WO2024040151A1

WO2024040151A1 - Sirp alpha fusion protein and anti-cd38 antibody combination therapies

Info

Publication number: WO2024040151A1
Application number: PCT/US2023/072362
Authority: WO
Inventors: Ingmar BRUNS; Gloria Hoi Ying LIN; Victor Ruberio LINCHA; Diane Dan WANG
Original assignee: Pfizer Inc.
Priority date: 2022-08-18
Filing date: 2023-08-17
Publication date: 2024-02-22

Abstract

Dosing regimens and methods for administering combination therapies combining SIRPαFc fusion proteins and anti-CD38 antibodies are provided, such as the SIRPαFc fusion protein TTI-622 and the anti-CD38 antibody isatuximab. The dosing regimens and methods may further include additional therapeutic agents.

Description

SIRP ALPHA FUSION PROTEIN AND ANTI-CD38 ANTIBODY COMBINATION THERAPIES

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing (P113970013WOOO-SEQ-LJG. xml; Size: 15,184 bytes; and Date of Creation: August 16, 2023) is herein incorporated by reference in its entirety.

BACKGROUND

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. The use of SIRPa to treat cancer by CD47 blockade is described in WO 2010/130053, incorporated herein by reference.

International Patent Application Publication No. WO 2014/094122, incorporated by reference in its entirety, 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. In this form, the SIRPaFc drug shows dramatic effects on the viability of cancer cells that present with a CD47+ phenotype.

CD38 is a glycoprotein located on the surface of many immune cells, including plasma cells and other lymphoid and myeloid cell populations. Expression of CD38 is high on myeloma cells, and it is a target for therapeutic strategies. The anti-CD38 antibodies isatuximab and daratumumab have been approved in the United States for the treatment of multiple myeloma.

The CD47 and CD38 blockade approaches in anti-cancer drug development and treatment shows great promise. However, improved dosing regimens and treatment methods are needed.

SUMMARY

Provided herein are combination therapies for the treatment of cancer, and related methods and compositions. In some embodiments, combination therapies provided herein include a SIRPaFc fusion protein and an anti-CD38 antibody. In some embodiments, the combination therapies further include one or both of carfilzomib and dexamethasone. In some embodiments, the SIRPaFc fusion protein is TTI-622 and the anti-CD38 antibody is isatuximab.

In some embodiments, provided herein is a method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, and a proteasome inhibitor to the patient.

In some embodiments, provided herein is a method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, carfilzomib is administered at 20 mg/m2 on days 1 and 2 and at 56 mg/m2 on days 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

In some embodiments, provided herein is a method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 and 15 of the 28 day cycle, carfilzomib is administered at 56 mg/m2 on days 1 , 2, 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts exemplary dosing regimens combining TTI-622 (622), isatuxmab (ISA), carfilizomib (CAR), and dexamethasone (DEX). Regimens are shown for cohorts 1 (#1 ), 2 (#2), and 3 (#3); each cohort includes a lead-in cycle (CO), cycle 1 (C1 ), and a cycle 2 I additional cycles (C>2). Doses are provided in the following units for the respective agent: dexamethasone: mg; isatuximab: mg/kg; carfilzomib: mg/m2; TTI-622: mg/kg. The doselimiting toxicity (DLT) period is the combination of the lead-in cycle (CO) and cycle 1 (C1 ).

DETAILED DESCRIPTION

The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. Exemplary embodiments (E) of the invention provided herein include:

E1 . A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, and a proteasome inhibitor to the patient.

E2. The method of E1 , wherein the SIRPaFc fusion protein is TTI-622 (SEQ ID NO: 8), the anti-CD38 antibody is isatuximab, and the proteasome inhibitor is carfilzomib.

E3. The method of any one of E1 -E2, wherein the combination therapy further comprises dexamethasone.

E4. A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, carfilzomib is administered at 20 mg/m2 on days 1 and 2 and at 56 mg/m2 on days 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

E5. A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 and 15 of the 28 day cycle, carfilzomib is administered at 56 mg/m2 on days 1 , 2, 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

E6. The method of any one of E4-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 E4-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 E4-E7, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8.

E9. The method of any one of E4-E8, wherein the 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 .

E10. The method of any one of E4-E9, wherein the anti-CD38 antibody is isatuximab. E11 . The method of any one of E1 -E10, wherein the cancer is a blood cancer or a solid tumor cancer. E12. The method of any one of E1 -E11 , 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); myelodysplastic syndrome, lymphoma, T cell lymphoma, Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, aggressive nonHodgkin’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-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma, or epithelioid sarcoma.

E13. The method of any one of E1-E12, wherein the cancer is relapsed or refractory (R/R) multiple myeloma.

E14. The method of E13, wherein the patient has previously been treated with 1 to 3 lines of therapy.

E15. The method of any one of E1-E14, wherein at least the SIRPaFc fusion protein and anti-CD38 antibody are administered until disease progression.

E16. The method of any one of E1-E15, wherein the patient has CD47-positive cancer cells. E17. The method of any one of E1-E16, wherein the anti-CD38 antibody is isatuximab and wherein the patient has fewer treatment related adverse effects as compared the treatment related adverse effects that would be expected for the same method except with the anti- CD38 antibody daratumumab.

E18. The method of E17, wherein the treatment related adverse effects are one or both of anemia and neutropenia.

E19. A SIRPaFc fusion protein or anti-CD38 antibody for use to treat a patient according to the method of any one of E1 -E18.

E20. Use of a SIRPaFc fusion protein or an anti-CD38 antibody in the manufacture of a medicament for use to treat a patient according to the method of any one of E1 -E18.

E21 . A kit comprising one or both of a SIRPaFc fusion protein and an anti-CD38 antibody and instructions for use according to the method of any one of E1-E18, and optionally further comprising one or more additional therapeutic agents according to the method of any one of E1 -E18.

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

All references cited herein, including patent applications, patent publications, UniProtKB accession numbers are herein incorporated by reference, as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al, Molecular Cloning: A Laboratory Manual 3rd. edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel, et al. eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R. I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al, eds., 1994); Current Protocols in Immunology (J. E. Coligan et al, eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and updated versions thereof.

Definitions

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

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

Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, 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. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

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

The terms "treating", "treat" or "treatment" refer 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. In some embodiments, the disease, disorder or condition is cancer.

The term “therapeutically 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).

The term “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. These 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.

SIRP Alpha Fusion Proteins

Dosing regimens and methods provided herein use a CD47-binding and blocking form of SIRPa, as a CD47 blockade drug or blocking agent. An agent or drug that has CD47 blockade activity is an agent that interferes with and dampens signal transmission that results when CD47 interacts with macrophage-presented SIRPa. CD47-binding forms of human SIRPa are the preferred CD47 blockade drugs for use in the regimens and methods provided herein. These drugs 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.

In some embodiments, the soluble form of SIRPa is an Fc fusion. More particularly, the drug suitably comprises the human SIRPa protein, in a form fused directly, or indirectly, with an antibody constant region, or Fc (fragment crystallisable). Unless otherwise stated, the term “human SIRPa” as used herein refers to a wild type, endogenous, mature form of human SIRPa. In humans, 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). Another form, 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.

In the dosing regimens and methods provided herein, useful SIRPaFc fusion 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. EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVS ESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA [SEQ ID NO: 1] In some embodiments, 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 1 18-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 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 antibody-dependent 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. By this definition, an Fc region that is wild type IgG 1 or lgG4 has effector function, whereas the Fc region of a human lgG4 mutated to eliminate effector function, such as by incorporation of an alteration series that includes Pro233, Val234, Ala235 and deletion of Gly236 (EU), is considered not to have effector function. In some embodiments, 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. In embodiments, the Fc region includes the lower hinge-CH2-CH3 domains.

In a specific embodiment, 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 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 3]

Thus, in some embodiments, the Fc region has either a wild type or consensus sequence of an lgG1 constant region. In alternative embodiments, the Fc region incorporated in the fusion protein is derived from any IgG 1 antibody having a typical effectoractive constant region. The 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).

In other embodiments, the Fc region has a sequence of a wild type human lgG4 constant region. In alternative embodiments, 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 IgG 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.

In some embodiments, 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]

In some embodiments, 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. In one specific and preferred embodiment, the Fc region incorporates an alteration at position 228 (EU numbering), in which the serine at this position is substituted by a proline (S²²⁸P), thereby to stabilize the disulfide linkage within the Fc dimer. Other alterations within the Fc region can include substitutions that alter glycosylation, such as substitution of Asn²⁹⁷ by glycine or alanine; half-life enhancing alterations such as T²⁵²L, T²⁵³S, and T²⁵⁶F 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. In another embodiment, the Fc region is modified to increase its biological half-life. Various approaches are possible. For example, one or more of the following mutations can be introduced; T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375.

In a specific embodiment, and in the case where the Fc component is an lgG4 Fc, the Fc incorporates at least the S²²⁸P 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 blockade drug used in the regimens and method provided herein is thus preferably 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 is the constant region of a human IgG having effector function.

In one embodiment, the fusion protein comprises a SIRPa component consisting at least of residues 32-137 of the V2 form of wild type human SIRPa, i.e., SEQ ID NO: 1 . In a preferred embodiment, the SIRPa component consists of residues 31-148 of the V2 form of human SIRPa, i.e., SEQ ID NO: 2. In another embodiment, the Fc component is the Fc component 1f 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.

In some embodiments, 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 effector function and having SEQ ID NO: 3. When the SIRPa component is SEQ ID NO: 1 , this fusion protein comprises SEQ ID NO: 6, shown below: EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVS ESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 6]

When the SIRPa component is SEQ ID NO: 2, this fusion protein comprises SEQ ID NO: 7, shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTV SESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 7]

The SIRPaFc fusion protein of SEQ ID NO: 7 is also known as TTI-621 , ontorpacept and PF-07901800. In alternative embodiments, the Fc component of the fusion protein is based on an lgG4, and preferably an lgG4 that incorporates the S²²⁸P mutation. In the case where the fusion protein incorporates the preferred SIRPa IgV domain of SEQ ID NO: 2, the resulting lgG4-based SIRPa-Fc protein has SEQ ID NO: 8, shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTV SESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 8]

The SIRPaFc fusion protein of SEQ ID NO: 8 is also known as TTI-622, maplirpacept and PF-07901801.

In one embodiment of a dosing regimen or method provided herein, a SIRPaFc fusion protein comprises, as the SIRPa component of the fusion protein, a sequence that comprises SEQ ID NO: 2. In one embodiment, the SIRPaFc fusion protein comprises the polypeptide of SEQ ID NO: 7 or SEQ ID NO: 8.

The 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, A21V, V27I/L, I31T/S/F, E47V/L, K53R, E54Q, H56P/R, S66T/G, K68R, V92I, F94V/L, V63I, and/or F103V.

In the SIRPaFc fusion protein, 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. Alternatively, 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, Hindi 11, 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. In one example, such a linker is based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser [SEQ ID NO: 9]) 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. In another embodiment, the linker is GTELSVRAKPS [SEQ ID NO: 10]. 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.

Anti-CD38 Antibody - Isatuximab

In some embodiments, an anti-CD38 antibody used with methods and dosing regimens provided herein is isatuximab-irfrc (“isatuximab”).

Isatuximab (SARCLISA®) is a monoclonal anti-CD38 antibody approved in various jurisdictions for patients with relapsed refractory multiple myeloma. Isatuximab is indicated A) in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, and B) in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.

The recommended dose of isatuximab is 10 mg/kg weekly in a first 28-day cycle and every two weeks in second and subsequent 28-day cycles.

In the IKEMA phase 3 trial (SARCLISA® + carfilzomib + dexamethasone (Kd)) , treatment was administered in 28-day cycles until disease progression or unacceptable toxicity. Isatuximab was administered as an IV infusion weekly in the first cycle and every 2 weeks thereafter. Carfilzomib was administered as an IV infusion during cycle 1 at a dose of 20 mg/m2 on days 1 and 2, and at 56 mg/m2 on days 8, 9, 15 and 16; during subsequent cycles, it was administered at 56 mg/m2 on days 1 , 2, 8, 9, 15, and 16. Dexamethasone (IV on the days of isatuximab and/or carfilzomib infusions, and orally on the other days) 20 mg was given on days 1 , 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle.

Isatuximab is described in US Patent No. US8, 153,765.

The heavy chain of isatuximab comprises the amino acid sequence:

QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTG YAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11 )

The light chain of isatuximab comprises the amino acid sequence: DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDR FTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12)

SIRP Alpha Fusion Protein and Anti-CD38 Antibody Combination Therapies

Provided herein are improved combination therapies containing SIRP alpha (SIRPa) fusion proteins and an anti-CD38 antibody.

In some embodiments, a SIRPa fusion protein and an anti-CD38 antibody combination therapy provided herein further comprises a proteasome inhibitor. In some embodiments, the proteasome inhibitor is carfilzomib. Carfilzomib (also known as PR-171) is a structural analogue of the microbial natural product epoxomicin. Carfilzomib selectively inhibits the chymotrypsin-like (CTL) activity of the 20S proteasome with minimal cross reactivity to the other proteasome classes.

In some embodiments, a SIRPa fusion protein and an anti-CD38 antibody combination therapy provided herein further comprises dexamethasone. Dexamethasone is a synthetic glucocorticoid.

In some embodiments, a combination therapy provided herein combines the SIRPa fusion protein TTI-622, the anti-CD38 antibody isatuximab, the proteasome inhibitor carfilzomib, and dexamethasone. In vitro, addition of carfilzomib to TTI-622 augments TTI- 622-mediated phagocytosis of multiple myeloma cells. It is hypothesized that carfilzomib results in upregulation of pro-phagocytic signals. Isatuximab is also pro-phagocytic and has been shown to augment the action of proteosome inhibitors (Martin TG, et al, Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab. Cells, 2019. 8(12): p. 1522). It is hypothesized that isatuximab further increases antibody-dependent cellular phagocytosis (ADCP).

In addition, without being bound by theory, it is hypothesized that the combination of TTI-622 with isatuximab may provide benefits as compared to the combination of TTI-622 with other ant-CD38 antibodies such as daratumumab. For example, there may be fewer treatment related adverse effects such as anemia or neutropenia when combining TTI-622 with isatuximab as compared to combining TTI-622 with daratumumab. For example, daratumumab may bind to red blood cells more strongly than isatuximab, and thus daratumumab may result in more adverse effects caused by red blood cell depletion (e.g. anemia) than isatuximab. Also, isatuximab has various mechanistic differences from daratumumab. See, e.g. Richardson, PG et aL, Isatuximab for the treatment of relapsed/refractory multiple myeloma, Expert Opinion on Biological Therapy, 20:12, pp 1395- 1404 (2020). For example, isatuximab and daratumumab bind to different epitopes on CD38, and isatuximab induces direct apoptosis in multiple myeloma cells (in contrast, daratumumab only induces apoptosis in the presence of cross-linking agents).

In a combination therapy comprising TTI-622, isatuximab, carfilzomib, and dexamethasone, in some embodiments, TTI-622 is administered once every 1 , 2, or 3 weeks. Exemplary dosing amounts of TTI-622 include 1 , 2, 4, 8, and 16 mg/kg. In some embodiments, TTI-622 is administered weekly at a dose of 4, 8, or 16 mg/kg. In some embodiments, TTI-622 is administered on days 1 , 8, 15, and 22 of a 28-day dosing cycle at a dose of 4, 8, or 16 mg/kg.

In a combination therapy comprising TTI-622, isatuximab, carfilzomib, and dexamethasone, in some embodiments, isatuximab is administered once every 1 , 2, or 3 weeks. Exemplary dosing amounts of isatuximab include 10 mg/kg. In some embodiments, isatuximab is administered once every 1 or 2 weeks at a dose 10 mg/kg. In some embodiments, isatuximab is administered on days 1 , 8, 15, and 22 of a 28-day dosing cycle at a dose of 10 mg/kg, or on days 1 and 15 of a 28-day dosing cycle at a dose of 10 mg/kg.

In a combination therapy comprising TTI-622, isatuximab, carfilzomib, and dexamethasone, in some embodiments, carfilzomib is administered 1 or 2 times per week. Exemplary dosing amounts of carfilzomib include 20, 27, 56 or 70 mg/m². In some embodiments, carfilzomib is administered 2 times per week at a dose of 20 or 56 mg/m². In some embodiments, carfilzomib is administered on days 1 , 2, 8, 9, 15 and 16 of a 28-day dosing cycle at a dose of 20 or 56 mg/m². In some embodiments, carfilzomib is administered on days 1 , 2, 8, 9, 15 and 16 of a 28-day dosing cycle at a dose of 20 mg/m² on days 1 and 2, and a dose of 56 mg/m² on days 8, 9, 15 and 16.

In a combination therapy comprising TTI-622, isatuximab, carfilzomib, and dexamethasone, in some embodiments, dexamethasone is administered 1 or 2 times per week. Exemplary dosing amounts of dexamethasone include 20 or 40 mg. In some embodiments, dexamethasone is administered 2 times per week a dose 20 mg. In some embodiments, dexamethasone is administered on days 1 , 2, 8, 9, 15, 16, 22, and 23 of a 28- day dosing cycle at a dose of 20 mg.

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, and 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 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. “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. In particular embodiments, 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 fungoides, 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.

In some other embodiments, 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.

In other embodiments, 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.

In some embodiments, a cancer treated with a dosing regimen or method provided herein is relapsed and/or refractory (R/R). In some embodiments, the cancer is R/R multiple myeloma. In some embodiments, a subject treated with a dosing regimen or method provided herein has been previously treated with 1-3 lines of therapy for the cancer.

A SIRPaFc fusion protein 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.

Incorporated by reference herein for all purposes is the content of U.S. Provisional Patent Application No. 63/371 ,801 filed August 18, 2022.

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

The foregoing description and following Examples detail certain specific embodiments of the disclosure and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the disclosure may be practiced in many ways and the disclosure should be construed in accordance with the appended claims and any equivalents thereof.

Although the disclosed teachings have been described with reference to various applications, methods, kits, and compositions, it will be appreciated that various changes and modifications can be made without departing from the teachings herein and the claimed disclosure below. The following examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented herein. While the present teachings have been described in terms of these exemplary embodiments, the skilled artisan will readily understand that numerous variations and modifications of these exemplary embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the current teachings.

EXAMPLES

In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner. Example 1 :

The objective of this study is to evaluate the safety and efficacy of TTI-622 in combination with isatuximab, carfilzomib, and dexamethasone.

Patients with relapsed / refractory (R/R) multiple myeloma (MM) who have previously been treated with 1 to 3 lines of therapy will receive TTI-622 in combination with isatuximab, carfilzomib, and dexamethasone. Patients are included in Cohort 1 , 2, or 3. The dosing regimen for each Cohort includes a Cycle 0 (CO; a lead-in phase), Cycle 1 , and Cycle 2 / additional Cycles (Cycle 2 optionally repeats).

Cohort 1 : All cycles (CO, C1 , and C2 1 additional Cycles) are 28 days in length. Cohort 1 , Cycle 0: At least 3 patients will be treated with increasing doses of TTI-622 (CO Day 1 : 1 mg/kg, CO Day 8: 2 mg/kg, CO Day 15: 4 mg/kg. CO Day 22: 4 mg/kg QW) for intrapatient dose-escalation in combination with 10 mg/kg isatuximab (Days 1 , 8, 15, and 22) and 40 mg dexamethasone (Days 1 , 8, 15, and 22). Cohort 1 , Cycle 1 : dexamethasone: 20 mg on each of Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on each of Days 1 , 8, 15, and 22; carfilzomib: 20 mg/m2 on Days 1 and 2, and 56 mg/m2 on Days 8, 9, 15, and 16; TTI-622: 4 mg/kg on Days 1 , 8, 15, and 22. Cohort 1 , Cycle 2 / additional cycles: dexamethasone: 20 mg on Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on Days 1 and 15; carfilzomib: 56 mg/m2 on Days 1 , 2, 8, 9, 15, and 16; TTI-622: 4 mg/kg on Days 1 , 8, 15, and 22.

Cohort 2: Cycle CO is 14 days in length; cycles C1 and C2 / additional Cycles are 28 days in length. Cohort 2, Cycle 0: dexamethasone: 40 mg on each of Days 1 and 8; isatuximab: 10 mg/kg on each of Days 1 and 8; TTI-622: 8 mg/kg on Days 1 and 8. Cohort

2, Cycle 1 : dexamethasone: 20 mg on each of Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on each of Days 1 , 8, 15, and 22; carfilzomib: 20 mg/m2 on Days 1 and 2, and 56 mg/m2 on Days 8, 9, 15, and 16; TTI-622: 8 mg/kg on Days 1 , 8, 15, and 22. Cohort 2, Cycle 2 / additional cycles: dexamethasone: 20 mg on Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on Days 1 and 15; carfilzomib: 56 mg/m2 on Days 1 , 2, 8, 9,

15, and 16; TTI-622: 8 mg/kg on Days 1 , 8, 15, and 22.

Cohort 3: Cycle CO is 14 days in length; cycles C1 and C2 / additional Cycles are 28 days in length. Cohort 3, Cycle 0: dexamethasone: 40 mg on each of Days 1 and 8; isatuximab: 10 mg/kg on each of Days 1 and 8; TTI-622: 16 mg/kg on Days 1 and 8. Cohort

3, Cycle 1 : dexamethasone: 20 mg on each of Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on each of Days 1 , 8, 15, and 22; carfilzomib: 20 mg/m2 on Days 1 and 2, and 56 mg/m2 on Days 8, 9, 15, and 16; TTI-622: 16 mg/kg on Days 1 , 8, 15, and 22. Cohort 3, Cycle 2 / additional cycles: dexamethasone: 20 mg on Days 1 , 2, 8, 9, 15, 16, 22, and 23; isatuximab: 10 mg/kg on Days 1 and 15; carfilzomib: 56 mg/m2 on Days 1 , 2, 8, 9, 15, and 16; TTI-622: 16 mg/kg on Days 1 , 8, 15, and 22.

The dosing protocols for Cohorts 1 -3 are also shown in FIG. 1 .

Dose-escalation in cohorts 2 and 3 will follow a 3+3 dose-escalation schema. If in cohort 1 only the lowest (1 mg/kg) or the lowest and the intermediate dose level (1 mg/kg and 2 mg/kg) of TTI-622 is tolerated after the initial infusion, no further dose-escalation will occur and 3 additional patients will be treated at the lowest or lowest and intermediate dose level(s) with a 56-day DLT period. Patients will be considered evaluable for DLTs if they receive all TTI-622 doses as applicable and at least 75% of the planned doses of the combination partners within the DLT observation period or if they experience an adverse event (AE) meeting DLT criteria during that time.

For each Cohort, starting on Cycle 1 , carfilzomib is administered on Day 1 and Day 2 at 20 mg/m2 IV, and if tolerated, then 56 mg/m2 can be given staring on Cyclel Day 9 and thereafter for all subsequent doses. Dexamethasone is administered orally (PO) or IV infusion. Post dose-limiting toxicity period, isatuximab dosing may be delayed for toxicity as per institutional guidelines (refer to SARCLISA® [isatuximab] package insert). When isatuximab and carfilzomib are given on the same day as TTI-622, at least 60 minutes must elapse between completion of the isatuximab or carfilzomib infusion and initiation of the TTI- 622 infusion. Any isatuximab or carfilzomib infusion-related reactions must be less than or equal to Grade 2 and have fully resolved to initiate the TTI-622 infusion on the same day.

Patients in Cohorts 1 , 2, and 3 will receive TTI-622 in combination with 10 mg/kg isatuximab starting at cycle 0 day 1 (lead-in phase) weekly for 6 (Cohorts 2 and 3) or 8 weeks (Cohort 1 ). TTI-622 will then continue weekly and isatuximab will continue every other week thereafter. Treatment will continue until disease progression or non-tolerable toxicity.

Claims

CLAIMS It is claimed:

1 . A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, and a proteasome inhibitor to the patient.

2. The method of claim 1 , wherein the SIRPaFc fusion protein is TTI-622 (SEQ ID NO: 8), the anti-CD38 antibody is isatuximab, and the proteasome inhibitor is carfilzomib.

3. The method of any one of claims 1-2, wherein the combination therapy further comprises dexamethasone.

4. A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, carfilzomib is administered at 20 mg/m2 on days 1 and 2 and at 56 mg/m2 on days 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

5. A method of treating a cancer in a patient, the method comprising administering a combination therapy of a SIRPaFc fusion protein, an anti-CD38 antibody, carfilzomib, and dexamethasone to the patient for at least 1 cycle, wherein each cycle is 28 days and the SIRPaFc fusion protein is administered at 4 mg/kg, 8 mg/kg or 16 mg/kg on days 1 , 8, 15, and 22 of the 28 day cycle, the anti-CD38 antibody is administered at 10 mg/kg on days 1 and 15 of the 28 day cycle, carfilzomib is administered at 56 mg/m2 on days 1 , 2, 8, 9, 15, and 16 of the 28 day cycle, and dexamethasone is administered at 20 mg on days 1 , 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycle.

6. The method of any one of claims 4-5, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1 .

7. The method of any one of claims 4-6, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 2.

8. The method of any one of claims 4-7, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8.

9. The method of any one of claims 4-8, wherein the 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 .

10. The method of any one of claims 4-9, wherein the anti-CD38 antibody is isatuximab.

11 . The method of any one of claims 1 -10, wherein the cancer is a blood cancer or a solid tumor cancer.

12. The method of any one of claims 1-11 , 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); myelodysplastic syndrome, lymphoma, T cell lymphoma, Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, aggressive nonHodgkin’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-Jones myeloma, sarcoma, soft tissue sarcoma, leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma, or epithelioid sarcoma.

13. The method of any one of claims 1-12, wherein the cancer is relapsed or refractory (R/R) multiple myeloma.

14. The method of claim 13, wherein the patient has previously been treated with 1 to 3 lines of therapy.

15. The method of any one of claims 1-14, wherein at least the SIRPaFc fusion protein and anti-CD38 antibody are administered until disease progression.

16. The method of any one of claims 1-15, wherein the patient has CD47-positive cancer cells.

17. The method of any one of claims 1-16, wherein the anti-CD38 antibody is isatuximab and wherein the patient has fewer treatment related adverse effects as compared the treatment related adverse effects that would be expected for the same method except with the anti- CD38 antibody daratumumab.

18. The method of claim 17, wherein the treatment related adverse effects are one or both of anemia and neutropenia.

19. A SIRPaFc fusion protein or anti-CD38 antibody for use to treat a patient according to the method of any one of claims 1 -18.

20. Use of a SIRPaFc fusion protein or an anti-CD38 antibody in the manufacture of a medicament for use to treat a patient according to the method of any one of claims 1 -18.

21 . A kit comprising one or both of a SIRPaFc fusion protein and an anti-CD38 antibody and instructions for use according to the method of any one of claims 1-18, and optionally further comprising one or more additional therapeutic agents according to the method of any one of claims 1-18.