Dosage regimen of SIRP alpha fusion protein for the treatment of cancer

Abstract

A dosing regimen and method for administering a SIRPaFc fusion protein are provided. The dosing regimen and method include both SIRPaFc monotherapy and combination therapy.

Description

Technical Field

[0001]

Background Art

[0002] Cancer cells are targeted for destruction through the recruitment and activation of macrophages by antibodies that bind to cancer cell antigens and by Fc receptors that bind to the Fc portion of those antibodies. The binding between CD47 on cancer cells and SIRPα on macrophages transmits a "don't eat me" signal that enables many tumor cells to evade destruction by macrophages. Inhibition of the CD47 / SIRPα interaction (CD47 blockade) has been shown to enable macrophages to "see" and destroy target CD47+ cancer cells. The use of SIRPα for treating cancer by CD47 blockade is described in WO 2010 / 130053, which is incorporated herein by reference in its entirety.

[0003] WO 2014 / 094122, which is incorporated herein by reference in its entirety, describes a protein drug that inhibits the interaction between CD47 and SIRPα. This CD47-blocking drug is a form of human SIRPα that incorporates a unique region of its extracellular domain linked to a particularly useful form of the IgG-based Fc region. In this form, the SIRPαFc drug exhibits a dramatic effect on the survival of cancer cells exhibiting the CD47+ phenotype. The effect is seen particularly in acute myeloid leukemia (AML) cells and in many other types of cancer.

[0004] The CD47-blockade approach in anti-cancer drug development has shown great promise. However, improved dosing regimens and treatment methods are needed for SIRPaFc agents.

Summary of the Invention

Problems to be Solved by the Invention

[0005]

Means for Solving the Problem

[0006] Provided herein are improved dosing regimens and treatment methods for SIRPaFc-based therapy. The dosing regimens and methods provided herein include both SIRPaFc monotherapy and combination therapy.

[0007] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg, 10 mg / kg, 12 mg / kg, 16 mg / kg, 18 mg / kg, 24 mg / kg, 28 mg / kg, 300 mg, 600 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg, Q1W, Q2W, or Q3W.

[0008] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W.

[0009] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W.

[0010] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W, 18 mg / kg Q3W, 16 mg / kg QW, or 28 mg / kg Q3W.

[0011] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and an anti-CD20 agent, administering the anti-CD20 agent to the patient at 375 mg / m2 Q1W for up to 8 doses, and administering the SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W.

[0012] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and an anti-CD20 agent, administering the anti-CD20 agent to the patient at 375 mg / m2 Q1W for up to 8 doses, and administering the SIRPaFc fusion protein to the patient according to a dosing regimen of 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W.

[0013] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering the SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W, 16 mg / kg Q1W, or 10 mg / kg Q2W.

[0014] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein, carfilzomib, and dexamethasone over N cycles, each cycle being 28 days, wherein the SIRPaFc fusion protein is administered at 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of a 28-day cycle, carfilzomib is administered at 20 mg / m2 or 70 mg / m2 on days 1, 8, and 15 of a 28-day cycle, and dexamethasone is administered at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle.

[0015] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, carfilzomib, and dexamethasone over N cycles, each cycle being 28 days, wherein the SIRPaFc fusion protein is administered at 10 mg / kg on days 1 and 15 of the 28-day cycle, carfilzomib is administered at 20 mg / m2 or 70 mg / m2 on days 1, 8, and 15 of the 28-day cycle, and dexamethasone is administered at 40 mg on days 1, 8, 15, and 22 of the 28-day cycle.

[0016] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient the SIRPaFc fusion protein according to a dosing regimen of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg Q2W.

[0017] In some embodiments, provided herein is a method of treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, wherein the SIRPaFc fusion protein is administered on days 1 and 8 of the 21-day cycle, doxorubicin is administered on day 1 of the 21-day cycle, N is 2, 3, 4, 5, 6, 7, or 8 cycles, and the second regimen follows the first regimen and comprises administering to the patient the SIRPaFc fusion protein according to a Q2W dosing regimen.

[0018] In some embodiments, provided herein is a method of treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of a SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, the SIRPaFc fusion protein being administered on days 1 and 8 of the 21-day cycle, doxorubicin being administered on day 1 of the 21-day cycle, N being 2, 3, 4, 5, 6, 7, or 8 cycles, and the second regimen follows the first regimen and comprises administering the SIRPaFc fusion protein to the patient according to a Q2W dosing regimen.

[0019] In some embodiments, provided herein is a method of treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of a SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, the SIRPaFc fusion protein being administered on days 1 and 8 of the 21-day cycle, doxorubicin being administered on day 1 of the 21-day cycle, N being 6 cycles, the second regimen follows the first regimen and comprises administering the SIRPaFc fusion protein to the patient according to a Q2W dosing regimen, doxorubicin being administered at a fixed dose of 75 mg / m2 in the first regimen, and the SIRPaFc fusion protein being administered at a dose of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg in each of the first and second regimens. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

Figure 1

[0021] The present invention can be more easily understood by referring to the following detailed description and examples of embodiments of the present invention included herein. It should be understood that the present invention is not limited to a specific manufacturing method and can naturally be modified. It should also be understood that the technical terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0022] Exemplary embodiments (E) of the invention provided herein include the following: E1. A method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg, 10 mg / kg, 12 mg / kg, 16 mg / kg, 18 mg / kg, 24 mg / kg, 28 mg / kg, 150 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg Q1W, Q2W, Q3W, or Q4W. E2. A method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W. E3. A method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W. E4. A method of treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W, 18 mg / kg Q3W, 16 mg / kg QW, or 28 mg / kg Q3W. E5. The method according to any one of E1 to E4, further comprising administering an anti-CD20 agent to the patient. A method for treating cancer in a patient, comprising administering to the patient a combination therapy of an SIRPaFc fusion protein and an anti-CD20 agent, administering the anti-CD20 agent to the patient at 375 mg / m2 Q1W for up to 8 doses, and administering the SIRPaFc fusion protein to the patient according to a dosing regimen of 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W. A method for treating cancer in a patient, comprising administering to the patient a combination therapy of an SIRPaFc fusion protein and an anti-CD20 agent, administering the anti-CD20 agent to the patient at 375 mg / m2 Q1W for up to 8 doses, and administering the SIRPaFc fusion protein to the patient according to a dosing regimen of 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W. The method according to any one of E5 to E7, wherein the anti-CD20 agent is rituximab. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a dosing regimen of 8 mg / kg Q1W, 16 mg / kg Q1W, or 10 mg / kg Q2W. The method according to E9, further comprising administering carfilzomib and dexamethasone to the patient, and optionally, the carfilzomib is administered IV and the dexamethasone is administered IV or orally. A method for treating cancer in a patient, comprising administering to the patient a combination therapy of an SIRPaFc fusion protein, carfilzomib, and dexamethasone over N cycles, each cycle being 28 days, the SIRPaFc fusion protein being administered at 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the 28-day cycle, carfilzomib being administered at 20 mg / m2 or 70 mg / m2 on days 1, 8, and 15 of the 28-day cycle, and dexamethasone being administered at 40 mg on days 1, 8, 15, and 22 of the 28-day cycle. A method of treating cancer in a patient, comprising administering to the patient a combination therapy of an SIRPaFc fusion protein, carfilzomib, and dexamethasone over N cycles, each cycle being 28 days, wherein the SIRPaFc fusion protein is administered at 10 mg / kg on days 1 and 15 of the 28-day cycle, carfilzomib is administered at 20 mg / m2 or 70 mg / m2 on days 1, 8, and 15 of the 28-day cycle, and dexamethasone is administered at 40 mg on days 1, 8, 15, and 22 of the 28-day cycle. The method according to any one of E11 or E12, wherein N is 1, 2, 3, 4, 5, 6, 7, or 8 cycles. A method of treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a dosing regimen of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg Q2W. A method of treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of an SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, wherein the SIRPaFc fusion protein is administered on days 1 and 8 of the 21-day cycle, doxorubicin is administered on day 1 of the 21-day cycle, N is 2, 3, 4, 5, 6, 7, or 8 cycles, and the second regimen follows the first regimen and comprises administering to the patient an SIRPaFc fusion protein according to a dosing regimen of Q2W. The method according to E15, wherein the doxorubicin is administered at a fixed dose of 75 mg / m2 in the first regimen, and the SIRPaFc fusion protein is administered at a dose of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg in each of the first and second regimens. A method for treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of an SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, the SIRPaFc fusion protein being administered on days 1 and 8 of the 21-day cycle, doxorubicin being administered on day 1 of the 21-day cycle, N being 6 cycles, the second regimen following the first regimen and comprising administering the SIRPaFc fusion protein to the patient according to a Q2W dosing regimen, the doxorubicin being administered at a fixed dose of 75 mg / m2 in the first regimen, and the SIRPaFc fusion protein being administered at a dose of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg in each of the first and second regimens, said method. E18. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to an 8 mg / kg QW dosing regimen. E19. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a 16 mg / kg QW dosing regimen. E20. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a 24 mg / kg QW dosing regimen. E21. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a 10 mg / kg Q2W dosing regimen. E22. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to an 18 mg / kg Q3W dosing regimen. E23. A method for treating cancer in a patient, comprising administering to the patient an SIRPaFc fusion protein according to a 28 mg / kg Q3W dosing regimen. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 12 mg / kg QW. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 12 mg / kg Q2W. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 18 mg / kg QW. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 18 mg / kg Q2W. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 24 mg / kg QW. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 24 mg / kg Q2W. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 24 mg / kg Q3W. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 32 mg / kg QW. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 32 mg / kg Q2W. A method for treating cancer in a patient, comprising administering a SIRPaFc fusion protein to the patient according to a dosing regimen of 32 mg / kg Q3W. A method for treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein according to a Q1W dosing regimen at a fixed dose of 150 mg, a fixed dose of 300 mg, a fixed dose of 600 mg, a fixed dose of 900 mg, a fixed dose of 1200 mg, a fixed dose of 1500 mg, a fixed dose of 1800 mg, a fixed dose of 2100 mg, or a fixed dose of 2400 mg. A method for treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein according to a Q2W dosing regimen at a fixed dose of 150 mg, a fixed dose of 300 mg, a fixed dose of 600 mg, a fixed dose of 900 mg, a fixed dose of 1200 mg, a fixed dose of 1500 mg, a fixed dose of 1800 mg, a fixed dose of 2100 mg, or a fixed dose of 2400 mg. A method for treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein according to a Q3W dosing regimen at a fixed dose of 150 mg, a fixed dose of 300 mg, a fixed dose of 600 mg, a fixed dose of 900 mg, a fixed dose of 1200 mg, a fixed dose of 1500 mg, a fixed dose of 1800 mg, a fixed dose of 2100 mg, or a fixed dose of 2400 mg. The method according to any one of E1 to E36, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1. The method according to any one of E1 to E37, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 2. The method according to any one of E1 to E38, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8. The method according to any one of E1 to E13 or E18 to E38, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8. The method according to any one of E14 to E17, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7. E42. The method according to any one of E1 to E37, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide having the amino acid sequence of SEQ ID NO: 1 or a variant thereof having 1, 2, 3, 4, or 5 amino acid substitutions compared to the sequence of SEQ ID NO: 1. E43. The method according to any one of E1 to E42, wherein the cancer is a blood cancer or a solid tumor cancer. E44. The method according to any one of E1 to E43, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML) and p53 mutant AML; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / neoplasms (MPDs); myelodysplastic syndromes, lymphoma, T-cell lymphoma, Hodgkin lymphoma, indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, Burkitt 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. E45. The method according to any one of E1 to E44, wherein the SIRPaFc fusion protein is administered over 12 or fewer doses. E46. The method according to any one of E1 to E45, wherein the SIRPaFc fusion protein is administered until disease progression. E47. The method according to any one of E1 to E46, wherein the patient has CD47-positive cancer cells. E48. The method according to any one of E1 to E47, wherein the SIRPaFc fusion protein is administered subcutaneously (SC) or intravenously (IV). E49. A SIRPaFc fusion protein for use in treating a patient according to the method according to any one of E1 to E48. E50. Use of a SIRPaFc fusion protein in the production of a medicament for use in treating a patient according to the method according to any one of E1 to E48. A kit comprising an SIRPaFc fusion protein and instructions for use according to the method according to any one of E51.E1 to E48.

[0023] The section headings used in this specification are for document organization purposes only and should not be construed as limiting the subject matter described.

[0024] All references cited in this specification, including patent applications, patent application publications, and UniProtKB accession numbers, are incorporated herein by reference as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0025] The technologies and procedures described or referenced in this specification are generally well understood and are conventional methodologies by those skilled in the art, for example, 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 (edited by F.M. Ausubel et al., (2003)); series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (edited by M.J. MacPherson, B.D. Hames and G.R. Taylor, (1995)), edited by Harlow and Lane, (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (edited by R.I. Freshney, (1987)); Oligonucleotide Synthesis (edited by M.J. Gait, 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (edited by J.E. Cellis, 1998) Academic Press; Animal Cell Culture (edited by R.I. Freshney, 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (edited by A. Doyle, J.B. Griffiths, and D.G. Newell, 1993 - 8) J.Wiley and Sons; Handbook of Experimental Immunology (edited by D.M. Weir and C.C. Blackwell); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P.Generally used methods include those described in widely used methodologies such as Calos, ed., 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 their revised editions.

[0026] Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings commonly understood by those of ordinary skill in the art.

[0027] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, "an" antibody includes one or more antibodies.

[0028] When aspects or embodiments of the present invention are described in terms of Markush groups or other groupings of alternatives, the present invention encompasses not only the complete groups listed as a whole, but also each individual member of the groups and all possible subgroups of the larger groups, as well as larger groups in which one or more of the group members are absent. The present invention also contemplates the explicit exclusion of one or more of any of the group members in the claimed invention.

[0029] Any example following the terms "e.g." or "for example" is not meant to be exhaustive or limiting.

[0030] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of the SIRPaFc fusion protein) means that the parameter may vary by up to 10% below or above the numerically described value for that parameter. For example, a dosage of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0031] The terms "treating", "treat" or "treatment" refer to any type of treatment, such as for alleviating, reducing or slowing the progression of a patient's disease, disorder or condition or any tissue damage associated with the disease. In some embodiments, the disease, disorder or condition is cancer.

[0032] The term "therapeutically effective amount" refers to the amount of an active ingredient that elicits a biological or medical response in a tissue, system, animal, individual or human being sought by a researcher, veterinarian, physician or other clinician, the response including one or more of the following: (1) prevention of a disease; e.g., prevention of a disease, condition or disorder in an individual who may have a predisposition to the disease, condition or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibition of a disease; e.g., inhibition of a disease, condition or disorder in an individual who has experienced or exhibited the pathology or symptoms of the disease, condition or disorder (i.e., arrest or slowing of further development of the pathology or symptoms); and (3) remission of a disease; e.g., remission of a disease, condition or disorder in an individual who has experienced or exhibited the pathology or symptoms of the disease, condition or disorder (i.e., reversal of the pathology or symptoms).

[0033] SIRPaFc fusion protein dosing regimen The present invention provides an improved SIRP alpha-Fc ("SIRPaFc") fusion protein dosing regimen and treatment method. In the dosing regimens and methods provided herein, the SIRPaFc fusion protein may be administered as a monotherapy or it may be administered in combination with one, two, or more additional therapeutic agents.

[0034] The dosing regimens and methods provided herein use SIRPα in its CD47-binding and blocking form as a CD47-blocking agent or blocker. An agent or drug having CD47-blocking activity is an agent that interferes with and attenuates the signaling that results when CD47 interacts with macrophage-presented SIRPα. Human SIRPα in its CD47-binding form is a preferred CD47-blocking agent for use in the regimens and methods provided herein. These agents are based on the extracellular region of human SIRPα. They include at least a region of the extracellular region sufficient to confer effective CD47-binding affinity and specificity. So-called "soluble" forms of SIRPα lacking the membrane-anchoring component have been described in the literature and are those referred to in WO 2010 / 070047 pamphlet (Novartis), WO 2013 / 109752 pamphlet (Stanford), and WO 2014 / 094122 pamphlet (Trillium), each of which is incorporated by reference in its entirety.

[0035] In a preferred embodiment, the soluble form of SIRPα is an Fc fusion. More particularly, the drug preferably comprises a human SIRPα protein in a form directly or indirectly fused to an antibody constant region, or Fc (fragment crystallizable). Unless otherwise stated, the term "human SIRPα" as used herein refers to the wild-type, endogenous, mature form of human SIRPα. In humans, the SIRPα protein is found in two major forms. One form, variant 1 or V1 form, has the amino acid sequence described as NCBI RefSeq NP_542970.1 (residues 27-504 constitute the mature form). Another form, variant 2 or V2 form, differs by only 13 amino acids and has the amino acid sequence described as CAA71403.1 in GenBank (residues 30-504 constitute the mature form). These two forms of SIRPα constitute approximately 80% of the forms of SIRPα present in humans, and both are encompassed by the term "human SIRPα" herein. Also encompassed by the term "human SIRPα" are its minor forms that are endogenous to humans and have the same property of triggering signal transduction through CD47 upon binding thereto. The present invention is most particularly directed to drug combinations comprising the human SIRP variant 2 form, or V2.

[0036] In the dosing regimens and methods provided herein, useful SIRPα Fc fusion proteins comprise one of three so-called immunoglobulin (Ig) domains present within the extracellular region of human SIRPα. More particularly, the SIRPα Fc protein of the present invention incorporates residues 32-137 (106-mer) of human SIRPα that constitute and define the IgV domain of the V2 form according to current nomenclature. This SIRPα sequence shown below is referred to herein as SEQ ID NO:1. EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA [SEQ ID NO:1]

[0037] In some embodiments, the SIRPαFc fusion protein incorporates the IgV domain defined by SEQ ID NO: 1 and additional adjacent residues that are contiguous within the SIRPα sequence. This form of the IgV domain, represented by residues 31-148 of the V2 form of human SIRPα, is an 118-mer having SEQ ID NO: 2 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPS[SEQ ID NO: 2]

[0038] The SIRPα fusion proteins of the invention can also incorporate an Fc region having effector functions. Fc refers to the "fragment crystallizable" and represents the constant region of an antibody and components within the hinge region that are mainly composed of the heavy chain constant region. Suitable Fc components include those having effector functions. An Fc component "having effector functions" is an Fc component that has at least some effector functions, for example, having at least some contribution to some ability to mediate antibody-dependent cell cytotoxicity or fix complement. Also, Fc binds to at least Fc receptors. These properties can be elucidated using assays established for this purpose. Functional assays include standard chromium release assays that detect target cell lysis. By this definition, an Fc region that is wild-type IgG1 or IgG4 has effector functions, while an Fc region of human IgG4 that has been mutated to eliminate effector functions, such as by incorporation of a series of mutations including deletion of Pro233, Val234, Ala235, and Gly236 (EU), is considered to have no effector functions. In some embodiments, Fc is based on a human antibody of the IgG1 isotype. The Fc regions of these antibodies are readily identifiable to those skilled in the art. In an embodiment, the Fc region includes the lower hinge-CH2-CH3 domains.

[0039] In certain embodiments, the Fc region is based on the amino acid sequence of human IgG1 described as residues 104-330 of P01857 in UniProtKB / Swiss-Prot, is shown below, and has the amino acid sequence referred to herein as SEQ ID NO: 3: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 3]

[0040] Thus, in some embodiments, the Fc region has either the wild-type sequence or the consensus sequence of the IgG1 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein can be derived from any IgG1 antibody having a typical effector-active constant region. The sequence of such an Fc region can correspond to the Fc region of any of the following IgG1 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).

[0041] In other embodiments, the Fc region has the sequence of the wild-type human IgG4 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein is derived from any IgG4 antibody that has an effector activity that, while present, is not significantly more potent than the IgG1 Fc region in nature and has a constant region having such effector activity. The sequence of such an Fc region can correspond, for example, to the Fc region of any of the following IgG4 sequences: P01861 (residues 99-327) from UniProtKB / Swiss-Prot and CAC20457.1 (residues 99-327) from GenBank.

[0042] In some embodiments, the Fc region is based on the amino acid sequence of human IgG4 described as P01861, residues 99-327 in UniProtKB / Swiss-Prot, and has the amino acid sequence shown below and referred to herein as SEQ ID NO: 4: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 4]

[0043] In some embodiments, the Fc region incorporates one or more modifications, usually about 10 or fewer, such as up to 1, 2, 3, 4, 5, or 6 such modifications, including amino acid substitutions that affect certain Fc properties. In one particular preferred embodiment, the Fc region has, at position 228 (EU numbering), a substitution of the serine at this position with proline (S 228 P), thereby incorporating a modification that stabilizes the disulfide linkages within the Fc dimer. Other modifications within the Fc region are substitutions that alter glycosylation, such as Asn with glycine or alanine 297Substitutions; modifications that enhance the half-life, such as T as taught in U.S. Patent No. 62777375 252 L, T 253 S, and T 256 F, and many others can be included. Particularly useful are modifications that enhance Fc properties while remaining silent with respect to conformation, for example, while retaining Fc receptor binding. In another embodiment, the Fc region is modified to increase its biological half-life. Various approaches are possible. For example, as described in U.S. Patent No. 6,277,375, one or more of the following mutations can be introduced: T252L, T254S, T256F.

[0044] In certain embodiments, when the Fc component is IgG4 Fc, the Fc incorporates at least the 228 S P mutation and has the amino acid sequence described below and referred to herein as SEQ ID NO: 5:

[0045] The CD47 blocking agents used in the regimens and methods provided herein are thus preferably SIRP fusion proteins useful for inhibiting the binding of human SIRPα and human CD47, thereby inhibiting or reducing the transmission of signals mediated through CD47 bound to SIRPα. The fusion protein comprises a human SIRPα component and an Fc component fused thereto. The SIRPα component comprises or consists of a single IgV domain of human SIRPα V2, and the Fc component is the constant region of human IgG having effector function.

[0046] In one embodiment, the fusion protein comprises an SIRPα component consisting of at least the V2 form of wild-type human SIRPα, i.e., residues 32-137 of SEQ ID NO: 2. In a preferred embodiment, the SIRPα component consists of the V2 form of human SIRPα, i.e., residues 31-148 of SEQ ID NO: 2. In another embodiment, the Fc component is the Fc component of human IgG1 designated P01857, and in a particular embodiment, has the amino acid sequence incorporating its lower hinge-CH2-CH3 region, i.e., SEQ ID NO: 3.

[0047] In some embodiments, the SIRPαFc fusion protein is provided and used in a secreted dimeric fusion form, the fusion protein having an SIRPα component having SEQ ID NO: 1, preferably SEQ ID NO: 2, and an Fc region having effector function and incorporating SEQ ID NO: 3 fused thereto. When the SIRPα component is SEQ ID NO: 1, this fusion protein comprises SEQ ID NO: 6 shown below: EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 6]

[0048] When the SIRPα component is SEQ ID NO: 2, this fusion protein contains SEQ ID NO: 7 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 7]

[0049] The SIRPaFc fusion protein of SEQ ID NO: 7 is also known as TTI-621.

[0050] In an alternative embodiment, the Fc component of the fusion protein is IgG4, preferably S 228Based on IgG4 incorporating the P mutation. When the fusion protein incorporates the preferred SIRPα IgV domain of SEQ ID NO: 2, the resulting IgG4-based SIRPα-Fc protein has SEQ ID NO: 8 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 8]

[0051] The SIRPaFc fusion protein of SEQ ID NO: 8 is also known as TTI-622.

[0052] In one embodiment of the dosing regimen or method provided herein, the SIRPaFc fusion protein comprises, as the SIRPα component of the fusion protein, a sequence comprising SEQ ID NO: 2. In one embodiment, the SIRPaFc fusion protein comprises the polypeptide of SEQ ID NO: 7 or SEQ ID NO: 8.

[0053] The SIRPα sequence incorporated within the SIRPaFc fusion protein can be modified as described in the literature. This can eliminate glycosylation sites in the protein, such as at position 89 and other positions. Other useful substitutions within SIRPα include one or more of the following: L4V / I, V6I / L, A21V, V27I / L, 131T / S / F, E47V / L, K53R, E54Q, H56P / R, S66T / G, K68R, V92I, F94V / L, V63I, and / or F103V.

[0054] In the SIRPαFc fusion protein, the SIRPα component and the Fc component may ultimately be produced as a dimer in which the single-chain polypeptide is linked through an interchain disulfide bond formed within the Fc region, either directly or indirectly, to provide a single-chain polypeptide. The nature of the fusion region is not critical. The fusion may be direct between the two components, with the SIRP component constituting the N-terminus of the fusion and the Fc component constituting the C-terminus. Alternatively, the fusion may be indirect through a linker consisting of one or more amino acids, preferably genetically encoded amino acids, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any number of amino acids from 5 to 100 amino acids, such as 5 to 50, 5 to 30, or 5 to 20 amino acids. The linker may contain a peptide encoded by DNA constituting a restriction site, such as BamHI, ClaI, EcoRI, HindIII, PstI, SalI, and XhoI sites.

[0055] The linker amino acids typically and desirably have some flexibility that allows the Fc and SIRP components to assume their active conformations. Residues that allow such flexibility are typically Gly, Asn, and Ser, and substantially any combination of these residues (particularly Gly and Ser) within the linker is likely to provide the desired ligation effect. In one example, such a linker can be based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser [SEQ ID NO: 9]) that can repeat as (G4S)n where n is 1, 2, 3, or greater, or based on (Gly)n, (Ser)n, (Ser-Gly)n, or (Gly-Ser)n, etc. In another embodiment, the linker is GTELSVRAKPS [SEQ ID NO: 10]. This sequence constitutes the SIRPα sequence adjacent to the C-terminus of the IgV domain (it is understood that this adjacent sequence can be considered as either the linker or in different forms of the IgV domain when ligated to the IgV minimal sequence described above). The fusion region or linker only needs to allow the components to assume their active conformations, and this can be achieved by any form of linker useful in the art.

[0056] The term "CD47" + "(or CD47+) is used with respect to the phenotype of cells targeted for binding by the polypeptides of the invention. Cells that are CD47 + can be identified by flow cytometry using a CD47 antibody as an affinity ligand. Appropriately labeled CD47 antibodies are commercially available for this use (for example, an antibody product of clone B6H12 is available from Santa Cruz Biotechnology). Cells to be examined for the CD47 phenotype can include standard tumor biopsy samples, particularly blood samples taken from a subject suspected of harboring cancer cells. CD47 disease cells of particular interest as targets for treatment with the fusion proteins of the invention are cells that "overexpress" CD47. These CD47 + + ​The cells are typically diseased cells and exhibit CD47 on their surfaces at a density that exceeds the normal CD47 density for a given type of cell. CD47 overexpression varies among different cell types and is herein meant to refer to any CD47 level determined to be higher than a measurable level on counterpart cells having a CD47 phenotype normal for that cell type, such as by flow cytometry or by immunostaining or by gene expression analysis as exemplified herein.

[0057] In some of the dosing regimens and methods provided herein, the SIRPaFc fusion protein is administered as a monotherapy.

[0058] In some of the dosing regimens and methods provided herein, the SIRPaFc fusion protein is administered as part of a combination therapy.

[0059] In some embodiments, the combination therapy provided herein includes carfilzomib. Carfilzomib (also known as PR-171) is a structural analog of the microbial natural product epoxomicin. Carfilzomib selectively inhibits the CTL activity of the 20S proteasome with minimal cross-reactivity to other proteasome classes.

[0060] In some embodiments, the combination therapy provided herein includes dexamethasone. Dexamethasone is a synthetic glucocorticoid.

[0061] In some embodiments, the combination therapy provided herein includes an anti-CD20 agent. The anti-CD20 agent includes, for example, an anti-CD20 antibody. Anti-CD20 antibodies include, for example, rituximab, ocrelizumab, and ofatumumab.

[0062] In some embodiments, the combination therapy provided herein includes doxorubicin. Doxorubicin is an anthracycline chemotherapeutic agent. Doxorubicin has the CAS number 23214-92-8.

[0063] In some embodiments, the combination therapy provided herein includes azacitidine. Azacitidine is an analog of cytidine and is used for the treatment of cancers including myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. Azacitidine has the CAS number 320-67-2.

[0064] In some embodiments, the combination therapy provided herein includes venetoclax. Venetoclax is a Bcl-2 inhibitor and is used for the treatment of cancers including chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. Venetoclax has the CAS number 1257044-40-8.

[0065] The SIRPaFc fusion protein provided herein can be administered at various dosages within the range of about 0.0001 to 100 mg / kg.

[0066] In some embodiments, TTI-621 (SEQ ID NO: 7) is administered in the range of 0.01 to 30 mg per kg of the subject's body weight. For example, the dosage of TTI-621 can be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, or 10.0 mg / kg.The dosage of TTI-621 can also include, for example, 0.2-2 mg / kg, 0.7-2 mg / kg, 1-5 mg / kg, 2-5 mg / kg, or 2-10 mg / kg. These dosages of TTI-621 can be administered to the subject, for example, once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), twice a month, once a month, once every two months, or once every three months.

[0067] In some embodiments, TTI-622 (SEQ ID NO: 8) is administered in the range of 0.1-50 mg per kg of the subject's body weight. For example, the dosage of TTI-622 can be 0.05 mg / kg, 0.2 mg / kg, 0.4 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, or 50 mg / kg. The dosage of TTI-622 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 TTI-622 can be administered to the subject, for example, once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), twice a month, once a month, once every two months, or once every three months.

[0068] In some embodiments, the SIRPaFc fusion proteins provided herein [e.g., TTI-622 (SEQ ID NO: 8)] are administered as a "flat" (also referred to as "fixed") dose, i.e., the dose is an amount per patient and the dose is independent of the patient's weight. In some embodiments, the 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, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg. The fixed dose of the SIRPaFc fusion protein may be administered in various regimens. In some embodiments, the dose is administered to the patient once a week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0069] In some embodiments, the SIRPaFc fusion protein is administered at a dose between a) a lower limit level of 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, or 2200 mg and b) an upper limit level of 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, or 3600 mg, wherein the lower limit level is a value less than the upper limit level.

[0070] The SIRPαFc protein provided herein exhibits very little binding to red blood cells. Thus, it is not necessary to consider "sink" of RBCs when dosing with the SIRPaFc fusion protein provided herein. It is estimated that the SIRPαFc fusion of the present invention may be effective at a dose less than half the dose required for a drug that binds to RBCs, such as a CD47 antibody, compared to other CD47 blocking drugs bound by RBCs. Further, the SIRPaFc fusion protein provided herein is a dedicated antagonist of SIRPα-mediated signals and exhibits very little CD47 agonism when bound thereto. Thus, it is not necessary to consider any stimulation induced by the drug when establishing a medically useful unit dosing regimen.

[0071] The dosing regimens and methods provided herein may be useful for treating various cancer cells. These include CD47 + cancer cells, particularly. Solid tumors may be treated with the dosing regimens and methods provided herein to reduce their size, number or growth rate and to control the proliferation of cancer stem cells. Such solid tumors are CD47 in the bladder, brain, breast, lung, colon, ovary, prostate, liver and also other tissues +It includes tumors. In one embodiment, the dosing regimens and methods provided herein can be used to inhibit the growth or proliferation of blood cancers. As used herein, "blood cancer" refers to cancers of the blood, including, among others, leukemia, lymphoma, and myeloma. "Leukemia" is a cancer of the blood in which too many white blood cells are produced that are not effective in the fight against infection, thus crowding out other parts of the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as either acute or chronic. Certain forms of leukemia may be, by way of example, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / neoplasms (MPDs); and myelodysplastic syndromes. "Lymphoma" may refer to, among others, Hodgkin lymphoma, both indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, and follicular lymphoma (small and large cell). Myeloma may refer to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma. In a particular embodiment, the dosing regimens and methods provided herein are useful for treating T cell lymphomas, a very heterogeneous group of lymphoid malignancies that are themselves divided into cutaneous and peripheral TCLs, which are themselves divided into nodal or extranodal forms. CTCL is derived from skin-homing T cells and consists of mycosis fungoides, Sézary syndrome, primary cutaneous T cell lymphoproliferative disorders, and anaplastic large cell lymphoma. A common feature of TCLs, with the exception of ALK and ALCL, is an aggressive course and poor response to treatment.

[0072] In some other embodiments, the blood cancer treated with the dosing regimens and methods is CD47 + leukemia, preferably selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndromes, preferably human acute myeloid leukemia.

[0073] In other embodiments, the blood cancers treated with the dosing regimens or methods provided herein are CD47 selected from Hodgkin lymphoma, both indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma (small and large cell), multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma + In addition to lymphoma or myeloma, it is leiomyosarcoma.

[0074] The SIRPαFc fusion protein provided herein can be administered to a subject via any of the established routes for protein delivery, particularly via intravenous, intradermal, and subcutaneous injection or infusion, or by oral or nasal administration.

[0075] In some embodiments, provided herein is a method of treating acute myeloid leukemia (AML) in a patient, the method comprising administering to the patient an SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 8 mg / kg Q1W.

[0076] In some embodiments, provided herein is a method of treating acute myeloid leukemia (AML) in a patient, the method comprising administering to the patient an SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 16 mg / kg Q1W.

[0077] In some embodiments, provided herein is a method of treating acute myeloid leukemia (AML) in a patient, the method comprising administering to the patient an SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 24 mg / kg Q1W.

[0078] In some embodiments, provided herein is a method of treating acute myeloid leukemia (AML) in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 32 mg / kg Q1W.

[0079] In some embodiments, provided herein is a method of treating multiple myeloma (MM) in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 8 mg / kg Q1W.

[0080] In some embodiments, provided herein is a method of treating MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 16 mg / kg Q1W.

[0081] In some embodiments, provided herein is a method of treating MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 24 mg / kg Q1W.

[0082] In some embodiments, provided herein is a method of treating MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 32 mg / kg Q1W.

[0083] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 300 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0084] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 600 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0085] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 900 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0086] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 1200 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0087] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 1500 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0088] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 1800 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0089] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 2100 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0090] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 2400 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0091] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 2700 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0092] In some embodiments, provided herein is a method of treating lymphoma or MM in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 at a fixed dose of 3000 mg according to a dosing regimen of Q1W, Q2W, or Q3W.

[0093] In some embodiments, provided herein is a method of treating DLBCL in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 8 mg / kg Q1W.

[0094] In some embodiments, provided herein is a method of treating DLBCL in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 16 mg / kg Q1W.

[0095] In some embodiments, provided herein is a method of treating DLBCL in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 24 mg / kg Q1W.

[0096] In some embodiments, provided herein is a method of treating DLBCL in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 32 mg / kg Q1W.

[0097] In some embodiments, provided herein is a method of treating DLBCL in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 8 mg / kg Q1W.

[0098] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 8 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0099] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 16 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0100] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 24 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0101] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 32 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0102] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 40 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0103] In some embodiments, provided herein is a method of treating solid tumor cancer in a patient, the method comprising administering to the patient a SIRPaFc fusion protein comprising the amino acid sequence of SEQ ID NO:8 according to a dosing regimen of 48 mg / kg Q2W. Optionally, the solid tumor cancer is ovarian cancer.

[0104] In some embodiments, provided herein is a method of treating AML in a patient, the method comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and azacitidine, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 8 mg / kg Q1W. Optionally, the AML is TP53 mutant AML.

[0105] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and azacitidine, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 16 mg / kg Q1W. Optionally, the AML is TP53 mutant AML.

[0106] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and azacitidine, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 24 mg / kg Q1W. Optionally, the AML is TP53 mutant AML.

[0107] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and azacitidine, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 32 mg / kg Q1W. Optionally, the AML is TP53 mutant AML.

[0108] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and azacitidine, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of a fixed 300 mg, a fixed 600 mg, a fixed 900 mg, a fixed 1200 mg, a fixed 1500 mg, a fixed 1800 mg, a fixed 2100 mg, a fixed 2400 mg, a fixed 2700 mg, or a fixed 3000 mg. Optionally, the SIRPaFc fusion protein is administered Q1W, Q2W, Q3W, or Q4W. Optionally, the AML is TP53 wild-type AML.

[0109] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, azacitidine, and venetoclax, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8 and is administered at a dosing regimen of 8 mg / kg Q1W. Optionally, the AML is TP53 wild-type AML.

[0110] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, azacitidine, and venetoclax, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8 and is administered at a dosing regimen of 16 mg / kg Q1W. Optionally, the AML is TP53 wild-type AML.

[0111] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, azacitidine, and venetoclax, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8 and is administered at a dosing regimen of 24 mg / kg Q1W. Optionally, the AML is TP53 wild-type AML.

[0112] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, azacitidine, and venetoclax, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8 and is administered at a dosing regimen of 32 mg / kg Q1W. Optionally, the AML is TP53 wild-type AML.

[0113] In some embodiments, provided herein is a method of treating AML in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, azacitidine, and venetoclax, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered in a dosing regimen of fixed 300 mg, fixed 600 mg, fixed 900 mg, fixed 1200 mg, fixed 1500 mg, fixed 1800 mg, fixed 2100 mg, fixed 2400 mg, fixed 2700 mg, or fixed 3000 mg. Optionally, the SIRPaFc fusion protein is administered Q1W, Q2W, Q3W, or Q4W. Optionally, the AML is TP53 wild-type AML.

[0114] In some embodiments, provided herein is a method of treating multiple myeloma (MM) in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, carfilzomib, and dexamethasone, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered in a dosing regimen of 8 mg / kg Q1W. Optionally, the MM is relapsed and / or refractory (R / R) MM.

[0115] In some embodiments, provided herein is a method of treating MM in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, carfilzomib, and dexamethasone, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered in a dosing regimen of 16 mg / kg Q1W. Optionally, the MM is R / R MM.

[0116] In some embodiments, provided herein is a method of treating multiple myeloma (MM) in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein, carfilzomib, and dexamethasone, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 10 mg / kg Q2W. Optionally, the MM is R / R MM.

[0117] In some embodiments, provided herein is a method of treating diffuse large B-cell lymphoma (DLBCL) in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein and an anti-CD20 targeting agent, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 8 mg / kg Q1W for 4 weeks, then 18 mg / kg Q3W. Optionally, the DLBCL is CD20+ DLBCL.

[0118] In some embodiments, provided herein is a method of treating DLBCL in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein and an anti-CD20 targeting agent, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 16 mg / kg Q1W for 4 weeks, then 28 mg / kg Q3W. Optionally, the DLBCL is CD20+ DLBCL.

[0119] In some embodiments, provided herein is a method of treating ovarian cancer in a patient, comprising administering to the patient a combination therapy of SIRPaFc fusion protein and pegylated liposomal doxorubicin (PLD), wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 12 mg / kg Q1W for 4 weeks, then 12 mg / kg Q2W. Optionally, the ovarian cancer is platinum-resistant ovarian cancer.

[0120] In some embodiments, provided herein is a method of treating ovarian cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and PLD, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 24 mg / kg Q1W for 4 weeks and then 24 mg / kg Q2W. Optionally, the ovarian cancer is platinum-resistant ovarian cancer.

[0121] In some embodiments, provided herein is a method of treating ovarian cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and PLD, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 48 mg / kg Q1W for 4 weeks and then 48 mg / kg Q2W. Optionally, the ovarian cancer is platinum-resistant ovarian cancer.

[0122] In some embodiments, provided herein is a method of treating ovarian cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and PLD, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8 and is administered at a dosing regimen of 48 mg / kg Q2W. Optionally, the ovarian cancer is platinum-resistant ovarian cancer.

[0123] The contents of U.S. Provisional Patent Application No. 63 / 345,693, filed May 15, 2022, and U.S. Provisional Patent Application No. 63 / 492,121, filed Mar. 24, 2023, are hereby incorporated by reference in their entirety for all purposes.

[0124] The following examples of specific embodiments for carrying out the invention are provided for illustrative purposes only and are in no way intended to limit the scope of the invention.

Examples

[0125] The following examples are described so that the present invention can be better understood. These examples are for illustrative purposes only and should in no way be construed as limiting the scope of the present invention.

[0126] (Example 1) Clinical study of TTI-622 in patients with progressive hematological malignancies, including multiple myeloma The purpose of this study is to evaluate the safety and preliminary efficacy of single-agent TTI-622 and TTI-622 in combination with carfilzomib and dexamethasone in patients with relapsed and / or refractory (R / R) multiple myeloma (MM).

[0127] This is a multi-site Phase 1a / 1b study. Phase 1a was designed to determine the MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anti-tumor activity of QW, Q2W, and Q3W single-agent TTI-622 in R / R lymphoma using a 3 + 3 dose-escalation schema. Phase 1b was designed to determine the safety and recommended dose of TTI-622 administered as a single agent and in combination with carfilzomib + dexamethasone in R / R MM and to evaluate preliminary efficacy. The secondary objective is to further characterize the safety, PK, and immunogenicity of TTI-622 when combined with carfilzomib + dexamethasone. Patients are enrolled in five separate cohorts: three cohorts explore different doses and dosing schedules of TTI-622 (8mg / kg QW, 16mg / kg QW, and 10mg / kg Q2W) in combination with approved doses of carfilzomib + dexamethasone. (Carfilzomib and dexamethasone are administered in 28-day cycles. Carfilzomib is administered on days 1, 8, and 15 of a 28-day cycle; it is administered IV at 20mg / m2 on day 1 of cycle 1 and, if tolerated, at 70mg / m2 IV starting on day 8 of cycle 1, with subsequent doses administered. Dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle; it is administered orally or IV at 40mg.) Two cohorts explore different doses of TTI-622 single-agent therapy (8mg / kg and 16mg / kg QW). Cohorts are opened in an alternating fashion. Three patients are dosed in each cohort and, after 28 days (21 days in single-agent therapy), enrollment is expanded to an additional 27 patients to explore efficacy. Eligibility criteria include: relapse or progression after ≥3 prior lines of therapy (including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies), progressive and measurable disease refractory to carfilzomib by IMWG at study entry; ≥18 years of age; ECOG performance status ≤2; adequate organ function; no known CNS involvement; no prior anti-CD47 or anti-SIRPα therapy.

[0128] The study endpoints include, for example, dose-limiting toxicity (DLT), frequency and severity of adverse events, overall response rate, disease control rate, time to response, duration of response, progression-free survival, minimal residual disease status, physical examination results, vital sign measurements, electrocardiogram results, ECOG performance status, laboratory evaluations, anti-drug antibodies to TTI-622, evaluation of single-dose PK of TTI-622, and PK after repeated administration of TTI-622 alone or in combination with carfilzomib and dexamethasone.

[0129] (Example 2) Clinical study of TTI-622 in patients with advanced hematological malignancies, including diffuse large B-cell lymphoma The purpose of this study is to evaluate the safety and preliminary efficacy of TTI-622 in combination with an anti-CD20 targeting agent in patients with CD20+ relapsed and / or refractory (R / R) diffuse large B-cell lymphoma (DLBCL).

[0130] This is a multi-site Phase 1a / 1b study. Phase 1a was designed to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary anti-tumor activity of TTI-622 as a single agent QW, Q2W, and Q3W in R / R lymphoma using a 3 + 3 dose escalation schema. The ongoing Phase 1b is to determine the safety, recommended dose, and preliminary efficacy of TTI-622 in combination with selected approved anti-cancer treatments for patients with hematological malignancies, including but not limited to anti-CD20 therapy in patients with CD20+ R / R DLBCL. The secondary objective is to further characterize the safety, PK, and immunogenicity of TTI-622 when combined with approved therapies. Patients are enrolled in two cohorts exploring different doses of TTI-622 (8 mg / kg QW for 4 weeks, then 18 mg / kg Q3W and 16 mg / kg QW for 4 weeks, then 28 mg / kg Q3W) in combination with anti-CD20 therapy (rituxan, an anti-CD20 agent, is administered at 375 mg / m2 weekly for up to 8 doses). The schema of these dosing regimens is shown in Figure 1. The cohorts are opened in an alternating fashion. Three patients are dosed in each cohort and after 28 days of continuation, enrollment is expanded to an additional 27 patients per cohort to explore efficacy. Key eligibility criteria include being 18 years of age or older; relapsed and / or refractory disease after treatment with 1 or more prior lines; not eligible for or progressing after high-dose chemotherapy (HDT) / autologous SCT; 1 or more sites of measurable disease as measured by Lugano 2014 classification; ECOG PS of 2 or less; adequate organ function, no known CNS involvement; no prior anti-CD47 or anti-SIRPα treatment.

[0131] Study endpoints include, for example, dose-limiting toxicity (DLT), frequency and severity of adverse events, overall response rate, disease control rate, time to response, duration of response, progression-free survival, physical examination results, vital sign measurements, electrocardiogram results, ECOG performance status, laboratory evaluations, anti-drug antibodies to TTI-622, evaluation of single-dose PK of TTI-622, and PK after repeated dosing of TTI-622 alone or in combination with an anti-CD20 targeting agent.

[0132] (Example 3) Clinical Study of TTI-621 in Combination with Doxorubicin in Patients with Unresectable or Metastatic High-Grade Leiomyosarcoma The purpose of this study is to evaluate the safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma (LMS).

[0133] This is a phase 1 / 2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The phase 1 dose escalation evaluated doses of TTI-621 (0.2 - 2.0 mg / kg) in combination with 75 mg / m 2 of doxorubicin in patients with high-grade soft tissue sarcoma. The expansion cohort evaluated TTI-621 (0.2 and 2.0 mg / kg) with doxorubicin in patients with pathologically confirmed LMS at a central laboratory. Doxorubicin was administered on day 1 and TTI-621 was administered on days 1 and 8 of a 21-day cycle for up to 6 cycles; patients continued TTI-621 monotherapy (days 1 and 15 of a 28-day cycle) until disease progression. The primary objectives of this study were to evaluate the safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK, and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study was completed without DLTs.

[0134] Study endpoints include, for example, the overall safety profile of TTI-621 in combination with and as monotherapy with doxorubicin, objective response rate, progression-free survival, overall survival, disease control rate, duration of response, duration of disease control, time to progression by radiographic diagnosis, time to new metastases, time to deterioration of ECOG performance status, and time to deterioration of patient-reported quality of life assessment.

Claims

1. A method of treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein at 8 mg / kg, 10 mg / kg, 16 mg / kg, 18 mg / kg, 24 mg / kg or 28 mg / kg according to a dosing regimen of Q1W, Q2W, or Q3W.

2. A method of treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein at 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W according to a dosing regimen.

3. A method of treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein at 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W according to a dosing regimen.

4. A method of treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein at 8 mg / kg Q1W, 18 mg / kg Q3W, 16 mg / kg QW, or 28 mg / kg Q3W according to a dosing regimen.

5. The method according to any one of claims 1 to 4, further comprising administering an anti-CD20 agent to the patient.

6. A method of treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and an anti-CD20 agent, administering the anti-CD20 agent to the patient at 375 mg / m2 Q1W for up to 8 doses, and administering the SIRPaFc fusion protein to the patient at 8 mg / kg Q1W for 4 weeks, followed by 18 mg / kg Q3W according to a dosing regimen.

7. A method for treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein and an anti-CD20 agent, wherein the anti-CD20 agent is administered to the patient at 375 mg / m2 Q1W for up to 8 doses, and the SIRPaFc fusion protein is administered to the patient according to a dosing regimen of 16 mg / kg Q1W for 4 weeks, followed by 28 mg / kg Q3W.

8. The method according to any one of claims 5 to 7, wherein the anti-CD20 agent is rituximab.

9. A method for treating cancer in a patient, comprising administering to the patient a combination therapy of a SIRPaFc fusion protein, carfilzomib, and dexamethasone over N cycles, each cycle being 28 days, wherein the SIRPaFc fusion protein is administered at 8 mg / kg or 16 mg / kg on days 1, 8, 15, and 22 of the 28-day cycle, carfilzomib is administered at 20 mg / m2 or 70 mg / m2 on days 1, 8, and 15 of the 28-day cycle, and dexamethasone is administered at 40 mg on days 1, 8, 15, and 22 of the 28-day cycle.

10. The method according to claim 9, wherein N is 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

11. A method for treating cancer in a patient, comprising administering to the patient a SIRPaFc fusion protein according to a dosing regimen of 0.2 mg / kg, 0.7 mg / kg, or 2.0 mg / kg Q2W.

12. A method for treating cancer in a patient, comprising a first regimen and a second regimen, wherein the first regimen comprises administering to the patient a combination therapy of a SIRPaFc fusion protein and doxorubicin over N cycles, each cycle being 21 days, the SIRPaFc fusion protein being administered on days 1 and 8 of the 21-day cycle, doxorubicin being administered on day 1 of the 21-day cycle, N being 2, 3, 4, 5, 6, 7, or 8 cycles, and the second regimen following the first regimen and comprising administering the SIRPaFc fusion protein to the patient according to a Q2W dosing regimen.

13. The method according to any one of claims 1 to 12, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO:

1.

14. The method according to any one of claims 1 to 13, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO:

2.

15. The method according to any one of claims 1 to 14, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO:

8.

16. The method according to any one of claims 1 to 13, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof having 1, 2, 3, 4, or 5 amino acid substitutions compared to the sequence of SEQ ID NO:

1.

17. The method according to any one of claims 1 to 16, wherein the cancer is a blood cancer or a solid tumor cancer.

18. The cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML) and p53 mutant AML; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / neoplasms (MPDS); myelodysplastic syndromes, lymphoma, T cell lymphoma, Hodgkin lymphoma, indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, Burkitt 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, the method according to any one of claims 1 to 17.

19. The method according to any one of claims 1 to 18, wherein the SIRPaFc fusion protein is administered over a dose of 12 or less.

20. The method according to any one of claims 1 to 18, wherein the SIRPaFc fusion protein is administered until disease progression.

21. The method according to any one of claims 1 to 20, wherein the patient has CD47-positive cancer cells.

22. A SIRPaFc fusion protein for use in treating a patient according to the method of any one of claims 1 to 21.

23. Use of a SIRPaFc fusion protein in the manufacture of a medicament for use in treating a patient according to the method of any one of claims 1 to 21.

24. A kit comprising a SIRPaFc fusion protein and instructions for use according to the method of any one of claims 1 to 21, optionally further comprising one or more additional therapeutic agents for use according to the method of any one of claims 1 to 21.

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