, both PF-07901801 and erlanatamab are administered on days 1 and 15 of each cycle.

Prior to Part 2A, Cycle 1, participants may receive PF-07901801 (TTI-622) monotherapy and a priming dose of erlanatamab as part of the induction cycle [also referred to as Cycle 0 (C0)]. An exemplary induction cycle is 35 days long, with PF-07901801 administered as monotherapy on days 1, 8, 15, and 22 of the induction cycle (e.g., at a dose of 8 mg/kg or 16 mg/kg) and a priming dose of erlanatamab administered on days 29 and 32 of the induction cycle (e.g., a first dose of 12 mg and a second dose of 32 mg).

During the induction cycle, participants receiving PF-07901801 (TTI-622) monotherapy QW may initiate a priming treatment with erlanatamab (12 and 32 mg), followed by a full dose of erlanatamab 44 mg or 76 mg at any time according to the required schedule if, based on the investigator's discretion, signs/symptoms of clinical or biochemical progression are observed during Cycle 0. Confirmed progression according to International Myeloma Working Group (IMWG) criteria is not required to initiate erlanatamab during Cycle 0.

If participants have been treated for at least 6 months (6 cycles) and have demonstrated a disease response of at least PR or better, with the response sustained for at least 2 months, the dose interval for both erlanatamab and PF-07901801 (TTI-622) will be changed from QW to Q2W (e.g., erlanatamab 44 mg QW to 44 mg Q2W) at the same erlanatamab dose level and the same PF-07901801 (TTI-622) dose level. If the dose interval is changed, the cycle length should be kept the same (i.e., 28-day cycle).

Medications in Part 2A may be administered according to the following dosing sequence: First, participants may receive premedication (antihistamine, acetaminophen) for up to four hours. Next, PF-07901801 (TTI-622) will be infused over approximately 60 minutes. Then, after at least 60 minutes have passed, erlanatamab will be administered. During this time, participants will receive premedication (antihistamine, acetaminophen, dexamethasone). Next, participants will receive erlanatamab.

Part 2B
Participants in Part 2B (randomized dose optimization) will be treated with the combination dose level selected from Part 2A at the Dose Level Review Meeting (DLRM).

Participants in Part 2B may receive first and second erlanatamab priming doses of 12 mg and 32 mg, respectively, prior to Day 1 of Cycle 1 (e.g., 7 and 4 days prior, respectively). Prior to Part 2B, participants may receive PF-07901801 (TTI-622) monotherapy and a priming dose of erlanatamab as part of the induction cycle (also referred to as Cycle 0 (C0)) as described above for Part 2A. Prior to Part 2B, participants may receive a priming dose of erlanatamab as part of the induction cycle (also referred to as Cycle 0 (C0)), but not PF-07901801 (TTI-622).

If a participant has been treated with erlanatamab on a 76 mg QW schedule for at least 6 months (6 cycles) and has demonstrated a disease response of at least PR or better that is sustained for at least 2 months, the dose interval for both erlanatamab and PF-07901801 will be changed from QW to Q2W (e.g., erlanatamab 76 mg QW to 76 mg Q2W) at the same erlanatamab dose level and PF-07901801 dose level. If the dose interval is changed, the cycle length should be kept the same (i.e., 28-day cycle).

Additionally, if participants receive erlanatamab 76 mg Q2W treatment for at least 6 months (6 cycles) and demonstrate a disease response of at least PR or better that is sustained for at least 2 months, the dose interval of PF-07901801 will be changed from QW to Q2W at the same PF-07901801 dose level. If the dose interval is changed, the cycle length should be kept the same (i.e., 28-day cycle).

Figure 2 is a schematic diagram showing various aspects of parts 2A and 2B.

For both Part 2A and Part 2B, on days when both PF-07901801 (TTI-622) and erlanatamab are administered, PF-07901801 will be administered before erlanatamab administration, and a minimum of 60 minutes must elapse from the completion of the PF-07901801 infusion before the start of the erlanatamab injection. PF-07901801 will be administered over the 60-minute infusion.

Study Population - Exemplary Inclusion Criteria Part 1: Received at least one but not more than three prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation/maintenance therapy is considered one line of therapy).
Part 2: Patients have received at least three prior lines of therapy for multiple myeloma and are refractory to at least one IMiD, one PI, and one anti-CD38 antibody.

Study Population - Exemplary Exclusion Criteria Part 1: Previous treatment with any anti-BCMA directed therapy, including bispecific antibodies, CAR-T, and ADCs Part 2: Previous treatment with any anti-BCMA directed therapy, with the exception of CAR-T Part 2: Previous treatment with CD47-SIRP alpha directed therapy

Claims (20)

A method of treating cancer in a patient, comprising administering to the patient a combination therapy comprising a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody. The method of claim 1, wherein the CD47 blocking agent comprises a CD47-binding form of human SIRP alpha (SIRPα). The method of any one of claims 1 to 2, wherein the CD47 blocking agent comprises an Fc fusion protein (SIRPαFc fusion protein) comprising the IgV domain of human SIRPα variant 2 attached to an antibody Fc region. The method of claim 3, wherein the SIRPαFc fusion protein comprises the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7. the anti-BCMA/anti-CD3 bispecific antibody comprises a first antigen-binding site that binds to CD3 and a second antigen-binding site that binds to BCMA, the first antigen-binding site comprising a VH and a VL, and the second antigen-binding site comprising a VH and a VL;
a) a first antigen-binding site VH comprises a heavy chain CDR (HCDR)1 of one or more of SEQ ID NOs: 18, 33, and 34, a HCDR2 of one or more of SEQ ID NOs: 19 and 35, and a HCDR3 of SEQ ID NO: 20; and a first antigen-binding site VL comprises a light chain CDR (LCDR)1 of SEQ ID NO: 21, a LCDR2 of SEQ ID NO: 22, and a LCDR3 of SEQ ID NO: 23;
b) The method of any one of claims 1 to 4, wherein the second antigen-binding site VH comprises a heavy chain CDR (HCDR)1 of one or more of SEQ ID NOs: 10, 30, and 31, a HCDR2 of one or more of SEQ ID NOs: 11 and 32, and a HCDR3 of SEQ ID NO: 12, and the second antigen-binding site VL comprises one or both of a light chain CDR (LCDR)1 of SEQ ID NO: 13, a LCDR2 of SEQ ID NO: 14, and a LCDR3 of SEQ ID NO: 15. The method of any one of claims 1 to 5, 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. The method of any one of claims 1 to 6, wherein the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab. The method of any one of claims 1 to 7, wherein a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, each cycle being 28 days, and the CD47 blocking agent is administered QW on days 1, 8, 15, and 22 of the first cycle. The method of any one of claims 1 to 8, wherein the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, each cycle being 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. A) the CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least six cycles, each cycle being 28 days, wherein the CD47 blocking agent is administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, and the anti-BCMA/anti-CD3 bispecific antibody is administered in cycles 1 through 6 in a regimen selected from: i) QW on days 1, 8, 15, and 22 of cycles 1 through 6; ii) QW on days 2, 8, 15, and 22 of cycle 1 and QW on days 1, 8, 15, and 22 of cycles 2 through 6; and iii) Q2W on days 2 and 15 of cycle 1 and Q2W on days 1 and 15 of cycles 2 through 6; or
B) The CD47 blocking agent and the anti-BCMA/anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, each cycle being 28 days, with the CD47 blocking agent administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, and the anti-BCMA/anti-CD3 bispecific antibody administered QW on days 1, 8, 15, and 22 of cycles 1 through 6, i) QW on days 1, 8, 15, and 22 of cycles 1 through 6, ii) QW on days 2, 8, 15, and 22 of cycle 1, and ii) QW on days 2, 8, 15, and 22 of cycle 1. 10. The method of any one of claims 1 to 9, wherein the CD47 blocking agent and anti-BCMA/anti-CD3 bispecific antibody are administered Q2W on days 1 and 15 of the seventh cycle. The method of any one of claims 1 to 10, wherein the CD47 blocking agent is administered to the patient during at least the induction cycle and the first cycle, the induction cycle preceding the first cycle, the induction cycle comprising at least 28 or 35 days, and the CD47 blocking agent is administered as monotherapy QW on days 1, 8, 15, and 22 of the induction cycle. The method of any one of claims 1 to 11, wherein the patient is administered a first priming dose and a second priming dose of the anti-BCMA/anti-CD3 bispecific antibody prior to the first cycle. A method of treating cancer in a patient, comprising administering to the patient a combination therapy comprising a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody, wherein the CD47 blocking agent is a SIRPαFc fusion protein (TTI-622) comprising the amino acid sequence of SEQ ID NO: 7, and the anti-BCMA/anti-CD3 bispecific antibody is erlanatamab. The method of any one of claims 1 to 13, wherein the cancer is a blood cancer or a solid tumor cancer. Cancers include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and p53-mutated AML, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myeloproliferative disorders/neoplasms (MPDS), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome, lymphoma, T-cell lymphoma, Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, The method of any one of claims 1 to 14, wherein the cancer is selected from the group consisting of myeloma, small cell follicular lymphoma, large cell follicular lymphoma, myeloma, multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, light chain or Bence-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma, or epithelioid sarcoma, and the cancer may be recurrent or refractory. The method of any one of claims 1 to 15, wherein the cancer is relapsed or refractory (R/R) multiple myeloma (MM). The method of any one of claims 1 to 16, wherein the patient has previously been treated with one to three lines of therapy. The method of any one of claims 1 to 17, wherein the patient has CD47-positive cancer cells. A CD47 blocking agent or an anti-BCMA/anti-CD3 bispecific antibody for use in treating a patient according to the method of any one of claims 1 to 18. A kit comprising one or both of a CD47 blocking agent and an anti-BCMA/anti-CD3 bispecific antibody, and instructions for use according to the method of any one of claims 1 to 19.