WO2024121777A1 - Agent bloquant cd47 et polythérapie anticorps bispécifique anti-bcma/anti-cd3 - Google Patents

Agent bloquant cd47 et polythérapie anticorps bispécifique anti-bcma/anti-cd3 Download PDF

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WO2024121777A1
WO2024121777A1 PCT/IB2023/062322 IB2023062322W WO2024121777A1 WO 2024121777 A1 WO2024121777 A1 WO 2024121777A1 IB 2023062322 W IB2023062322 W IB 2023062322W WO 2024121777 A1 WO2024121777 A1 WO 2024121777A1
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bcma
cycle
days
seq
bispecific antibody
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PCT/IB2023/062322
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English (en)
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Ingmar BRUNS
Mohamed A ELMELIEGY
Gregory Joseph Finn
Gloria Hoi Ying LIN
Diane Dan WANG
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Pfizer Inc.
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Publication of WO2024121777A1 publication Critical patent/WO2024121777A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • Cancer cells are targeted for destruction by antibodies that bind to cancer cell antigens, and through recruitment and activation of macrophages by way of Fc receptor binding to the Fc portion of that antibody. Binding between CD47 on cancer cells and SIRPa on macrophages transmits a “don’t eat me” signal that enables many tumour cells to escape destruction by macrophages. It has been shown that inhibition of the CD47/SIRPa interaction (CD47 blockade) will allow macrophages to “see” and destroy the target CD47+ cancer cell.
  • SIRPa International Patent Application Publication No.
  • WO 2014/094122 describes a protein drug that inhibits the interaction between CD47 and SIRPa.
  • This CD47 blockade drug is a form of human SIRPa that incorporates a particular region of its extracellular domain linked with a particularly useful form of an IgG-based Fc region.
  • the SIRPaFc drug shows dramatic effects on the viability of cancer cells that present with a CD47+ phenotype.
  • bispecific antibodies that are directed to both a T cell antigen and a tumor cell antigen (e.g. B-cell maturation antigen).
  • Bispecific antibodies that simultaneously bind to T cells and tumor cell antigens can lead to T-cell activation, proliferation, and tumor cell death.
  • Simultaneous binding of bispecific antibodies to CD3 on T cells and target antigens on tumor cells brings the T cells into close proximity with target tumor cells, leading to 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 a malignant human T cell lymphoma containing a t(4; 16) translocation. The gene is selectively expressed in the B- cell lineage with the highest expression in plasma blasts and plasma cells, antibody secreting cells.
  • BCMA binds two ligands, B-cell activation factor (BAFF) (also called B-lymphocyte stimulator (BLyS) and APOL-related leukocyte expressed ligand (TALL-1 )) and a proliferationinducing ligand (APRIL) with affinity of 1 pM and 16nM, respectively.
  • BAFF B-cell activation factor
  • BALL-1 APOL-related leukocyte expressed ligand
  • APRIL proliferationinducing ligand
  • BCMA Binding of APRIL or BAFF to BCMA promotes a signaling cascade involving NF-kappa B, Elk-1 , c-Jun N-terminal kinase and the p38 mitogen-activated protein kinase, which produce signals for cell survival and proliferation.
  • BCMA is also expressed on malignant B cells and several cancers that involve B lymphocytes including multiple myeloma, plasmacytoma, Hodgkin's Lymphoma, and chronic lymphocytic leukemia.
  • autoimmune diseases where plasmablasts are involved such as systemic lupus erythematosus (SLE) and rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • rheumatoid arthritis BCMA expressing antibodyproducing cells secrete autoantibodies that attack self.
  • BCMA also found in a soluble form (i.e. soluble BCMA or sBCMA) in peripheral blood of multiple myeloma (MM) patients and can result in a sink for BCMA-specific therapies.
  • soluble BCMA or sBCMA soluble BCMA
  • sBCMA soluble BCMA
  • MM myeloma
  • Exemplary anti-BCMA / anti-CD3 bispecific antibodies include AMG420 (Amgen), AMG701 (Amgen), CC-93269 (Bristol Myers Squibb), elranatamab (Pfizer), REGN5458 (Regeneron), REGN5459 (Regeneron), teclistamab (Janssen), and TNB-383B (TeneoBio).
  • MM is a hematological B-cell malignancy characterized by dysregulated proliferation of bone marrow (BM) plasma cells.
  • BM bone marrow
  • MM patients typically receive many lines of treatment as their disease progresses and becomes refractoryto various therapeutic approaches. Trials that have treated patients with BCMA-directed therapy in the relapsed / refractory multiple myeloma (RRMM) population have included heavily pretreated patients.
  • RRMM refractory multiple myeloma
  • the CD47 blockade and anti-BCMA / anti-CD3 bispecific antibody approaches in anticancer drug development and treatment shows great promise for various types of cancer, including B cell lymphomas such as MM.
  • B cell lymphomas such as MM.
  • improved dosing regimens and treatment methods are needed.
  • combination therapies for the treatment of cancer, and related methods and compositions.
  • combination therapies provided herein include a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody.
  • the CD47 blocking agent is a SIRPa-Fc fusion protein (for example, TTI-622) and the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • provided herein is a method of treating a cancer in a patient, the method comprising administering a combination therapy comprising a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody to the patient.
  • a method of treating a cancer in a patient comprising administering a combination therapy comprising a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody to the patient, wherein the CD47 blocking agent is a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO: 7 (TTI-622/ maplirpacept), and wherein the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • the CD47 blocking agent is a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO: 7 (TTI-622/ maplirpacept)
  • the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • provided herein is a method of treating a cancer in a patient, the method comprising administering acombination therapy comprising an anti-BCMA / anti- CD3 bispecific antibody and a proteasome inhibitor to the patient.
  • 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.
  • the cancer is triple class refractory multiple myeloma.
  • the multiple myeloma of the subject is refractory to all three types of the following multiple myeloma therapies (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody.
  • the cancer is double class refractory multiple myeloma.
  • the multiple myeloma of the subject is refractory to at least two of the following three types of multiple myeloma therapies (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody.
  • the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma, and the subject has received stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant or allogeneic stem cell transplant. In some embodiments, the subject is minimum residual disease positive post stem cell transplant.
  • the cancer is multiple myeloma, wherein in some embodiments the subject has progressed or is intolerant of an established multiple myeloma therapy.
  • the established multiple myeloma therapy comprises at least one drug selected from the group consisting of a proteasome inhibitor, an I M id drug and an anti-CD38 antibody.
  • the cancer is multiple myeloma wherein the subject has received at least four prior therapies and the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises an proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 monoclonal antibody, and wherein the subject has demonstrated disease progression on the last therapy.
  • the subject has received a prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.
  • the subject has not received any prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.
  • the cancer is multiple myeloma
  • the subject has received at least one, at least two, at least three or at least four prior multiple myeloma therapies
  • the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody, and the subject has demonstrated disease progression on the last multiple myeloma therapy.
  • the subject has received at least three prior multiple myeloma therapies.
  • the subject has received at least four prior multiple myeloma therapies.
  • the previous multiple myeloma therapies the subject received comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed therapy.
  • the previous multiple myeloma therapies the subject received do not comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed therapy.
  • the cancer is multiple myeloma
  • the subject has received at least one or at least two prior multiple myeloma therapies, the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor and (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent.
  • the subject has demonstrated disease progression on the last multiple myeloma therapy.
  • the cancer is multiple myeloma, and the subject has not received any prior multiple myeloma therapies. In some embodiments, the subject has not received any prior multiple myeloma therapies after the diagnosis of multiple myeloma.
  • 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 stemcell transplant ineligible. In some embodiments, the subject is allogeneic stem cell transplant ineligible. In some embodiments, the subject is ineligible for autologous stem cell transplant and is also ineligible for allogeneic stem cell transplant.
  • FIG. 1 depicts an exemplary dosing regimen combining elranatamab, carfilzomib, and dexamethasone.
  • Each cycle is 28 days.
  • the regimen includes Cycle 1 (C1 ), Cycles 2-6 (C2- C6), and Cycles 7 and beyond (C7+).
  • C1 Cycle 1
  • C2- C6 Cycles 2-6
  • C7+ Cycles 7 and beyond
  • elranatamab is dosed on Days 1 , 8, 15, and 22 of C1 -C6, and on Days 1 and 15 of C7 and beyond.
  • Each elranatamab dose is 44 mg or 76 mg.
  • Carfilzomib is dosed on Days 1 , 8, and 15 of all Cycles.
  • the carfilzomib dose on Cycle 1 Day 1 is 20 mg/m 2 ; the carlfilzomib dose all other days is 70 mg/m 2 .
  • Dexamethasone is dosed on Days 1 , 8, 15, and 22 of all Cycles. Each dexamethasone dose is 40 mg.
  • FIG. 2 depicts a schematic of the study design for Parts 2A and 2B of exemplary dosing regimens combining elranatamab and TTI-622.
  • Exemplary embodiments (E) of the invention provided herein include:
  • a method of treating a cancer in a patient comprising administering a combination therapy comprising a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody to the patient.
  • E2 The method of E1 , wherein the CD47 blocking agent comprises a CD47-binding form of human SIRPalpha (SIRPa).
  • SIRPa human SIRPalpha
  • E3 The method of E2, wherein the CD47-binding form of human SIRPa is a CD47- binding fragment of human SIRPa.
  • E4 The method of E3, wherein the CD47-binding fragment of human SIRPa comprises the IgV domain of human SIRPa.
  • E5 The method of any one of E1 -E4, wherein the CD47 blocking agent comprises an Fc fusion protein comprising the IgV domain of human SIRPa variant 2 attached to an antibody Fc region (SIRPaFc fusion protein).
  • the CD47 blocking agent comprises an Fc fusion protein comprising the IgV domain of human SIRPa variant 2 attached to an antibody Fc region (SIRPaFc fusion protein).
  • E6 The method of E5, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1 .
  • E7 The method of any one of E5-E6, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
  • E8 The method of any one of E5-E7, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7.
  • SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof having one, two, three, four, or five amino acid substitutions as compared the sequence of SEQ ID NO: 1 .
  • 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, wherein the second antigen binding site comprises a VH and a VL, and wherein one or both of : a) the first antigen binding site VH comprises the heavy chain CDR (HCDR) 1 of one or more of SEQ ID NO: 18, 33, and 34, the HCDR2 of one or more of SEQ ID NO: 19 and 35, and the HCDR3 of SEQ ID NO: 20; and the first antigen binding site VL comprises the light chain CDR (LCDR) 1 of SEQ ID NO: 21 , the LCDR2 of SEQ ID NO: 22, and the LCDR3 of SEQ ID NO: 23; and b) the second antigen binding site VH comprises the heavy chain CDR (HCDR)
  • 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 -E1 1 , 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 -E12, wherein the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • E14 The method of E1 or any one of E10-E13 when dependent on E1 , wherein the CD47 blocking agent is an anti-CD47 or an anti-SIRPa antibody.
  • E15 The method of any one of E1 -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, wherein each cycle is 28 days, wherein 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 -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, wherein each cycle is 28 days, wherein 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 ill) Q2W on days 2 and 15 of the first cycle.
  • E17 The method of any one of E1 -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, wherein each cycle is 28 days, 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 ill) Q2W on days 2 and 15 of the first cycle.
  • E18 The method of any one of E1 -E17, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered QW on days 1 , 8, 15, and 22 of the first through sixth cycles, and Q2W on days 1 and 15 of the seventh cycle.
  • E19 The method of any one of E1 -E18, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered in the first through sixth cycles in a regimen selected from i) QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1 , 8, 15, and 22 of the second through sixth cycles, and iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second through sixth cycles, and in the seventh cycle Q2W on days 1 and 15.
  • the CD47 blocking agent and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 6 cycles, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered QW on days 1 , 8, 15, and 22 of the first through sixth cycles, the anti-BCMA / anti-CD3 bispecific antibody is administered in the first through sixth cycles in a regimen selected from i) QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1 , 8, 15, and 22 of the second through sixth cycles, and iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second through sixth cycles; or
  • the CD47 blocking agent and the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered QW on days 1 , 8, 15, and 22 of the first through sixth cycles, the anti-BCMA / anti-CD3 bispecific antibody is administered in the first through sixth cycles in a regimen selected from i) QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) QW on days 2, 8, 15, and 22 of the first cycle and QW on days 1 , 8, 15, and 22 of the second through sixth cycles, and iii) Q2W on days 2 and 15 of the first cycle and Q2W on days 1 and 15 of the second through sixth cycles and the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered Q2W on days 1 and 15 of the seventh cycle.
  • E21 The method of any one of E1 -E20, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered at doses 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 -E21 , wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered 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 -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, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered at doses 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) 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.
  • E24 The method of any one of E15 to E23, wherein if after at least six cycles disease response shows at least a partial response (PR) or better with responses persisting f orat least two months, 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.
  • PR partial response
  • E25 The method of any one of E1 -E24, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered at doses comprising 8 mg/kg or 16 mg/kg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of the seventh cycle.
  • E26 The method of any one of E1 -E25, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered in the first through sixth cycles in a regimen selected from i) doses comprising 44 mg or 76 mg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) doses 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 the second through sixth cycles, and iii) doses 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.
  • E27 The method of any one of E1 -E26, wherein the CD47 blocking agent and the anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein the CD47 blocking agent is administered at doses comprising 8 mg/kg or 16 mg/kg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of the seventh cycle, and wherein the anti- BCMA / anti-CD3 bispecific antibody is administered in the first through sixth cycles in a regimen selected from i) doses comprising 44 mg or 76 mg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) doses 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 the second through sixth cycles, and iii) doses comprising 44 mg or 76 mg Q2W on
  • E28 The method of any one of E1 -E27, wherein prior to the first cycle, the CD47 blocking agent is administered to the patient as a monotherapy for at least one dose.
  • E29 The method of any one of E1 -E28, wherein the CD47 blocking agent is administered to the patient for at least a lead-in cycle and a first cycle, wherein the lead-in cycle precedes the first cycle, wherein the lead-in cycle comprises at least 28 or 35 days, and wherein the CD47 blocking agent is administered as a monotherapy QW on days 1 , 8, 15, and 22 of the lead-in cycle.
  • E30 The method of any one of E28 and E29, wherein the CD47 blocking agent is administered as a monotherapy at a dose comprising 8 mg/kg or 16 mg/kg.
  • E31 The method of any one of E1 -E30, wherein prior to the first cycle, af irst priming dose and a second priming dose of the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient.
  • E32 The method of any one of E1 -E30, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient for at least a lead-in cycle and a first cycle, wherein the lead-in cycle precedes the first cycle, wherein the lead-in cycle comprises 7 days, and wherein 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 lead-in cycle.
  • E33 The method of any one of E1 -E31 , wherein the CD47 blocking agent and anti- BCMA / anti-CD3 bispecific antibody are administered to the patient for at least a lead-in cycle and a first cycle, wherein the lead-in cycle precedes the first cycle, wherein the lead-in cycle comprises 35 days, wherein the CD47 blocking agent is administered on days 1 , 8, 15, and 22 of the lead-in cycle, and wherein the anti-BCMA / anti-CD3 bispecific antibody is administered as af irst priming dose and a second priming dose on days 29 and 32 of the lead- in cycle.
  • E34 The method of any one of E31 -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-E20 and E24-E27 further wherein the CD47 blocking agent and the anti-BCMA / anti-CD3 bispecific antibody are administered Q2W on days 1 and 15 of an eighth and additional cycles until disease progression.
  • E36 The method of E35, wherein the CD47 blocking agent is administered at doses comprising 8 mg/kg or 16 mg/kg Q2W and the anti-BCMA / anti-CD3 bispecific antibody is administered at doses comprising 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.
  • a method of treating acancer in a patient comprising administering a combination therapy comprising a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody to the patient, wherein the CD47 blocking agent is a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO: 7 (TTI-622 / maplirpacept), and wherein the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • E39 The method of E38, wherein TTI-622 and elranatamab are administered to the patient for at least a firstcycle, wherein each cycle is 28 days, wherein TTI-622 is administered at doses comprising 8 mg/kg or 16 mg/kg QW on days 1 , 8, 15, and 22 of the first cycle and elranatamab 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.
  • E40 The method of E38 or E39, wherein TTI-622 and elranatamab are administered to the patient for at least 7 cycles, wherein each cycle is 28 days, wherein TTI-622 is administered at doses comprising 8 mg/kg or 16 mg/kg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, and 8 mg/kg or 16 mg/kg Q2W on days 1 and 15 of the seventh cycle, and wherein elranatamab is administered in the first through sixth cycles in a regimen selected from i) doses comprising 44 mg or 76 mg QW on days 1 , 8, 15, and 22 of the first through sixth cycles, ii) doses comprising 44 mg or 76 mg QW on days 2, 8, 15, and 22 of the firstcycle and 44 mg or 76 mg QW on days 1 , 8, 15, and 22 of the second through sixth cycles, and iii) doses 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
  • E41 The method of any one of E1 -E40, wherein i) the CD47 blocking agent is administered to the patient at least 60 minutes before the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient on days that 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 the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient.
  • E42 The method of any one of E1 to E41 , wherein at least one dose of a premedication is administered to the patient prior to each dose of the CD47 blocking agent; and/or prior to the first priming dose, the second priming dose and/or the 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 a cancer in a patient, the method comprising administering a combination therapy comprising an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor to the patient.
  • E45 The method of E44, wherein the anti-BCMA / anti-CD3 bispecific antibody and the proteasome inhibitor are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered 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 doses comprising 44 mg or 76 mg.
  • E47 The method of any one of E44-E46, wherein the proteasome inhibitor is administered at doses comprising 20 mg/m 2 or 70 mg/m 2 .
  • E48 The method of any one of E44-E47, further comprising administering dexamethasone to the patient.
  • E49 The method of E48, wherein the anti-BCMA / anti-CD3 bispecific antibody and the proteasome inhibitor are administered to the patient for at least a first cycle, wherein each cycle is 28 days, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered QW on days 1 , 8, 15, and 22 of the first cycle, the proteasome inhibitor is administered QW on days 1 , 8, and 15 of the first cycle, and the dexamethasone is administered QW on days 1 , 8, 15, and 22 of the first cycle.
  • E50 The method of E48 or E49, wherein the dexamethasone is administered at doses of 40 mg.
  • E51 The method of any one of E44-E50, wherein one or both of the anti-BCMA / anti- CD3 bispecific antibody is elranatamab and the proteasome inhibitor is carfilzomib.
  • E52 The method of any one of E45-E51 , wherein prior to the first cycle, a first priming dose and a second priming dose of the anti-BCMA / anti-CD3 bispecific antibody are administered to the patient.
  • E53 The method of any one of E45-E52, wherein the anti-BCMA / anti-CD3 bispecific antibody is administered to the patient for at least a lead-in cycle and a first cycle, wherein the lead-in cycle precedes the first cycle, wherein the lead-in cycle comprises 7 or 14 days, and wherein 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 lead-in 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 -E54, wherein the cancer is a blood cancer or a solid tumor cancer.
  • E56 The method of any one of E1 -E55, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML) and p53 mutated AML; chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); myeloproliferative disorder/neoplasm (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, small cell follicular lymphoma, large cell follicular lymphoma, myeloma, multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, light chain or Bence-Jone
  • E57 The method of any one of E1 -E56, wherein the cancer is relapsed or refractory (R/R) multiple myeloma (MM).
  • E58 The method of any one of E1 -E57, wherein the patient has previously been treated with 1 to 3 lines of therapy.
  • E59 The method of any one of E1 -E58, wherein at least the anti-BCMA / anti-CD3 bispecific antibody is administered until disease progression.
  • E60 The method of any one of E1 -E43, wherein the patient has CD47-positive cancer cells.
  • a CD47 blocking agent or anti-BCMA / anti-CD3 bispecific antibody for use to treat a patient according to the method of any one of E1 -E43, or E55-E60 when dependent on any one of E1 -E43.
  • E62 Use of a CD47 blocking agent or an anti-BCMA / anti-CD3 bispecific antibody in the manufacture of a medicament for use to treat a patient according to the method of any one of E1 -E43 or E55-E60 when dependent on any one of E1 -E43.
  • a kit comprising one or both of aCD47 blocking agent and an anti-BCMA / anti- CD3 bispecific antibody and instructions for use according to the method of any one of E1 - E43, and optionally further comprising one or more additional therapeutic agents according to the method of any one of E1 -E43, or E55-E60 when dependent on any one of E1 -E43.
  • E65 Use of an anti-BCMA / anti-CD3 bispecific antibody or a proteasome inhibitor in the manufacture of a medicament for use to treat a patient according to the method of any one of E44-E54 or E55-E60 when dependent on any one of E44-E54.
  • a kit comprising one or both of an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor and instructions for use according to the method of any one of E44- E54 or E55-E60 when dependent on any one of E44-E54, and optionally further comprising one or more additional therapeutic agents according to the method of any one of E44-E54 or E55-E60 when dependent on any one of E44-E54.
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • an antibody includes one or more antibodies.
  • the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members.
  • the present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.
  • the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter.
  • a dose of about 5 mg means 5% ⁇ 10%, i.e. it may vary between 4.5 mg and 5.5 mg.
  • identity refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules or RNA molecules) or between polypeptide molecules. “Identity” measures the percent of identical matches between two or more sequences with gap alignments addressed by a particular mathematical model of computer programs (e.g. algorithms), which are well known in the art.
  • treating refers to any type of treatment, e.g. such as to relieve, alleviate, or slow the progression of the patient’s disease, disorder or condition or any tissue damage associated with the disease.
  • the disease, disorder or condition is cancer.
  • terapéuticaally effective amount refers to the amount of active ingredient that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1 ) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology).
  • CD47+ (or CD47+) is used with reference to the phenotype of cells targeted for binding by SIRP alpha fusion proteins or other CD47-binding agents.
  • Cells that are CD47+ can be identified by flow cytometry using CD47 antibody as the affinity ligand.
  • CD47 antibodies that are labeled appropriately are available commercially for this use (for example, the antibody product of clone B6H12 is available from Santa Cruz Biotechnology).
  • the cells examined for CD47 phenotype can include standard tumour biopsy samples including particularly blood samples taken from the subject suspected of harbouring endogenous CD47+ cancer cells.
  • CD47 disease cells of particular interest as targets for therapy with SIRP alpha fusion proteins are those that “over-express” CD47.
  • CD47+ cells typically are disease cells, and present CD47 at a density on their surface that exceeds the normal CD47 density for a cell of a given type.
  • CD47 overexpression will vary across different cell types, but is meant herein to refer to any CD47 level that is determined, for instance by flow cytometry as exemplified herein or by immunostaining or by gene expression analysis or the like, to be greater than the level measurable on a counterpart cell having a CD47 phenotype that is normal for that cell type.
  • an “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., through at least one antigen binding site, located in the variable region of the immunoglobulin molecule.
  • a target such as a polypeptide, carbohydrate, polynucleotide, lipid, etc.
  • the term “antibody” can encompass any type of antibody (e.g. monospecific, bispecific), and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g. an “antigen-binding fragment”), and any other modified configuration of an immunoglobulin molecule that comprises an antigen binding site.
  • An exemplary antibody comprises i) a variable region of the light chain, heavy chain or both and ii) a constant region of the heavy chain comprising three sequential immunoglobulin domains (CH1 , CH2, and CH3) and of the light chain comprising a single immunoglobulin domain (CL).
  • a “bispecific antibody” refers to a molecule that has binding specificity for at least two different epitopes. In some embodiments, bispecific antibodies can bind simultaneously two different antigens. In other embodiments, the two different epitopes may reside on the same antigen. In certain embodiments, the bispecific antibody is capable of simultaneously binding two antigens expressed on two distinct cells.
  • 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.
  • 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, and contribute to the formation of the antigen binding site of antibodies.
  • CDRs complementarity determining regions
  • appropriate amino acid substitution preferably, conservative amino acid substitution
  • Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore an antibody produced by a host cell by expression of aspecif ic nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This particularly may be the case where the final two C- terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to Kabat EU index). Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of an antibody or SIRPaFc region provided herein may or may not be present.
  • Elranatamab is a BCMA x CD3 bispecific antibody. Elranatamab is described, for example in US Patent No. 9,969,809, incorporated by reference in its entirety. The selected sequences of Elranatamab are shown in Table 1 herein. Elranatamab is also known as PF- 06863135 and these terms are used interchangeably herein.
  • Dosing regimens and methods provided herein include a CD47 blocking agent.
  • a CD47 blocking agent can be any molecule that interferes with and dampens or blocks signal transmission that results when CD47 interacts with macrophage-presented SIRPa.
  • a CD47-binding form of human SIRPa is the CD47 blocking agent for use in the regimens and methods provided herein. These molecules are based on the extracellular region of human SIRPa. They comprise at least a region of the extracellular region sufficient to confer effective CD47 binding affinity and specificity. So-called “soluble” forms of SIRPa, lacking the membrane anchoring component, are described in the literature and include those referenced in WO 2010/070047 (Novartis), WO2013/109752 (Stanford), and WO2014/094122 (Trillium), each incorporated by reference in its entirety.
  • the soluble form of SIRPa is an Fc fusion.
  • the drug suitably comprises the human SI RPa protein, in a form fused directly, or indirectly, with an antibody constant region, or Fc (fragment crystallisable).
  • human SIRPa refers to a wild type, endogenous, mature form of human SIRPa.
  • the SIRPa protein is found in two major forms.
  • One form, the variant 1 or V1 form has the amino acid sequence set out as NCBI RefSeq NP 542970.1 (residues 27-504 constitute the mature form).
  • Anotherform, the variant 2 or V2 form differs by 13 amino acids and has the amino acid sequence set out in GenBank as CAA71403.1 (residues 30-504 constitute the mature form).
  • These two forms of SIRPa constitute about 80% of the forms of SIRPa present in humans, and both are embraced herein by the term “human SIRPa”.
  • Also embraced by the term “human SIRPa” are the minor forms thereof that are endogenous to humans and have the same property of triggering signal transduction through CD47 upon binding thereto.
  • the present invention is directed most particularly to the drug combinations that include the human SIRP variant 2 form, or V2.
  • useful SIRPaFcfusion proteins comprise one of the three so-called immunoglobulin (Ig) domains that lie within the extracellular region of human SIRPa. More particularly, the present SIRPaFc proteins incorporate residues 32-137 of human SIRPa (a 106-mer), which constitute and define the IgV domain of the V2 form according to current nomenclature. This SIRPa sequence, shown below, is referenced herein as SEQ ID NO: 1 .
  • SIRPaFc fusion proteins incorporate the IgV domain as defined by SEQ ID NO: 1 , and additional, flanking residues contiguous within the SIRPa sequence.
  • This form of the IgV domain represented by residues 31 -148 of the V2 form of human SIRPa, is a 118-mer having SEQ ID NO: 2 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTV SESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPS [SEQ ID NO: 2]
  • the present SIRPa fusion proteins can also incorporate an Fc region having effector function.
  • Fc refers to “fragment crystallisable” and represents the constant region of an antibody comprised principally 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 having at least some effector function, such as at least some contribution to antibodydependent cellular cytotoxicity or some ability to fix complement. Also, the Fc will at least bind to Fc receptors. These properties can be revealed using assays established for this purpose. Functional assays include the standard chromium release assay that detects target cell lysis.
  • an Fc region that is wild type lgG1 or lgG4 has effector function, whereas the Fc region of a human lgG4 mutated to eliminate effectorf unction, such as by incorporation of an alteration series that includes Pro233, Val234, Ala235 and deletion of Gly236 (EU), is considered not to have effectorf unction.
  • the Fc is based on human antibodies of the IgG 1 isotype. The Fc region of these antibodies will be readily identifiable to those skilled in the art.
  • the Fc region includes the lower hinge-CH2-CH3 domains.
  • the Fc region is based on the amino acid sequence of a human lgG1 set out as P01857 in UniProtKB/Swiss-Prot, residues 104-330, and has the amino acid sequence shown below and referenced herein as SEQ ID NO: 3: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPGK [SEQ ID NO: 3]
  • the Fc region has either a wild type or consensus sequence of an lgG1 constant region.
  • the Fc region incorporated in the fusion protein is derived from any IgG 1 antibody having atypical effectoractive constant region.
  • sequences of such Fc regions can correspond, for example, with the Fc regions of any of the following IgG 1 sequences (all referenced from GenBank), for example: BAG65283 (residues 242-473), BAC04226.1 (residues 247-478), BAC05014.1 (residues 240-471 ), CAC20454.1 (residues 99-320), BAC05016.1 (residues 238-469), BAC85350.1 (residues 243-474), BAC85529.1 (residues 244-475), and BAC85429.1 (residues (238-469).
  • the Fc region has a sequence of a wild type human lgG4 constant region.
  • the Fc region incorporated in the fusion protein is derived from any lgG4 antibody having a constant region with effector activity that is present but, naturally, is significantly less potent than the Ig G 1 Fc region.
  • the sequences of such Fc regions can correspond, for example, with the Fc regions of any of the following lgG4 sequences: P01861 (residues 99-327) from UniProtKB/Swiss-Prot and CAC20457.1 (residues 99-327) from GenBank.
  • the Fc region is based on the amino acid sequence of a human lgG4 set out as P01861 in UniProtKB/Swiss-Prot, residues 99-327, and has the amino acid sequence shown below and referenced herein as SEQ ID NO: 4: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 4]
  • the Fc region incorporates one or more alterations, usually not more than about 10, e.g., up to 1 , 2, 3, 4, 5 or 6 such alterations, including amino acid substitutions that affect certain Fc properties.
  • the Fc region incorporates an alteration at position 228 (EU numbering), in which the serine at this position is substituted by a proline (S 228 P), thereby to stabilize the disulfide linkage within the Fc dimer.
  • alterations within the Fc region can include substitutions that alter glycosylation, such as substitution of Asn 297 by glycine or alanine; half-life enhancing alterations such as T 252 L, T 253 S, and T 256 F as taught in US62777375, and many others. Particularly useful are those alterations that enhance Fc properties while remaining silent with respect to conformation, e.g., retaining Fc receptor binding.
  • the Fc region is modified to increase its biological half-life.
  • one or more of the following mutations can be introduced; T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375.
  • the Fc incorporates at least the S 228 P mutation, and has the amino acid sequence set out below and referenced herein as SEQ ID NO: 5: ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 5]
  • the CD47 blocking agent used in the regimens and methods provided herein is thus in some embodiments a SIRP fusion protein useful to inhibit the binding of human SIRPa and human CD47, thereby to inhibit or reduce transmission of the signal mediated via SIRPa-bound CD47, the fusion protein comprising a human SIRPa component and, fused therewith, an Fc component, wherein the SIRPa component comprises or consists of a single IgV domain of human SIRPa V2 and the Fc component contains a human IgG Fc domain having effector function.
  • the fusion protein comprises a SIRPa component comprising at least of residues 32-137 of the V2 form of wild type human SIRPa, i.e. , SEQ ID NO: 1 .
  • the SIRPa component comprises residues 31 -148 of the V2 form of human SIRPa, i.e., SEQ ID NO: 2.
  • the Fc component is the Fc component of the human lgG1 designated P01857, and in a specific embodiment has the amino acid sequence that incorporates the lower hinge-CH2-CH3 region thereof i.e., SEQ ID NO: 3.
  • the Fc component is the Fc component of the human lgG4 designated P01861 , and in a specific embodiment has the amino acid sequence that incorporates the lower hinge-CH2-CH3 region thereof and the mutation S228P, i.e., SEQ ID NO: 5.
  • the SIRPaFc fusion protein is provided and used in a secreted dimeric fusion form, wherein the fusion protein incorporates a SIRPa component having SEQ ID NO: 1 and preferably SEQ ID NO: 2 and, fused therewith, an Fc region having effectorfunction and having SEQ ID NO: 3.
  • the fusion protein comprises SEQ ID NO: 6, shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTV SESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 6]
  • TTI-621 The SIRPaFc fusion protein of SEQ ID NO: 6 is also known as TTI-621 or ontorpacept.
  • TTI-621 / ontorpacept comprises a dimer of proteins of SEQ ID NO: 6.
  • the Fc component of the fusion protein is based on an lgG4, and preferably an lgG4 that incorporates the S 228 P mutation.
  • the fusion protein incorporates the preferred SIRPa IgV domain of SEQ ID NO: 2, and the lgG4 Fc region is SEQ ID NO: 5, the fusion protein comprises SEQ ID NO: 7, shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTV SESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQ
  • TTI-622 / maplirpacept comprises a dimer of proteins of SEQ ID NO: 7.
  • a SIRPaFc fusion protein comprises, as the SIRPa component of the fusion protein, a sequence that comprises the polypeptide of SEQ ID NO: 2. In one embodiment, the SIRPaFc fusion protein comprises the polypeptide of SEQ ID NO: 6 or SEQ ID NO: 7.
  • SIRPa sequence incorporated within the SIRPaFc fusion protein can be varied, as described in the literature. This can eliminate glycosylation sites in the protein, such as at position 89 and elsewhere.
  • Other, useful substitutions within SIRPa include one or more of the following: L4V/I, V6I/L, A21 V, V27I/L, I31 T/S/F, E47V/L, K53R, E54Q, H56P/R, S66T/G, K68R, V92I, F94V/L, V63I, and/or F103V.
  • the SIRPa component and the Fc component are fused, either directly or indirectly, to provide a single chain polypeptide that may optionally be ultimately produced as a dimer in which the single chain polypeptides are coupled through inter-chain disulfide bonds formed within the Fc region.
  • the nature of the fusing region is not critical.
  • the fusion may be direct between the two components, with the SIRP component constituting the N-terminal end of the fusion and the Fc component constituting the C-terminal end.
  • the fusion may be indirect, through a linker comprised of one or more amino acids, desirably genetically encoded amino acids, such as two, three, four, five, six, seven, eight, nine or ten amino acids, or any number of amino acids between 5 and 100 amino acids, such as between 5 and 50, 5 and 30 or 5 and 20 amino acids.
  • a linker may comprise a peptide that is encoded by DNA constituting a restriction site, such as a BamHI, Clal, EcoRI, Hind 111 , Pstl, Sall and Xhol site and the like.
  • the linker amino acids typically and desirably have some flexibility to allow the Fc and the SIRP components to adopt their active conformations. Residues that allow for such flexibility typically are Gly, Asn and Ser, so that virtually any combination of these residues (and particularly Gly and Ser) within a linker is likely to provide the desired linking effect.
  • a linker is based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser [SEQ ID NO: 8]) which may repeat as (G4S)n where n is 1 , 2, 3 or more, or is based on (Gly)n, (Ser)n, (Ser-Gly)n or (Gly-Ser)n and the like.
  • the linker is GTELSVRAKPS [SEQ ID NO: 9].
  • This sequence constitutes SIRPa sequence that C- terminally flanks the IgV domain (it being understood that this flanking sequence could be considered either a linker or a different form of the IgV domain when coupled with the IgV minimal sequence described above). It is necessary only that the fusing region or linker permits the components to adopt their active conformations, and this can be achieved by any form of linker useful in the art.
  • aSIRPaFc fusion protein may administered in methods and regimens provided herein the range of 0.1 to 50 mg/kg subject body weight.
  • a SIRPaFc fusion protein dosage can be 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg , 6 mg/kg , 7 mg/kg , 8 mg/kg , 9 mg/kg , 10 mg/kg , 11 mg/kg , 12 mg/kg , 13 mg/kg , 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg,
  • SIRPaFc fusion protein dosages 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 or 10-20 mg/kg.
  • These dosages of SIRPaFc fusion protein can be administered to asubject, for example, once a week (Q1 W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), two times a month, once a month, once every two months, or once every three months.
  • These dosing frequencies may be part of dosing cycles, such as 14-day, 21 -day, or 28-day cycles.
  • a SIRPaFc fusion protein provided herein (e.g. TTI-622) is administered as a “flat” (also referred to as a “fixed”) dose - i.e. the dose is the amount per patient, and the dose does not depend on the mass of the patient.
  • a SIRPaFc fusion protein such as TTI-622 is administered at a fixed dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1 100 mg, 1 150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg,
  • a fixed dose of SIRPaFcf usion protein may be administered in various regimens.
  • the dose is administered to a patient weekly (QW), every 2 weeks (Q2W), every 3 weeks (Q3W), or every 4 weeks (Q4W).
  • a SIRPaFc fusion protein is administered at a dose between a) a lower level of 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1 100, 1 150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, or 2200 mg and b) an upper level of 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1 100, 1 150, 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,
  • CD47 blockade agent can be used in the present methods and combinations, instead of or in addition to the SI RPa-based drugs.
  • these other drugs include particularly anti-CD47 antibodies, which bind to CD47 and antagonize the interaction with SIRPa. By blocking that interaction, and because of the Fc region of the antibody, the effect of the CD47 antibodies can be similar to the effect of the SIRPa-based Fc fusion drugs.
  • Examples of CD47 antibodies are described in the literature such as US2008/0107654 (Chugai), W02009/091601 (Stanford), WO2013/1 19714 (InhibRx), W02016/109415 (Celgene) and WO2016/081423 (Janssen).
  • anti-CD47 antibodies bind red blood cells, a dosing regimen that takes this into account has been developed and is described in WO2014/149477.
  • the properties of a useful anti-CD47 antibody include the ability to bind to CD47 in a way that ultimately inhibits signaling by SIRPa, i.e. , as an antagonist.
  • anti-SIRPa antibodies may also be used as the CD47 blocking agent.
  • the method further comprises administering to the subject at least one dose of a premedication prior to each dose of the CD47 blocking agent.
  • the premeditation may comprise acetaminophen (or equivalent such as paracetamol) and/or an anti-histamine such as diphenhydramine (or equivalent).
  • diphenhydramine is administered at a dose of 25 mg, oral or intravenous.
  • the premedication dosing can be the same or different prior to each dose of the CD47 blocking agent.
  • Dosing regimens and methods provided herein include an anti-BCMA / anti-CD3 bispecific antibody.
  • an anti-BCMA / anti-CD3 bispecific antibody can be any molecule that can simultaneously bind 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.
  • BCMA B-cell maturation antigen
  • TNFRSF17 and CD269 B-cell maturation antigen
  • BCMA expression is upregulated during B-cell maturation into plasma blasts and plasma cells, but it is not expressed on naive B cells, hematopoietic stem cells or normal tissues such as the heart, lung, kidney, or tonsil.
  • BCMA expression was identified at each disease stage, and on patients with differing cytogenetic risks.
  • BCMA expression was not influenced by treatment with autologous stem cell transplant (ASCT) or chemotherapy.
  • ASCT autologous stem cell transplant
  • bispecific antibodies against BCMA have been shown to induce T-cell activation, reduce tumor burden and prolong survival.
  • anti-BCMA / anti-CD3 bispecific antibodies examples include, but are not limited to, AMG 420 (BCMAxCD3 bispecific T-cell engager, BiTE®, Amgen), AMG 701 (BCMAxCD3 BiTE®, Amgen), CC-93269 (BCMAxCD3 bispecific antibody, Celgene), teclistamab (JNJ-64007957 - Jansen), elranatamab (BCMAxCD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio/AbbVie), linvoseltamab (REGN5458 - BCMAxCD3 bispecific antibody, Regeneron), alnuctamab (CC-93269 - BMS), AFM26 (BCMAxCD16 tetravalent bispecific antibody, Affimed GmbH), HPN217 (BCMAxALBxCD3 trispecific, Harpoon Therapeutics).
  • AMG 420 BCMAxCD3 bispecific T-cell engager
  • 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 wherein the second antigen binding site specifically binding to a BCMA.
  • an anti-BCMA / anti-CD3 bispecific antibody may have any of the features or characteristics of any of the BCMA bispecific antibodies provided in WO2016/166629, which is hereby incorporated by reference for all purposes.
  • the first antigen binding site specifically binds to CD3.
  • Information about CD3 is provided, for example, via UniProtKB #P07766.
  • the first antigen binding site comprises three CDRs of aheavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 24, and/or three CDRs of a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 25.
  • the VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 18, 33, and 34, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 19 and 35, a VH CDR3 comprising the sequence shown in SEQ ID NO: 20, and/or the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 21 , a VL CDR2 comprising the sequence shown in SEQ ID NO: 22, a VL CDR3 comprising the sequence shown in SEQ ID NO: 23.
  • the VH comprises the sequence shown in SEQ ID NO: 24, and/or the VL comprises the sequence shown in SEQ ID NO: 25.
  • the bispecific antibody comprises a first heavy chain and a first light chain comprising the first antigen binding site, wherein the first heavy chain comprises the amino acid sequence shown in SEQ ID NO: 28, and/or the first light chain comprises the amino acid sequence shown in SEQ ID NO: 29.
  • the second antigen binding site specifically binds to BCMA.
  • Information about BCMA is provided, for example, via UniProtKB ID # Q02223.
  • the antigen binding site comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 16, and/or three CDRs of a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 17.
  • the VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 10, 30, and 31 , a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 1 1 and 32 , a VH CDR3 comprising the sequence shown in SEQ ID NO: 12, and/or the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 13, a VL CDR2 comprising the sequence shown in SEQ ID NO: 14, a VL CDR3 comprising the sequence shown in SEQ ID NO: 15.
  • the VH comprises the sequence shown in SEQ ID NO: 16, and/or the VL comprises the sequence shown in SEQ ID NO: 17.
  • the bispecific antibody comprises a second heavy chain and a second light chain comprising the second antigen binding site, wherein the second heavy chain comprises the amino acid sequence shown in SEQ ID NO: 26, and/or the second light chain comprises the amino acid sequence shown in SEQ ID NO: 27.
  • 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
  • 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.
  • the BCMA bispecific antibody is elranatamab.
  • Elranatamab is a heterodimeric humanized full-length bispecific antibody comprised of one B-cell maturation antigen (BCMA) binding arm and one cluster of differentiation (CD3) binding arm paired through hinge mutation technology. It utilizes a modified human lgG2Da fragment crystallizable (Fc) region.
  • BCMA B-cell maturation antigen
  • CD3 cluster of differentiation
  • Fc fragment crystallizable
  • SEQ ID Nos 18-25, 28, 29, and 33-35 are the sequences of the CD3 arm of elranatamab
  • SEQ ID Nos 10-17, 26, 27, and 30-32 are the sequences of the BCMA arm of elranatamab.
  • the dosage of elranatamab may be selected from one of the following: 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 44 mg, 76 mg, 1 16 mg and 152 mg.
  • a dosing method or regimen provided herein involving an anti- BCMA / anti-CD3 bispecific antibody may include one, two, or more priming doses. Priming doses can be utilised to initially sensitize the immune system at lower doses therefore reducing the rate, duration and grade of cytokine release syndrome (CRS) and Immune Effector Cell- Associated Neurotoxicity Syndrome (ICANS).
  • a first priming dose may be 4 mg to 32 mg and a second priming dose may be from 12 mg to 44 mg.
  • Exemplary priming doses for elranatamab are a first dose of 12 mg and a second dose of 32 mg.
  • An exemplary priming dose schedule is to administer the first priming dose (e.g.
  • the second priming dose (e.g. 32 mg) on day 4, followed by a therapeutic dose.
  • the therapeutic dose (e.g. 44 mg or 76 mg) is on day 8 (i.e. 1 week after the first priming dose).
  • the therapeutic dose is 32 mg to 76 mg.
  • the therapeutic dose may be selected from 44 mg or 76 mg.
  • the first priming dose is 12 mg
  • the second priming dose is 32 mg
  • the therapeutic dose is 44 mg or 76 mg.
  • an anti-BCMA / anti-CD3 bispecific antibody may be administered in methods and regimens provided herein once a week (Q1 W or QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).
  • the antibody is administered QW or Q2W.
  • the dose interval may be changed from QW to Q2W at the same dose level/dosage (for example, 76 mg QW to 76 mg Q2W or 44 mg QW to 44 mg Q2W).
  • dosing frequencies may be part of dosing cycles, such as 14-day, 21 -day, or 28-day cycles.
  • the method furthercomprising administering to the subject at least one dose of a premedication prior to 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 is administered to the subject.
  • the premedication is administered prior to the first and second priming doses and the first therapeutic dose.
  • the premeditation may be acetaminophen (or equivalent such as paracetamol), diphenhydramine (or equivalent) and/or dexamethasone (or equivalent).
  • dexamethasone is administered at a dexamethasone dosing of about 10 mg to about 40 mg daily oral or intravenous, such as 20 mg.
  • acetaminophen is administered at a dose of 650 mg or paracetamol is administered at a dose of 500 mg.
  • diphenhydramine is administered at a dose of 25 mg, oral or intravenous.
  • the premedication dosing can be the same or diff erentwhile the subject is on the priming dosing, the first therapeutic and subsequent dosing of the bispecific antibody.
  • Anti-BCMA/ Anti-CD3 Bisoecific Antibody and Proteasome Inhibitor Combination Therapies Provided herein are combination therapies containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor.
  • the anti-BCMA / anti- CD3 bispecific antibody is elranatamab and the proteasome inhibitor is carfilzomib.
  • combination therapies containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor also include dexamethasone.
  • Carfilzomib is a second generation proteosome inhibitorthat binds irreversibly, while potentially improving resistance and decreasing potential for off target toxicity.
  • Glucocorticoids such as dexamethasone
  • Glucocorticoids are a backbone of treatment for multiple myeloma in both the newly diagnosed and relapsed/refractory setting.
  • Carfilzomib was first approved in the US in 2012 based on response rate in monotherapy reported in a single-arm multicenter study conducted in patients with at least 2 prior lines, having responded to at least 1 prior line and being refractory to the most recent therapy. Patients received carfilzomib 20 mg/m 2 at each dose in Cycle 1 , and 27 mg/m 2 in subsequent cycles. Dexamethasone 4 mg PO or IV was administered prior to carfilzomib doses in the first and second cycles. A total of 266 patients were enrolled. The objective response rate (ORR) as determined by the independent review committee (IRC) assessment using International Myeloma Working Group (IMWG) criteriawas 23.7% (95% CI: 18.7-29.4).
  • ORR objective response rate
  • Carfilzomib is a standard-of-care proteasome inhibitor which has demonstrated significant activity in MM, initially as monotherapy and more recently with enhanced activity in combination with drugs that engage the immune system, 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 have shown an immunogenic potential role of proteasome inhibition in eliciting an anti-myeloma immune response.
  • a combination therapy containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may include any of the therapeutic molecules, dosage amounts and dosage frequencies as described in Example 1 .
  • a combination therapy containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may comprise a dosing regimen of elranatamab 44 mg QW and carfilzomib 70 mg/m 2 QW.
  • a combination therapy containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may comprise a dosing regimen of elranatamab 44 mg Q2W and carfilzomib 70 mg/m 2 QW.
  • a combination therapy containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may comprise a dosing regimen of elranatamab 76 mg QW and carfilzomib 70 mg/m 2 QW.
  • a combination therapy containing an anti-BCMA / anti-CD3 bispecific antibody and a proteasome inhibitor may comprise a dosing regimen of elranatamab 76 mg Q2W and carfilzomib 70 mg/m 2 QW.
  • CD47 Blocking Agent and Anti-BCMA / Anti-CD3 Bisoecific Antibody Combination Therapies Provided herein are combination therapies containing a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody.
  • the CD47 blocking agent is a SIRPa-Fc fusion protein (for example, TTI-622) and the anti-BCMA / anti-CD3 bispecific antibody is elranatamab.
  • Suppressive, anti-phagocytic “don’t-eat-me” signals mediated via CD47 on tumor cells to membrane bound SIRPa on macrophage serve to circumvent innate immune surveillance of cancers.
  • CD47 blocking agents such as PF-07901801 (TTI-622) (SI RPa-fusion) interacts with its ligand CD47 while the Fc region binds to Fey receptors on the macrophages. This blocks the CD47 anti-phagocytic signal, enabling macrophage activation resulting in tumor cell phagocytosis.
  • tumor cell antigens are processed and presented by macrophages as MHC peptide complexes to T cells, resulting in T cell activation and tumor cell destruction.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody may include any of the therapeutic molecules, dosage amounts and dosage frequencies as described in Example 1 .
  • acombination therapy containing a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 44 mg QW and PF-07901801 8 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA/ anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 44 mg QW and PF-07901801 16 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA/ anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 44 mg Q2W and PF-07901801 8 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA/ anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 44 mg Q2W and PF-07901801 16 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA/ anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 76 mg QW and PF-07901801 8 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 76 mg QW and PF-07901801 16 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA / anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 76 mg Q2W and PF-07901801 8 mg/kg QW.
  • a combination therapy containing a CD47 blocking agent and an anti-BCMA/ anti-CD3 bispecific antibody may comprise a dosing regimen of elranatamab 76 mg Q2W and PF-07901801 16 mg/kg QW.
  • SIRPaFc proteins provided herein display negligible binding to red blood cells. There is accordingly no need to account for an RBC “sink” when dosing with SIRPaFc fusion proteins provided herein. Relative to other CD47 blockade drugs that are bound by RBCs, it is estimated that the present SIRPaFc fusions can be effective at doses that are less than half the doses required for drugs that become RBC-bound, such as CD47 antibodies. Moreover, the SIRPaFc fusion proteins provided herein are a dedicated antagonist of the SIRPa-mediated signal, they display negligible CD47 agonism when binding thereto. There is accordingly no need, when establishing medically useful unit dosing regimens, to account for any stimulation induced by the drug.
  • Dosing regimens and methods provided herein may be is useful to treat a variety of cancer cells. These include particularly CD47+ cancer cells, including liquid (hematological) and solid tumours. Solid tumours can be treated with the dosing regimens and methods provided herein, to reduce the size, number or growth rate thereof and to control growth of cancer stem cells. Such solid tumours include CD47+ tumours in bladder, brain, breast, lung, colon, ovary, prostate, liver and other tissues as well. In one embodiment, dosing regimens and methods provided herein can used to inhibit the growth or proliferation of hematological cancers. As used herein, “hematological cancer” refers to a cancer of the blood, and includes leukemia, lymphoma and myeloma among others.
  • Leukemia refers to a cancer of the blood, in which too many white blood cells that are ineffective in fighting infection are made, thus crowding out the other parts that make up the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Certain 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 disorder/neoplasm (MPDS); and myelodysplastic syndrome.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MPDS myeloproliferative disorder/neoplasm
  • myelodysplastic syndrome myelodysplastic syndrome
  • Lymphoma may refer to a 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.
  • dosing regimens and methods provided herein are useful to treat T cell lymphomas that are a very heterogeneous group of lymphoid malignancies divided into cutaneous and peripheral TCL, which themselves are divided into nodal or extranodal types.
  • CTCL derive from skin-homing T cells and consist of mycosis f ungoides, Sezary syndrome, primary cutaneous T cell lymphoproliferative disorders, and anaplastic large cell lymphoma.
  • the common features of TCL are aggressive course and poor response to therapy, with the exception of ALK and ALCL.
  • the hematological cancer treated with 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.
  • the hematological cancer treated with a dosing regimen or method 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, and light chain or Bence-Jones myeloma as well as leimyosarcoma.
  • Hodgkin’s lymphoma both indolent and aggressive non-Hodgkin’s lymphoma
  • Burkitt's lymphoma Burkitt's lymphoma
  • follicular lymphoma small cell and large cell
  • multiple myeloma MM
  • giant cell myeloma giant cell myeloma
  • a cancer treated with a dosing regimen or method provided herein is relapsed and/or refractory (R/R).
  • a subject treated with a dosing regimen or method provided herein has been previously treated with 1 -3 lines of therapy for the cancer.
  • 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.
  • the cancer is triple class refractory multiple myeloma.
  • the multiple myeloma of the subject is refractory to all three types of the following multiple myeloma therapies (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody.
  • the cancer is double class refractory multiple myeloma.
  • the multiple myeloma of the subject is refractory to at least two of the following three types of multiple myeloma therapies (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody.
  • the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma, and the subject has received stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant or allogeneic stem cell transplant. In some embodiments, the subject is minimum residual disease positive post stem cell transplant.
  • the cancer is multiple myeloma, wherein in some embodiments the subject has progressed or is intolerant of an established multiple myeloma therapy.
  • the established multiple myeloma therapy comprises at least one drug selected from the group consisting of a proteasome inhibitor, an I M id drug and an anti-CD38 antibody.
  • the cancer is multiple myeloma wherein the subject has received at least four prior therapies and the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises an proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 monoclonal antibody, and wherein the subject has demonstrated disease progression on the last therapy.
  • the subject has received a prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.
  • the subject has not received any prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.
  • the cancer is multiple myeloma
  • the subject has received at least one, at least two, at least three or at least four prior multiple myeloma therapies
  • the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti- CD38 antibody, and the subject has demonstrated disease progression on the last multiple myeloma therapy.
  • the subject has received at least three prior multiple myeloma therapies.
  • the subject has received at least four prior multiple myeloma therapies.
  • the previous multiple myeloma therapies the subject received comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed therapy.
  • the previous multiple myeloma therapies the subject received do not comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed therapy.
  • the cancer is multiple myeloma
  • the subject has received at least one or at least two prior multiple myeloma therapies, the subject’s multiple myeloma is refractory or relapsed to (1 ) a prior multiple myeloma therapy that comprises a proteasome inhibitor and (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent.
  • the subject has demonstrated disease progression on the last multiple myeloma therapy.
  • the cancer is multiple myeloma, and the subject has not received any prior multiple myeloma therapies. In some embodiments, the subject has not received any prior multiple myeloma therapies after the diagnosis of multiple myeloma.
  • 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 stemcell transplant ineligible. In some embodiments, the subject is allogeneic stem cell transplant ineligible. In some embodiments, the subject is ineligible for autologous stem cell transplant and is also ineligible for allogeneic stem cell transplant.
  • a CD47 blocking agent and anti-BCMA / anti-CD3 bispecific antibody provided herein can be administered to the subject through any of the routes established for protein delivery, in particular, intravenous, intradermal and subcutaneous injection or infusion, or by oral or nasal administration.
  • the CD47 blocking agent e.g. the SIRPaFc fusion protein TTI-622
  • the anti-BCMA / anti-CD3 bispecific antibody e.g. elranatamab
  • such embodiments are also further embodiments for use in that treatment, or alternatively for the manufacture of a medicament for use in that treatment.
  • Phase 1 b open-label, prospective, multi-center, non-randomized study to evaluate safety, efficacy, PK, and pharmacodynamics of elranatamab in combination with carf ilzomib plus dexamethasone (Part 1 ) and elranatamab in combination with PF-07901801 (TTI-622) monotherapy (Part 2) in participants with relapsed / refractory (R/R) multiple myeloma (MM) (RRMM). Study endpoints will be evaluated using a dose escalation approach.
  • PART 2A Dose Escalation will evaluate the tolerability, safety, PK, PD, and preliminary activity of PF-07901801 (TTI-622) monotherapy and PF-07901801 (TTI-622) in combination with elranatamab. Based on the totality of the data, two combination dose levels of PF-07901801 and elranatamab will be selected for further evaluation in Part 2B.
  • PART 2B Randomized Dose Optimization will evaluate the tolerability, safety, PK, PD, and activity of elranatamab in combination with PF-07901801 (TTI-622) to determine the RP2D of the combination.
  • Part 1 Elranatamab and Carfilzomib/Dexamethasone
  • the number of participants to be enrolled will depend on the number of dose levels evaluated and the number of participants treated at each dose level. Approximately 3-6 dose-limiting toxicity (DLT)-evaluable participants will be treated at each dose level of the combination therapy, with at least 6 DLT-evaluable participants treated at the elranatamab combination recommended Phase 2 dose (RP2D) level.
  • DLT dose-limiting toxicity
  • the safety data will be evaluated by a dose level review committee once DLT evaluable participants have completed the DLT observation period [from Cycle 0 day 1 (C0D1 ) through the end of Cycle 1 ].
  • the target DLT rate is ⁇ 30% and the dose escalation/de-escalation decisions will be guided by a Bayesian Logistic Regression Model (BLRM) approach to recommend the RP2D of elranatamab plus carfilzomib and dexamethasone (Part 1 ).
  • BLRM Bayesian Logistic Regression Model
  • other available evidence such as safety data beyond the DLT window, clinical activity, pharmacokinetics (PK), and pharmacodynamics data will also be evaluated in determining the tolerability profile and decision to escalate.
  • Dose escalation decisions and RP2D will be determined with agreement between the investigators and the sponsor at the Dose Level Review Meeting (DLRM).
  • Carfilzomib dosing may be modified for hematologic or other toxicity as per institutional guidelines. In general, dose modifications of carfilzomib will follow applicable product prescribing information (see, e.g. Kyprolis (carfilzomib) USPI). Carfilzomib dose levels are 70 mg, 56 mg, 45 mg, and 36 mg per product prescribing information.
  • the dose interval will be changed from QW to once every 2 weeks (Q2W) at the same elranatamab dose level (e.g., change from elranatamab 76 mg QW to 76 mg Q2W or 44 mg QW to 44 mg Q2W). If the dose interval is changed, cycles should remain the same length (i.e., 28-day cycles). Carfilzomib plus dexamethasone dose interval does not change.
  • elranatamab priming doses Prior to Part 1 Cycle 1 , participants may receive elranatamab priming doses as part of a lead-in 14-day priming dose Cycle [also referred to a Cycle 0 (CO); Day 1 of Cycle 1 follows Day 14 of Cycle 0].
  • elranatamab is administered at increasing doses over multiple days of the 14-day cycle.
  • elranatamab may be administered on days 1 , 4, and 8 of the priming dose cycle, more specifically, elranatamab may be administered at doses of 12 mg on day 1 , 32 mg on day 4, and 44 mg or 76 mg on day 8 of the 14-day priming dose cycle.
  • the agents in Part 1 may be administered according to the following dosing sequence.
  • the participant may receive premedication (dexamethasone) for around 0.5 hour to 4 hours.
  • carfilzomib is infused for about 30 minutes.
  • at least 60 minutes elapses before elranatamab is administered.
  • Part 2A For the 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 to be enrolled will depend on the number of dose levels evaluated and the number of participants treated at each dose level. It is estimated that approximately up to 24 DLT- evaluable participants will be enrolled and treated in Part 2A dose escalation.
  • Part 2B participants will be randomized to one of two cohorts to evaluate the safety, tolerability and anti-myeloma activity of the PF-07901801 plus elranatamab combination to determine the optimal combination dose for f urtherclinical development.
  • the randomized dose optimization approximately 30 participants will be randomized at 1 :1 ratio to dose level A (DLA) and dose level B (DLB).
  • DLA dose level A
  • DLB dose level B
  • the actual number of participants to be enrolled will depend on the tolerability of the initial 3-6 DLT evaluable participants. It is estimated that approximately up to 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. Part 2B randomization will only start after DL2 is deemed tolerable.
  • the first (approximately) 6 participants enrolled to DLA and DLB are planned for the DLT evaluation.
  • the safety data will be evaluated by a dose level review committee once the first 6 DLT evaluable participants have completed the DLT observation period (from C0D1 through the end of Cycle 1 ). If both DLA and DLB are tolerable, then randomization will be expanded to a total of approximately 15 participants for each dose level. If one or both of DLA and DLB is not tolerable, other dose levels (DLs) maybe be added and a protocol amendment will be issued. If DL2 is not tolerable, DL1 will be evaluated further with a minimum of 6 DLT evaluable participants.
  • the target DLT rate is ⁇ 30% in Part 2 and the tolerability assessment will be guided by a Bayesian optimal interval design (BOIN) approach to recommend dose escalation/de- escalation (DL1 to DL2 to Part 2B) and dose expansion (DLA and DLB to full 15 participants).
  • BOIN Bayesian optimal interval design
  • the isotonic estimate of the toxicity rate from BOIN approach will guide the determination of the RP2D of elranatamab plus PF-07901801 (TTI-622).
  • TTI-622 PF-07901801
  • other available evidence such as safety data beyond the DLT window, clinical activity, PK, and pharmacodynamics data will also be evaluated in determining the tolerability profile.
  • Dose escalation decisions and RP2D will be determined with agreement between the investigators and the sponsor at the DLRM.
  • PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and elranatamab 44 mg or 76 mg QW over 28-day cycles.
  • TTI-622 8 mg/kg or 16 mg/kg
  • elranatamab 44 mg or 76 mg QW over 28-day cycles.
  • PF-07901801 and elranatamab are both administered on days 1 , 8, 15, and 22 of each cycle.
  • PF- 07901801 and elranatamab are both administered on days 1 and 15 of each cycle.
  • PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and elranatamab 44 mg or 76 mg over 28-day cycles.
  • PF-07901801 is administered on days 1 , 8, 15, and 22, and elranatamab is administered on days 2 and 15.
  • PF- 07901801 is administered on days 1 , 8, 15, and 22, and elranatamab is administered on days 1 and 15 of each cycle.
  • PF-07901801 and elranatamab are both administered on days 1 and 15 of each cycle.
  • PF-07901801 (TTI-622) (8 mg/kg or 16 mg/kg) and elranatamab 76 mg QW over 28- day cycles.
  • PF-07901801 is administered on days 1 , 8, 15, and 22, and elranatamab is administered on days 2, 8, 15, and 22.
  • PF-07901801 and elranatamab are both administered on days 1 , 8, 15, and 22 of each cycle.
  • PF-07901801 and elranatamab are both administered on days 1 and 15 of each cycle.
  • PF-07901801 Prior to Part 2A Cycle 1 , participants may receive PF-07901801 (TTI-622) monotherapy and elranatamab priming doses as part of a lead-in Cycle [also referred to a Cycle 0 (CO)].
  • An exemplary lead-in Cycle is 35 days in length, and PF-07901801 is administered as a monotherapy on Days 1 , 8, 15, and 22 of the lead-in Cycle (e.g. at a dose of 8 mg/kg or 16 mg/kg), and elranatamab priming doses are administered on days 29 and 32 of the lead-in Cycle (e.g. at a first dose of 12 mg and a second dose of 32 mg).
  • the dose interval for both elranatamab and PF-07901801 will be changed from QW to Q2W at the same elranatamab dose level (e.g., change from elranatamab 44 mg QW to 44 mg Q2W) and the same PF-07901801 (TTI-622) dose level. If the dose interval is changed, cycles should remain the same length (i.e., 28-day cycles).
  • the agents in Part 2A may be administered according to the following dosing sequence.
  • the participant may receive premedication (antihistamine, acetaminophen) for up to 4 hours.
  • PF-07901801 TTI-622
  • TTI-622 PF-07901801
  • the participant receives premedication (antihistamine, acetaminophen, dexamethasone).
  • the participant receives elranatamab.
  • Part 2B Participants in Part 2B will be treated with combination dose levels selected from Part 2A at the Dose Level Review Meeting (DLRM).
  • DLRM Dose Level Review Meeting
  • Participants in Part 2B may receive a first and a second elranatamab priming dose of 12 mg and 32 mg, respectively, prior to Cycle 1 Day 1 (e.g. 7 days prior and 4 days prior, respectively).
  • participants may receive PF-07901801 (TTI-622) monotherapy and elranatamab priming doses as part of a lead-in Cycle [also referred to a Cycle 0 (CO)] as described above regarding Part 2A.
  • prior to Part 2B participants may receive elranatamab priming doses as part of a lead-in Cycle [also referred to a Cycle 0 (CO)] but not PF-07901801 (TTI-622).
  • the dose interval for both elranatamab and PF- 07901801 will be changed from QW to Q2W at the same elranatamab dose level (e.g., change from elranatamab 76 mg QW to 76 mg Q2W) and the same PF-07901801 dose level. If the dose interval is changed, cycles should remain the same length (i.e., 28-day cycles).
  • the dose interval for PF-07901801 will be changed from QW to Q2W at the same PF-07901801 dose level. If the dose interval is changed, cycles should remain the same length (i.e., 28-day cycles).
  • FIG. 2 is a schematic depicting various aspects of Parts 2A and 2B.
  • PF-07901801 For both Part 2A and Part 2B, on days when PF-07901801 (TTI-622) and elranatamab are both administered, PF-07901801 is administered prior to the administration of elranatamab, and a minimum of 60 minutes must elapse from the completion of the PF- 07901801 infusion before initiation of the elranatamab injection. PF-07901801 is administered over 60-minute infusion.
  • Part 1 Received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation / maintenance therapy will be considered as 1 line of therapy).
  • Part 2 Received at least 3 prior lines of therapy for multiple myeloma who are refractory to at least one IMiD, one PI, and one anti-CD38 antibody.

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Abstract

L'invention concerne des posologies et des méthodes d'administration de polythérapies combinant un agent bloquant CD47 et un anticorps bispécifique anti-BCMA/anti-CD3. Les posologies et les méthodes peuvent en outre comprendre des agents thérapeutiques supplémentaires.
PCT/IB2023/062322 2022-12-09 2023-12-06 Agent bloquant cd47 et polythérapie anticorps bispécifique anti-bcma/anti-cd3 WO2024121777A1 (fr)

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