Combination therapy comprising a SIRP alpha fusion protein and an anti-CD19 antibody for the treatment of cancer

Abstract

Provided is a combination therapy comprising a SIRPaFc fusion protein and an anti-CD19 agent. The combination therapy may optionally further comprise an E3 ubiquitin ligase modulator.

Description

Technical Field

[0001] Reference to Electronic Sequence Listing The content of the electronic sequence listing (P113970010WO00-SEQ-LJG.xml, size: 26,811 bytes, and creation date: May 25, 2023) is incorporated herein by reference in its entirety.

Background Art

[0002] Cancer cells are targeted for destruction by antibodies that bind to cancer cell antigens and through the recruitment and activation of macrophages via Fc receptors that bind to the Fc portion of the antibody. Binding between CD47 on cancer cells and SIRP alpha (「SIRPa」) of macrophages transmits a 「don't eat me」 signal that enables many tumor cells to avoid destruction by macrophages. Inhibition of the CD47 / SIRPa interaction (CD47 blockade) has been shown to enable macrophages to 「observe」 and destroy target CD47+ cancer cells. The use of SIRPa for the treatment of cancer by CD47 blockade is described in WO2010 / 130053, which is incorporated herein by reference.

[0003] International Patent Application Publication No. WO2014 / 094122, which is incorporated herein by reference in its entirety, describes a protein drug that inhibits the interaction between CD47 and SIRPa. This CD47 blocking agent is a form of human SIRPa that incorporates a specific region of the extracellular domain linked to a particularly useful form of the Fc region of IgG. In this form, the SIRPaRFc drug exhibits a dramatic effect on the survival rate of cancer cells presenting the CD47+ phenotype. This effect is seen particularly in acute myeloid leukemia (AML) cells and many other types of cancer.

[0004] CD19 is a 95 kDa transmembrane glycoprotein of the immunoglobulin superfamily that contains two extracellular immunoglobulin-like domains and an extensive cytoplasmic tail. This protein is a pan-B lymphocyte surface receptor that is widely expressed from the early stages of pre-B cell development until downregulated during the final differentiation into plasma cells. It is specific to the B lymphocyte lineage and is not expressed in hematopoietic stem cells and other immune cells, except for some follicular dendritic cells. CD19 functions as a positive regulator of B cell receptor (BCR) signaling and is important for B cell activation and proliferation, as well as the development of the humoral immune response. It functions as a co-stimulatory molecule in association with CD21 and CD81 and is important for the B cell response to T cell-dependent antigens. The cytoplasmic tail of CD19 is physically associated with a family of tyrosine kinases that induce downstream signaling pathways via the src family of protein tyrosine kinases. CD19 is highly expressed in almost all chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), as well as many other different types of leukemia, including acute lymphocytic leukemia (ALL) and hairy cell leukemia (HCL), making it an attractive target for lymphoid-derived cancers.

[0005] Tafasitamab (formerly known as MOR208 and XmAb® 5574) is a humanized monoclonal antibody that targets the antigen CD19, a transmembrane protein involved in B cell receptor signaling. Tafasitamab has been engineered in the IgG Fc region to enhance antibody-dependent cell-mediated cytotoxicity (ADCC), thereby improving an important mechanism for tumor cell killing and potentially enhancing efficacy compared to conventional antibodies, i.e., non-enhanced antibodies. Tafasitamab has been studied or is currently being studied in several clinical trials, such as those for CLL, ALL, and NHL. Tafasitamab received accelerated approval from the U.S. Food and Drug Administration (FDA) in July 2020 for use in combination with lenalidomide to treat adults with R / R DLBCL. In August 2021, the European Commission approved the conditional marketing authorization of tafasitamab in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplantation (ASCT). Despite the discovery and development of several anti-cancer agents in recent years, there remains a need for improved methods or treatment approaches for treating such types of cancer due to the poor prognosis of many types of cancer, including CD19-expressing tumors.

[0006] Accordingly, there is a need for improved dosing regimens and treatment methods using SIRPaFc agents and CD19 targeting agents. SUMMARY OF THE INVENTION

[0007] Provided herein is a combination therapy of an SIRPaFc fusion protein and a CD19 targeting agent. The dosing regimens and methods provided herein include both an SIRPaFc fusion protein and an anti-CD19 antibody. The combination therapy may further include an E3 ubiquitin ligase modulator.

[0008] In some embodiments, provided herein is a method for treating cancer in a patient, comprising co-administering to the patient an SIRPaFc fusion protein and an anti-CD19 antibody.

[0009] In some embodiments, provided herein is a method for treating cancer in a patient, the method comprising subjecting the patient to a combination therapy of an SIRPaFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator over at least a first cycle, a second cycle, a third cycle, and a fourth cycle, each cycle being 28 days, wherein in the first cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21; in the second cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21; in the third cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21; in the fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21.

[0010] In some embodiments, provided herein is a method for treating cancer in a patient, the method comprising administering to the patient a combination therapy of SIRPaFc fusion protein, anti-CD19 antibody, and an E3 ubiquitin ligase modulator over at least a first cycle, a second cycle, a third cycle, and a fourth cycle, each cycle being 28 days long. In the first cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, 15, and 22; and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the second cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the third cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the fourth cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1 and 15; the anti-CD19 antibody isAdministered on the 1st and 15th days at a dose of 12 mg / kg, the E3 ubiquitin ligase modulator is administered from the 1st day to the 21st day at a dose of 25 mg, the SIRPaFc fusion protein is TTI-622, the anti-CD19 antibody is tafasitamab, and the E3 ubiquitin ligase modulator is lenalidomide.

Brief Description of the Drawings

[0011]

Figure 1

Modes for Carrying Out the Invention

[0012] The present invention can be more easily understood by referring to the following detailed description and examples of the present invention included herein. It should be understood that the present invention is not naturally limited to specific methods of preparation that can be various. Also, it is understood that the terms used herein are for the purpose of simply describing a specific embodiment and are not intended to be limiting.

[0013] Exemplary embodiments (E) of the present invention provided herein include the following.

[0014] E1. A method for treating cancer in a patient, comprising co-administering an SIRPaFc fusion protein and an anti-CD19 antibody to the patient.

[0015] E2. The method according to E1, further comprising administering an E3 ubiquitin ligase modulator.

[0016] E3. The method according to any one of E1 to E2, wherein the SIRPaFc fusion protein is administered Q1W or Q2W.

[0017] The method according to any one of E1 to E3, wherein the anti-CD19 antibody is administered Q1W or Q2W.

[0018] The method according to any one of E1 to E4, wherein the E3 ubiquitin ligase modulator is administered daily.

[0019] A method for treating cancer in a patient, the method comprising administering to the patient a combination therapy of an SIRPaFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator in at least a first cycle, a second cycle, a third cycle, and a fourth cycle, each cycle being 28 days, in the first cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21, in the second cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21, in the third cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21, in the fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21, the method.

[0020] E7. The method is continued from at least the fifth cycle to a maximum of the twelfth cycle. In the fifth to twelfth cycles, the SIRPaFc fusion protein is administered on the first day and the fifteenth day, the anti-CD19 antibody is administered on the first day and the fifteenth day, and the E3 ubiquitin ligase modulator is administered from the first day to the twenty-first day. The method according to E6.

[0021] E8. The method is continued during at least the thirteenth cycle. In the thirteenth cycle, the SIRPaFc fusion protein is administered on the first day and the fifteenth day, the anti-CD19 antibody is administered on the first day and the fifteenth day, and the E3 ubiquitin ligase modulator is not administered. The method according to E7.

[0022] E9. The method according to any one of E1 to E8, wherein the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg.

[0023] E10. The method according to any one of E1 to E9, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg.

[0024] E11. The method according to any one of E1 to E10, wherein the E3 ubiquitin ligase modulator is administered at a dose of 25 mg.

[0025] E12. A method for treating cancer in a patient, the method comprising administering a combination therapy of an SIRPaFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator to the patient in at least the first cycle, the second cycle, the third cycle, and the fourth cycle. Each cycle is 28 days. In the first cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22. The anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, 8, 15, and 22. The E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the second cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22. The anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15, and 22. The E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the third cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22. The anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15, and 22. The E3 ubiquitin ligase modulator is administered at a dose of 25 mg from day 1 to day 21. In the fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15 at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is administered on days 1 and 15 at a dose of 12 mg / kg; and the E3 ubiquitin ligase modulator is administered from day 1 to day 21 at a dose of 25 mg, the method.

[0026] E13. The method according to E12, wherein the method is continued from at least the fifth cycle to the twelfth cycle, and in the fifth cycle to the twelfth cycle, the SIRPaFc fusion protein is administered on days 1 and 15 at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is administered on days 1 and 15 at a dose of 12 mg / kg; and the E3 ubiquitin ligase modulator is administered from day 1 to day 21 at a dose of 25 mg.

[0027] E14. The method according to E13, wherein the method is continued to at least the thirteenth cycle, and in the thirteenth cycle, the SIRPaFc fusion protein is administered on days 1 and 15 at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is administered on days 1 and 15 at a dose of 12 mg / kg; and the E3 ubiquitin ligase modulator is not administered.

[0028] E15. The method according to any one of E1 to E14, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 1.

[0029] E16. The method according to any one of E1 to E15, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide comprising the amino acid sequence of SEQ ID NO: 2.

[0030] E17. The method according to any one of E1 to E16, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 7.

[0031] E18. The method according to any one of E1 to E16, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO: 8.

[0032] E19. The method according to any one of E1 to E15, 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 as compared to the sequence of SEQ ID NO: 1.

[0033] E20. The method according to any one of E1 to E19, wherein the anti-CD19 antibody comprises a heavy chain variable region comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 11), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 12), and an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 13), and a light chain variable region comprising an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 14), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 15), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 16).

[0034] E21. The anti-CD19 antibody is The method according to any one of E1 to E20, comprising the heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 17) and the light chain variable region of DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 18).

[0035] E22. The method according to any one of E1 to E21, wherein the anti-CD19 antibody comprises an Fc domain containing an amino acid substitution at position S239 and / or position I332, wherein the numbering follows the EU index as in the case of Kabat.

[0036] E23. The method according to E22, wherein the anti-CD19 antibody comprises an Fc domain containing an amino acid substitution of S239D and an amino acid substitution of I332E, wherein the numbering follows the EU index as in the case of Kabat.

[0037] E24. The anti-CD19 antibody is The method according to any one of E1 to E23, comprising the heavy chain region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19) and the light chain region of DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20).

[0038] E25. The method according to any one of E1 to E24, wherein the E3 ubiquitin ligase modulator comprises lenalidomide, pomalidomide, or thalidomide.

[0039] E26. The method according to any one of E1 to E25, wherein the E3 ubiquitin ligase modulator is lenalidomide.

[0040] The method according to any one of E1 to E26, wherein the E3 ubiquitin ligase modulator is administered orally.

[0041] The method according to any one of E1 to E27, wherein the SIRPaFc fusion protein and the anti-CD19 antibody are administered intravenously or subcutaneously.

[0042] The method according to any one of E1 to E28, wherein the cancer is a CD19-positive cancer.

[0043] The method according to any one of E1 to E29, wherein the cancer is a CD47-positive cancer.

[0044] The method according to any one of E1 to E30, wherein the cancer is a hematological malignancy or a solid tumor cancer.

[0045] The method according to any one of E1 to E31, wherein the cancer is a lymphoma or leukemia.

[0046] The method according to any one of E1 to E32, wherein the cancer is chronic lymphocytic leukemia, acute lymphoblastic leukemia, or non-Hodgkin lymphoma.

[0047] The method according to any one of E1 to E33, wherein the cancer is a non-Hodgkin lymphoma selected from the group consisting of follicular lymphoma (FL), small lymphocytic lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma.

[0048] A SIRPaFc fusion protein or an anti-CD19 antibody for use in treating a patient according to the method of any one of E1 to E34.

[0049] Use of an SIRPaFc fusion protein or an anti-CD19 antibody in the manufacture of a medicament for use in treating a patient according to the method according to any one of E36.E1 to E34.

[0050] E37. A kit comprising an SIRPaFc fusion protein or an anti-CD19 antibody according to the method according to any one of claims 1 to 34 and an instruction manual, optionally comprising one or more additional therapeutic agents according to the method according to any one of E1 to E34.

[0051] Without being bound by theory, in the combination methods provided herein that include an SIRPaFc fusion protein (e.g., TTI-622), an anti-CD19 antibody (e.g., tafasitamab), and an E3 ubiquitin ligase modulator (e.g., lenalidomide), one or more of the following anti-cancer effects are thought to occur in consideration of the combination treatment: 1) increased antibody-dependent cell phagocytosis (ADCP): tafasitamab and lenalidomide increase the "eat" signal, while TTI-622 blocks the "don't eat me" signal on tumor cells; 2) increased antibody-dependent cell cytotoxicity (ADCC): lenalidomide decreases the threshold of NK cell activation, thereby promoting tafasitamab-mediated ADCC; 3) specific killing: lenalidomide has specific tumor killing activity. These activities can occur in various types of cancer such as DLBCL.

[0052] In some embodiments, the disclosure relates to the use of an SIRPaFc fusion protein in combination with an anti-CD19 antibody for the treatment of cancer in a patient.

[0053] In some embodiments, the present disclosure relates to a composition comprising a SIRPaFc fusion protein for use in the treatment of cancer in a patient, wherein the patient is also treated with an anti-CD19 antibody. In some aspects, the present disclosure relates to a composition comprising a SIRPaFc fusion protein for use in the treatment of a disorder that is cancer in a patient, wherein the SIRPaFc fusion protein is used in combination with an anti-CD19 antibody. In some embodiments, the SIRPaFc fusion protein can be administered simultaneously or sequentially with the anti-CD19 antibody.

[0054] In some embodiments, the present disclosure relates to a method of treating cancer, the method comprising co-administering a therapeutically effective amount of a SIRPaFc fusion protein and an anti-CD19 antibody to a patient in need of such treatment.

[0055] In some embodiments, the present disclosure relates to a method of treating cancer by administering to a patient in combination a SIRPaFc fusion protein or a pharmaceutically acceptable salt thereof and an anti-CD19 antibody.

[0056] In another aspect, the present disclosure relates to the use of a SIRPaFc fusion protein in combination with an anti-CD19 antibody for the treatment of cancer.

[0057] In some embodiments, the methods of treating cancer described herein can include the co-administration of a SIRPaFc fusion protein and an anti-CD19 antibody, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents can be chemotherapeutic agents. In some embodiments, examples of the one or more additional therapeutic agents include, but are not limited to, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof.

[0058] In some embodiments, the method of treating cancer described herein may include the combined use of an SIRPaFc fusion protein, an anti-CD19 antibody, and lenalidomide.

[0059] In some embodiments, the method of treating cancer described herein may include the combined use of an SIRPaFc fusion protein and an anti-CD19 antibody, wherein the anti-CD19 antibody is tafasitamab, and tafasitamab is administered at a dose of 12 mg / kg body weight.

[0060] In some embodiments, the method of treating cancer described herein may include the combined use of an SIRPaFc fusion protein and an anti-CD19 antibody, wherein the SIRPaFc fusion protein is TTI-622, and TTI-622 is administered at a body weight dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22 of the first, second, and third 28-day cycles and on days 1 and 15 of subsequent 28-day cycles, and the anti-CD19 antibody is tafasitamab, and tafasitamab is administered at a body weight dose of 12 mg / kg on days 1, 4, 8, 15, and 22 of the first 28-day cycle, on days 1, 8, 15, and 22 of the second and third 28-day cycles, and on days 1 and 15 of one or more subsequent cycles.

[0061] In some embodiments, the method for treating cancer described herein may include the combined use of a SIRPaFc fusion protein, an anti-CD19 antibody, and lenalidomide, wherein the SIRPaFc fusion protein is TTI-622, and TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg of body weight, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is tafasitamab, and tafasitamab is administered at a dose of 12 mg / kg of body weight; and lenalidomide is administered at a dose of 25 mg.

[0062] In some embodiments, the method for treating cancer described herein may include the combined use of a SIRPaFc fusion protein, an anti-CD19 antibody, and lenalidomide, wherein the SIRPaFc fusion protein is TTI-622, and TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg of body weight, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is tafasitamab, and tafasitamab is administered at a dose of 12 mg / kg of body weight; and lenalidomide is administered at a dose of 25 mg from day 1 to day 21 of a 28-day cycle.

[0063] In some embodiments, the method for treating cancer described herein may include the combined use of SIRPaFc fusion protein, anti-CD19 antibody, and lenalidomide, wherein the SIRPaFc fusion protein is TTI-622, and TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg of body weight, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22 of the first, second, and third 28-day cycles and on days 1 and 15 of subsequent 28-day cycles. The anti-CD19 antibody is tafasitamab, and tafasitamab is administered at a dose of 12 mg / kg of body weight on days 1, 4, 8, 15, and 22 of the first 28-day cycle, on days 1, 8, 15, and 22 of the second and third 28-day cycles, and on days 1 and 15 of one or more subsequent cycles. Lenalidomide is administered at a dose of 25 mg from day 1 to day 21 of a 28-day cycle.

[0064] In some embodiments, the cancer is CD19-positive cancer.

[0065] In some embodiments, the cancer is a blood cancer. Non-limiting examples of blood cancers include acute myeloid leukemia (AML), chronic myeloid leukemia (CML) including the accelerated phase of CML and the blast crisis phase of CML (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), B-cell lymphoma, T-cell lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL) including Burkitt lymphoma, multiple myeloma (MM), amyloidosis, Waldenström macroglobulinemia, refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), myelodysplastic syndromes (MDS) including refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T), and myeloproliferative syndromes. In some embodiments, the cancer is non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL), Hodgkin lymphoma or follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma.

[0066] In some embodiments, the cancer is chronic lymphocytic leukemia. In some embodiments, the cancer is CD19-positive chronic lymphocytic leukemia.

[0067] In some embodiments, the cancer is a non-Hodgkin lymphoma, including follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or Burkitt lymphoma. In some embodiments, the cancer is a B-cell lymphoma. In some embodiments, the cancer is a CD19-positive non-Hodgkin lymphoma. In some embodiments, the cancer is a CD19-positive advanced non-Hodgkin lymphoma. In some embodiments, the cancer is a indolent Hodgkin lymphoma. In some embodiments, the cancer is a relapsed or refractory non-Hodgkin lymphoma. In some embodiments, the cancer is a relapsed or refractory CD19-positive advanced non-Hodgkin lymphoma. In some embodiments, the cancer is a relapsed or refractory CD19-positive indolent non-Hodgkin lymphoma.

[0068] In some embodiments, the cancer is relapsed. In some embodiments, a relapsed cancer is a cancer that recurs after a period in which the cancer was not detected.

[0069] In some embodiments, the cancer is refractory. In some embodiments, refractory cancer does not respond to cancer treatment. It is also known as resistant cancer. In some embodiments, the cancer is resistant to rituximab. In some embodiments, the cancer does not respond to treatment with rituximab. In some embodiments, the cancer is rituximab-resistant recurrent cancer. In some embodiments, the patient has become refractory to a rituximab-containing regimen. In some embodiments, the tumor is inoperable. In some embodiments, an inoperable tumor cannot be removed by surgery. In some embodiments, the cancer has not been previously treated. In some embodiments, the cancer is locally advanced. In some embodiments, "locally advanced" refers to cancer that is extensive to some degree but still limited to one area. In some cases, "locally advanced" may refer to a small tumor that has not spread but has invaded nearby organs or tissues, making removal by surgery alone difficult. In some embodiments, the cancer is metastatic. In some embodiments, metastatic cancer is cancer that has spread from the part of the body where the cancer started (the primary site) to one or more other parts of the body.

[0070] In some embodiments, the patient has a recurrent or refractory CD19-positive advanced non-Hodgkin lymphoma. In some embodiments, the patient has both CD19-positive non-Hodgkin lymphoma and recurrent or refractory non-Hodgkin lymphoma.

[0071] In some embodiments, the patient has a recurrent or refractory CD19-positive advanced non-Hodgkin lymphoma. In some embodiments, the patient has a recurrent or refractory CD19-positive advanced non-Hodgkin lymphoma and has undergone at least one previous treatment regimen.

[0072] In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin lymphoma. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin lymphoma and has progressed on at least one previous treatment regimen. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin lymphoma and is refractory to any anti-CD20 monoclonal antibody or any anti-CD19 monoclonal antibody. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin lymphoma, has progressed on at least two previous treatment regimens, and is refractory to any anti-CD20 monoclonal antibody.

[0073] In some embodiments, the present disclosure relates to an agent for use in the treatment of cancer in a patient in need thereof. The agent comprises an SIRPaFc fusion protein and an anti-CD19 antibody and is in a single dosage form or separate dosage forms.

[0074] In some embodiments, the method of treating cancer described herein may comprise a combination of an SIRPaFc fusion protein, an anti-CD19 antibody, and any one or more additional therapeutic agents.

[0075] In some embodiments, the present disclosure relates to the use of an SIRPaFc fusion protein in the manufacture of an agent for treating cancer, wherein the SIRPaFc fusion protein is administered together with an anti-CD19 antibody and the agent is in a single dosage form or separate dosage forms. In some embodiments, the SIRPaRFc fusion protein is administered together with an anti-CD19 antibody and one or more additional therapeutic agents.

[0076] In some embodiments, the present disclosure relates to the use of an SIRPaFc fusion protein in the manufacture of an agent for treating cancer in a patient, wherein the patient is also treated with an anti-CD19 antibody and any one or more additional therapeutic agents. In some embodiments, the SIRPaFc fusion protein may be administered simultaneously or sequentially with the anti-CD19 antibody.

[0077] In another aspect, the present disclosure relates to the use of an SIRPaFc fusion protein in combination with an anti-CD19 antibody in the manufacture of a medicament for use in the treatment of cancer. In some embodiments, the present disclosure relates to the use of an SIRPaFc fusion protein in combination with an anti-CD19 antibody and any one or more additional therapeutic agents in the manufacture of a medicament for use in the treatment of cancer.

[0078] In another aspect, the present disclosure relates to the use of an SIRPaFc fusion protein in the manufacture of a medicament for the treatment of cancer, wherein the SIRPaFc fusion protein is administered together with an anti-CD19 antibody and any one or more additional therapeutic agents.

[0079] In some embodiments, the one or more additional therapeutic agents can be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents include, but are not limited to, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate, anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof.

[0080] In one aspect, the present disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered in combination with an SIRPaFc fusion protein to a subject in need of such treatment.

[0081] In one aspect, the present disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered in combination with an SIRPaFc fusion protein.

[0082] In some embodiments, the SIRPaFc fusion protein can be administered as a single dosage form or separate dosage forms in combination with an anti-CD19 antibody and any one or more additional therapeutic agents. In some embodiments, when administered as separate dosage forms, the anti-CD19 antibody may be administered before, simultaneously with, or after the administration of the SIRPaFc fusion protein. In some embodiments, when administered as separate dosage forms, one or more dosages of the SIRPaFc fusion protein can be administered before the anti-CD19 antibody. In some embodiments, the anti-CD19 antibody is administered before the administration of the SIRPaFc fusion protein. As used herein, the administration of the SIRPaFc fusion protein, anti-CD19 antibody, and optionally one or more additional therapeutic agents "in combination" refers to the administration of the agents not only simultaneously or sequentially, but also to the administration of the agents during a single treatment cycle, as would be understood by one of ordinary skill in the art. When the SIRPaFc fusion protein is administered in combination with an anti-CD19 antibody and optionally one or more additional therapeutic agents, a therapeutically effective combination is administered.

[0083] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0084] All references cited herein, including patent applications, patent 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.

[0085] The techniques and procedures described or referred to in this specification are generally well understood and widely employed by those skilled in the art using conventional methodologies. For example, the widely used 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.

[0086] Definitions Unless otherwise defined, scientific and technical terms used in connection with the present invention have the meanings commonly understood by one of ordinary skill in the art.

[0087] 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.

[0088] When aspects or embodiments of the present invention are described by a Markush group or other selection group, the present invention not only generally encompasses the entire recited group, but also individually encompasses each member of the group, all possible subgroups of the main group, and main groups in which one or more of the members of the group are absent. The present invention also contemplates any one or more explicit exclusions of members of the group in the claimed invention.

[0089] Any examples following the terms "for example (eg)" or "for example (for example)" are not intended to be exhaustive or limiting.

[0090] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a SIRPaFc fusion protein or an anti-CD19 antibody) means that the parameter can vary by up to 10% below or 10% above the recited numerical value of that parameter. For example, a dosage of about 5 mg means ±10% of 5%, i.e., can vary between 4.5 mg and 5.5 mg.

[0091] The terms "treating," "treat," or "treatment" refer to any type of treatment, for example, alleviating, reducing, or delaying 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.

[0092] The term "therapeutically effective amount" refers to the amount of an active ingredient that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, and can include one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may have a predisposition to the disease, condition, or disorder but has not yet experienced or exhibited the disease state or symptoms of the disease, (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the disease state or symptoms of the disease, condition, or disorder (i.e., preventing or slowing further progression of the disease state and / or symptoms), and (3) alleviating a disease, e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or exhibiting the disease state or symptoms of the disease, condition, or disorder (i.e., reversing the disease state or symptoms).

[0093] SIRPaFc fusion protein The present invention provides a combination therapy comprising an SIRP alpha-Fc ("SIRPaFc") fusion protein.

[0094] The dosing regimens and methods provided herein use the CD47-binding and blocking form of SIRPa as a CD47 blocker or inhibitor. An agent or drug having CD47-blocking activity is an agent that interferes with and attenuates the signaling that occurs when CD47 interacts with macrophage-presented SIRPa. The CD47-binding form of human SIRPa is a preferred CD47 blocker for use in the regimens and methods provided herein. These drugs are based on the extracellular region of human SIRPa. They include at least the region of the extracellular region sufficient to confer effective CD47-binding affinity and specificity. So-called "soluble" forms of SIRPa lacking a membrane anchor component have been described in the literature and include those referred to in WO2010 / 070047 (Novartis), WO2013 / 109752 (Stanford), and WO2014 / 094122 (Trillium), each of which is incorporated by reference in its entirety.

[0095] In a preferred embodiment, the soluble form of SIRPa is an Fc fusion. More specifically, the drug preferably comprises a human SIRPa protein in a form directly or indirectly fused to an antibody constant region, i.e., Fc (fragment crystallizable). Unless otherwise specified, the term "human SIRPa" as used herein refers to the wild-type, endogenous, mature form of human SIRPa. In humans, the SIRPa protein has been 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, has 13 different amino acids and has the amino acid sequence described in GenBank as CAA71403.1 (residues 30 - 504 constitute the mature form). These two forms of SIRPa constitute approximately 80% of the forms of SIRPa present in humans and are both included in the term "human SIRPa" herein. The term "human SIRPa" also includes minor forms that are endogenous to humans and have the same property of causing signal transduction via CD47 when binding to humans. The present invention most specifically targets combinations of drugs that include the human SIRPa variant 2 form, i.e., V2.

[0096] In the dosing regimens and methods provided herein, useful SIRPaFc fusion proteins include one of three so-called immunoglobulin (Ig) domains present within the extracellular region of human SIRPa. More specifically, this SIRPaFc protein incorporates residues 32 - 137 of human SIRPa (106-mer), which constitute and define an IgV domain of the V2 type according to the current nomenclature. This SIRPa sequence shown below is referred to herein as SEQ ID NO: 1.

[0097] EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKGHFPRVTTVSESTKENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA [SEQ ID NO: 1]

[0098] In some embodiments, the SIRPaFc fusion protein incorporates the IgV domain defined by SEQ ID NO: 1 and additional flanking residues adjacent within the SIRPa sequence. This form of the IgV domain represented by residues 31 - 148 of the V2 form of human SIRPa is an 118-mer having SEQ ID NO: 2 shown below.

[0099] EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKGHFPRVTTVSESTKENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA [SEQ ID NO: 2]

[0100] This SIRPa fusion protein can also incorporate an Fc region with effector function. Fc refers to the "fragment crystallizable" and represents the constant region of an antibody mainly composed of components within the heavy chain constant region and the hinge region. Suitable Fc components include those with effector function. An Fc component "with effector function" is an Fc component having at least some effector function, such as at least some contribution to antibody-dependent cell cytotoxicity or some ability to 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 lysis of target cells. By this definition, the Fc region that is wild-type IgG1 or IgG4 has effector function, but the Fc region of human IgG4 mutated to remove effector function, such as by incorporation of a modified series including Pro233, Val234, Ala235, and lack of Gly236 (EU), is considered to have no effector function. In some embodiments, Fc is based on the human antibody of the IgG1 isotype. The Fc regions of these antibodies will be readily identifiable to those skilled in the art. In a plurality of embodiments, the Fc region includes the lower hinge-CH2-CH3 domain.

[0101] In certain embodiments, the Fc region is based on the amino acid sequence of human IgG1 shown as residues 104-330 in UniProtKB / Swiss-Prot, and has the amino acid sequence shown below and referred to herein as SEQ ID NO: 3: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 3]

[0102] Thus, in some embodiments, the Fc region has either the wild-type or consensus sequence of the IgG1 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein is derived from any IgG1 antibody having a typical effector activity constant region. The sequence of such Fc regions can correspond to the Fc region of any of the following IgG1 sequences (all cited from GenBank), for example: BAG65283 (residues 242-473), BAC04226.1 (residues 247-478), BAC05014.1 (residues 240-471), CAC20454.1 (residues 99-320), BAC05016.1 (residues 238-469), BAC85350.1 (residues 243-474), BAC85529.1 (residues 244-475), and BAC85429.1 (residues 238-469).

[0103] 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 having a constant region with effector activity that is present but significantly less potent than the IgG1 Fc region in nature. The sequence of such Fc regions can correspond to the Fc region of any of the following IgG4 sequences: P01861 (residues 99-327) of UniProtKB / Swiss-Prot and CAC20457.1 (residues 99-327) of GenBank.

[0104] In certain embodiments, the Fc region is based on the amino acid sequence of human IgG4 shown at residues 99 - 327 of P01861 in UniProtKB / Swiss-Prot and has the amino acid sequence shown below, which is referred to herein as SEQ ID NO: 4: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 4]

[0105] In some embodiments, the Fc region incorporates one or more modifications, usually fewer than about 10 (e.g., up to 1, 2, 3, 4, 5, or 6) such modifications, which include amino acid substitutions that affect specific Fc properties. In one particular and preferred embodiment, the Fc region incorporates a modification at position 228 (EU numbering), where the serine at this position is substituted by proline (S228P), thereby stabilizing the disulfide linkages within the Fc dimer. Other modifications within the Fc region include substitutions that modify glycosylation, e.g., substitution of Asn 297 with glycine or alanine; modifications that enhance the half-life, such as those described in US62777375, T 252 L, T 253 S, and T 256 F, and many others may be included. Particularly useful are modifications that enhance Fc properties while remaining silent with respect to conformation, e.g., modifications that retain Fc receptor binding. In another aspect, 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 mutations of T252L, T254S, T256F can be introduced.

[0106] In certain embodiments, when the Fc component is IgG4 Fc, the Fc incorporates at least the S 228 P mutation and has the amino acid sequence shown below and referred to herein as SEQ ID NO: 5: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 5]

[0107] Accordingly, the CD47 blockers used in the regimens and methods provided herein preferably provide a fusion protein useful for inhibiting the binding of human SIRPa and human CD47, thereby inhibiting or reducing the transmission of signals mediated through CD47 bound to SIRPα, the fusion protein comprising a human SIRPα component and an Fc component fused to the human SIRPα component, the SIRPα component comprising or consisting of a single IgV domain of human SIRPα V2, and the Fc component being the constant region of a human IgG having effector function.

[0108] In one embodiment, the fusion protein comprises at least residues 32-137 of the V2 type of wild-type human SIRPα, i.e., the SIRPα component consisting of SEQ ID NO: 1. In a preferred embodiment, the SIRPα component consists of residues 31-148 of the V2 type of human SIRPα, i.e., SEQ ID NO: 22. In another embodiment, the Fc component is the Fc component of human IgG1 designated P01857 and, in certain aspects, has the amino acid sequence incorporating its lower hinge-CH2-CH3 region, i.e., SEQ ID NO: 3.

[0109] In some embodiments, the SIRPaFc fusion protein is provided and used in a secreted dimeric fusion form, where the fusion protein incorporates an SIRPα component having SEQ ID NO: 1 and preferably SEQ ID NO: 2, and an Fc region that has effector function and is fused to the SIRPα component having SEQ ID NO: 3. When the SIRPα component is SEQ ID NO: 1, this fusion protein includes SEQ ID NO: 6 shown below: EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 6]

[0110] When the SIRPα component is SEQ ID NO: 2, this fusion protein includes SEQ ID NO: 7 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 7]

[0111] The SIRPaFc fusion protein of SEQ ID NO: 7 is also known as TTI-621.

[0112] In an alternative embodiment, the Fc component of the fusion protein is based on IgG4, preferably IgG4 S228P incorporating mutations. When the fusion protein incorporates the preferred SIRPaIgV domain of SEQ ID NO: 2, the resulting IgG4-based SIRPa-Fc protein has SEQ ID NO: 8 shown below: EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[SEQ ID NO: 8]

[0113] The SIRPaFc fusion protein of SEQ ID NO: 8 is also known as TTI-621.

[0114] In one aspect of the dosing regimens or methods provided herein, the SIRPaFc fusion protein comprises, as the SIRPa component of the fusion protein, a sequence comprising the sequence of SEQ ID NO: 2. In one embodiment, the SIRPaFc fusion protein comprises the polypeptide of SEQ ID NO: 7 or SEQ ID NO: 8.

[0115] The SIRPa sequence incorporated within the SIRPaFc fusion protein can vary as described in the literature. This can eliminate glycosylation sites of the protein, such as at position 89 and other locations. Other useful substitutions within SIRPa 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.

[0116] In the SIRPαFc fusion protein, the SIRPα component and the Fc component are fused either directly or indirectly to provide a single polypeptide chain, which is optionally ultimately produced as a dimer in which the single-chain polypeptide is coupled through an intra-chain disulfide bond formed within the Fc region. The nature of the fusion region is not critical. The fusion may be direct between the two components, with the SIRPa 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 composed of one or more amino acids, preferably 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. The linker may also be a peptide encoded by DNA constituting a restriction site, such as BamHI, ClaI, EcoRI, HindIII, PstI, SalI and XhoI sites, etc.

[0117] The linker amino acids typically and desirably have a degree of flexibility to allow the Fc and SIRP components to adopt their active conformations. Residues that allow such flexibility are typically Gly, Asn, and Ser, and thus substantially any combination of these residues (particularly Gly and Ser) within the linker can provide the desired ligation effect. In one example, such linkers are based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser), which may be repeated as (G4S)n (SEQ ID NO: 21), where n is 1, 2, 3, or more, or may be 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 IgV domain at the C-terminus (it is understood that this adjacent sequence can be considered as either of different types of IgV domains when coupled to the linker or the IgV minimal sequence described above). It is only necessary that the fusion region or linker allows the components to adopt their active conformations, which can be achieved by any type of linker useful in the art.

[0118] “CD47 + ” (or CD47+) is a term used with respect to the phenotype of cells that are targets of binding by this polypeptide. 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, the antibody product of clone B6H12 is available from Santa Cruz Biotechnology). Cells to be tested for the CD47 phenotype may include standard tumor biopsy samples, particularly blood samples taken from a subject suspected of harboring endogenous CD47 + cancer cells. CD47 disease cells of particular interest as targets for therapies using this fusion protein are those that “overexpress” CD47. These CD47 +The cells are typically diseased cells and present CD47 on their surface at a density that exceeds the normal CD47 density for a given type of cell. CD47 overexpression is diverse across different cell types and refers to any CD47 level that is determined to be higher than the level measurable on corresponding cells having a normal CD47 phenotype for that cell type, such as by flow cytometry as exemplified herein, or by immunostaining, or by gene expression analysis, etc.

[0119] The SIRPaFc fusion proteins provided herein can be administered at various dosages within the range of about 0.0001 to 100 mg / kg.

[0120] In some embodiments, TTI-621 (SEQ ID NO: 7) is administered in the range of 0.01 to 30 mg / kg of subject 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 may 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.

[0121] In some embodiments, TTI-622 (SEQ ID NO: 8) is administered in the range of 0.1 - 50 mg / kg of subject body weight. For example, the dosage of TTI-622 can be 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, or 50 mg / kg. Examples of dosages of TTI-622 include 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.

[0122] 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. That is, the dose is an amount per patient and the dose does not depend on the patient's body weight. In some embodiments, SIRPaFc fusion proteins such as TTI-622 are 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 can 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).

[0123] In some embodiments, the SIRPaFc fusion protein is administered between a) a lower limit 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, 2050, 2050, 2050, 2050, 2050, 2050, 2050, 2050, 2050, 2150 mg, or 2200 mg and b) an upper limit 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, where the lower limit is a value less than the upper limit.

[0124] The SIRPFc protein provided herein has negligible binding to red blood cells. Thus, there is no need to consider RBC “sinking” when dosing the SIRPaFc fusion protein provided herein. Compared to other CD47 blockers that bind to RBCs, this SIRPaFc fusion is estimated to be effective at less than half the dose required for drugs that bind to RBCs, such as CD47 antibodies. Further, the SIRPaFc fusion protein provided herein is a dedicated antagonist of SIRPa-mediated signals and exhibits very little CD47 agonism when binding to it. Thus, no consideration of any stimulations induced by the drug is required when establishing a medically useful unit dosing regimen.

[0125] Anti-CD19 agent The term "CD19" refers to a protein known as CD19 having the following synonyms: B4, B-lymphocyte antigen CD19, B-lymphocyte surface antigen B4, CVID3, differentiation antigen CD19, MGC12802, and T-cell surface antigen Leu-12. This term also encompasses naturally occurring variant forms of CD19, such as splice variants, allelic variants, and isoforms.

[0126] The terms "MOR208" and "XmAb5574" and "tafasitamab" are used as synonyms for anti-CD19 antibodies according to Table 1. Table 1 shows the amino acid sequences of MOR208 / tafasitamab. The MOR208 antibody is described in U.S. Patent Application No. 12 / 377,251, which is incorporated by reference in its entirety.

[0127] The term "anti-CD19 antibody" or "antibody that binds to CD19" refers to an antibody that can bind to CD19 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent when targeting CD19.

[0128] The use of anti-CD19 antibodies in non-specific B-cell lymphoma is discussed in WO2007076950 (US2007154473), both of which are incorporated by reference in their entirety. The use of CD19 antibodies in CLL, NHL, and ALL is described in Scheuermann et al., CD19 Antigen in Leukemia and Lymphoma Diagnosis and Immunotherapy, Leukemia and Lymphoma, Vol. 18, 385 - 397 (1995), which is incorporated by reference in its entirety.

[0129] Additional antibodies specific to CD19 are described in WO2005012493 (US7109304), WO2010053716 (US12 / 266,999) (Immunomedics); WO2007002223 (US US8097703) (Medarex); WO2008022152 (12 / 377,251) and WO2008150494 (Xencor), WO2008031056 (US11 / 852,106) (Medimmune); WO2007076950 (US11 / 648,505) (Merck Patent GmbH); WO2009 / 052431 (US12 / 253,895) (Seattle Genetics); WO2010095031 (12 / 710,442) (Glenmark Pharmaceuticals), WO2012010562 and WO2012010561 (International Drug Development), WO2011147834 (Roche Glycart), and WO2012156455 (Sanofi), which are hereby incorporated by reference in their entirety.

[0130] In some embodiments, the anti-CD19 antibody used in the methods and compositions provided herein is tafasitamab (MOR208). Tafasitamab has the sequences shown in Table 1 below. **Table 1**

[0131] E3 ubiquitin ligase modulator In some embodiments, the combination therapies provided herein include an E3 ubiquitin ligase modulator. These modulators are sometimes also referred to as immunomodulatory drugs (IMiDs). These modulators target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (CRL4 CRBN known as) and promote the ubiquitination of the transcription factors IKZF1 and IKZF3 by CRL4 CRBN CRL4 CRBNExamples of such modulators include thalidomide, lenalidomide, and pomalidomide. They regulate CRL4 activity through binding to the CRBN subunit.

[0132] The dosing regimens and methods provided herein may be useful for treating various cancer cells. These include, in particular, CD47-positive and / or CD19-positive cancer cells, including liquid (blood) tumors and solid tumors. Solid tumors can be treated with the dosing regimens and methods provided herein to reduce their size, number, or growth rate and control the growth of cancer stem cells. Such solid tumors include CD47-positive and / or CD19-positive tumors, including those of the bladder, brain, breast, lung, colon, ovary, prostate, liver, and other tissues. In one embodiment, the dosing regimens and methods provided herein can be used to inhibit the growth or proliferation of blood cancers. As used herein, "blood cancer" refers to cancer of the blood, including, among others, leukemia, lymphoma, myeloma, etc. "Leukemia" refers to a cancer of the blood in which an overabundance of white blood cells is produced that are ineffective in fighting infection, thereby crowding out other components of the blood such as platelets and red blood cells. Cases of leukemia are understood to be classified as acute or chronic. Specific forms of leukemia can 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" can refer to, among others, Hodgkin lymphoma, both indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, and follicular lymphoma (small and large cell). Myeloma can refer to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence Jones myeloma. In certain embodiments, the dosing regimens and methods provided herein are useful for treating T-cell lymphomas (TCLs), a very heterogeneous group of lymphoid malignancies that are classified as cutaneous TCL and peripheral TCL, which themselves are classified into nodal or extranodal types. CTCL is derived from skin-homing T cells and consists of mycosis fungoides, Sézary syndrome, primary cutaneous T-cell proliferative disorders, and anaplastic large cell type lymphoma. A general characteristic of TCLs, except for ALK and ALCL, is their rapid progression and poor response to treatment.

[0133] In some other embodiments, the blood cancer treated with the dosing regimen and method is CD47-positive or CD19-positive leukemia, preferably selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome, preferably human acute myeloid leukemia.

[0134] In other embodiments, the blood cancer treated with the dosing regimen or method provided herein is a CD47-positive or CD19-positive lymphoma or myeloma selected from Hodgkin lymphoma, both indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma (small cell and large cell types), multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence Jones myeloma, and leiomyosarcoma.

[0135] The SIRPaFc fusion protein or anti-CD19 antibody 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.

[0136] The pharmaceutical composition of the SIRPaFc fusion protein or anti-CD19 antibody can include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection. These injectable formulations can be prepared by known methods. For example, the injectable formulation can be prepared by dissolving, suspending, or emulsifying, for example, the above-described fusion protein or antibody, or a salt thereof, in a sterile aqueous medium or an oily medium conventionally used for injection. Exemplary pharmaceutical compositions containing an antibody specific for CD19 that can be used in connection with the present disclosure are disclosed, for example, in WO2008 / 022152 or WO2018 / 002031, both of which are incorporated herein by reference in their entireties.

[0137] The contents of U.S. Provisional Patent Application No. 63 / 351,117, filed Jun. 10, 2022, and U.S. Provisional Patent Application No. 63 / 494,500, filed Apr. 6, 2023, are incorporated herein by reference for all purposes.

[0138] The following examples of specific embodiments for carrying out the present invention are provided for illustrative purposes only and are in no way intended to limit the scope of the present invention.

[0139] In the foregoing description and the following examples, certain specific embodiments of the present disclosure are described in detail to explain the best mode contemplated by the inventors. However, no matter how detailed the foregoing may be expressed in text, it should be understood that the present disclosure may be implemented in many ways and that the present disclosure should be construed in accordance with the appended claims and any equivalents thereof.

[0140] The disclosed teachings are described with reference to various uses, methods, kits, and compositions, but it will be understood that various changes and modifications may be made without departing from the teachings of this specification and the disclosed claims 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. Although the present teachings are described with respect to these exemplary embodiments, those skilled in the art will readily understand that numerous changes and modifications of these exemplary embodiments are possible without undue experimentation. Such modifications and variations are within the scope of the present teachings.

[0141] Example To better understand the present invention, the following examples are described. These examples are for illustrative purposes only and are not intended to be construed as limiting the scope of the present invention in any way.

[0142] Example 1: Clinical Trial of TTI-622 with Tafasitamab and Lenalidomide in Patients with Diffuse Large B-Cell Lymphoma

[0143] The objective of this study is to evaluate the safety and preliminary efficacy of TTI-622 in combination with tafasitamab and lenalidomide in patients with relapsed / refractory (R / R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for stem cell transplantation.

[0144] This study is a multi-center international two-component (Phase 1b followed by Phase 2) study of TTI-622 in combination with tafasitamab and lenalidomide, targeting participants with RRDLBCL who have completed at least one systemic treatment (including at least one anti-CD20 therapy), are not candidates for autologous stem cell transplantation (ASCT), or are ineligible for intensive chemotherapy due to age (>70 years) or comorbidities, or are unable or unwilling to undergo ASCT. In Part 2 of the study, participants may not have received more than two lines of prior treatment (induction, transplantation, and consolidation are considered one line of treatment). Prior treatment with CAR-T is permitted. In Part 2, up to five patients with prior CAR-T are permitted to participate in the study.

[0145] Part 1 will be conducted with approximately 20 participants. The objective of the Phase 1b component preceding the dose optimization part (Part 2) of this study is to evaluate the safety, tolerability, PK, and PD of TTI-622 in combination with the standard doses of tafasitamab and lenalidomide.

[0146] The mTPI-2-guided escalation / de-escalation approach will be used in Phase 1b to identify the safe dose of TTI-622 when tafasitamab and lenalidomide are co-administered, according to the Summary of Product Characteristics (SmPC) of tafasitamab and lenalidomide. The dose levels of TTI-622 to be investigated are as follows. · Cohort 1 (DL1): 4 mg / kg or a fixed dose of 300 mg of TTI-622 QW C1-3, then C4+Q2W · Cohort 2 (DL2): 10 mg / kg or a fixed dose of 750 mg of TTI-622 QW C1-3, then C4+Q2W · Cohort 3 (DL3): 18 mg / kg or 1350 mg fixed dose of TTI-622 QWC 1-3, then C4+Q2W

[0147] Treatments are administered in 28-day cycles. Lenalidomide is administered up to cycle 12, and TTI-622 and tafasitamab are administered until disease progression or unacceptable toxicity occurs.

[0148] In cycle 1, TTI-622 is administered by IV infusion at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg, or fixed doses of 300 mg, 750 mg, or 1350 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 4, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1-21.

[0149] In cycle 2, TTI-622 is administered by IV infusion at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg, or fixed doses of 300 mg, 750 mg, or 1350 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1-21.

[0150] In cycle 3, TTI-622 is administered by IV infusion at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg, or fixed doses of 300 mg, 750 mg, or 1350 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1-21.

[0151] In cycles 4 to 12, TTI-622 is administered by intravenous infusion on days 1 and 15 at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg, or fixed doses of 300 mg, 750 mg or 1350 mg. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1 and 15. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0152] In cycles 4 to 13, TTI-622 is administered by intravenous infusion on days 1 and 15 at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg, or fixed doses of 300 mg, 750 mg or 1350 mg. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1 and 15.

[0153] The dosing regimen is summarized in Table 2 below.

Table 2

[0154] Figure 1 provides a schematic diagram of the study.

[0155] The sponsor may further increase the dose based on new PK, PD, efficacy, and safety data. A safety review team consisting of the investigator responsible for the trial, including at least one medically qualified member, and the trial physicians for the participants enrolled in a particular cohort will review all safety data after following each participant for at least 28 days from the first dose of combination therapy. A patient is considered evaluable for DLT if they have received all applicable doses (see above) during the DLT observation period or have experienced an adverse event (AE) that meets the DLT criteria during that period. If a patient experiences a non-DLT event where they need to hold the dose according to the dose modification guidelines, additional patients may be enrolled. If DL3 is intolerable, an additional cohort (DL4) can be considered, starting with 18 mg / kg of TTI-622 at C1 (or another dose level lower than DL3 but higher than DL2) and administered Q2W.

[0156] At least three DLT - evaluable participants are treated at each dose level of the combination therapy. At least nine DLT - evaluable participants are treated at the estimated MTD or the highest test dose level of TTI - 622 before proceeding to Phase 2.

[0157] In Phase 2, a dosing regimen identical or similar to that used in Phase 1 described above can be used. Optionally, in Phase 2, the dose of TTI - 622 can be changed compared to the Phase 1 regimen such that TTI - 622 is administered at a fixed dose of 300 mg, 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg instead of a weight - based (mg / kg) dose. Optionally, when administered at a fixed dose, TTI - 622 can be administered at the same frequency as provided in Phase 1 for the weight - based dose.

[0158] For a participant to be eligible for enrollment in the study, the following major selection criteria must be met: Age and gender: Appropriately consented male or female 18 years of age or older (or the minimum age for consent according to local regulations) with the willingness and ability to attend all study visits and evaluations. Disease characteristics: Histologically confirmed progressive measurable relapsed and / or refractory CD19 + diffuse large B - cell lymphoma (unless otherwise specified); T - cell / histiocyte - rich large B - cell lymphoma, Epstein - Barr virus - positive DLBCL, grade 3b follicular lymphoma or composite lymphoma containing a DLBCL component, and subsequent DLBCL relapse, histological transformation from early - stage diagnosis of low - grade lymphoma to DLBCL (follicular lymphoma, marginal zone lymphoma, early - stage diagnosis of chronic lymphocytic leukemia). Progression after transformation to DLBCL must be observed prior to enrollment.

[0159] Have received at least one systemic treatment, are not candidates as per the instructions of the principal investigator of the clinical trial, or have no intention of undergoing high-dose chemotherapy or subsequent autologous stem cell transplantation. At least one line of prior treatment must include a treatment containing anti-CD20. In Part 2, prior systemic treatment is only permitted up to two lines.

[0160] Participants who meet any of the following characteristics / conditions are excluded: Medical conditions: 1. Primary refractory DLBCL (response less than PR, or progression during or within 6 months after treatment with first-line therapy). 2. Double or triple hit DLBCL and CNS lymphoma. (Double / triple hit: co-detection of MYC with BCL2 and / or BCL6 translocation(s) defined by fluorescence in situ hybridization. Testing for MYC, BCL2, and BCL6 prior to trial registration is not required.) 3. History of malignancies other than DLBCL. However, the following are excluded: basal cell carcinoma or squamous cell carcinoma of the skin, or appropriately treated Bowen's disease; previous follicular lymphoma transformed into DLBCL; or any prior malignancy more than 3 years before randomization with no evidence of subsequent recurrence or progression without treatment regardless of stage, or stage 0-1 intraepithelial carcinoma less than 3 years before randomization (with a low probability of recurrence or progression as determined by the principal investigator of the clinical trial). 4. Previous cancer treatment, radiotherapy within 2 weeks, or major surgery within 2 weeks, or unresolved toxicity of grade >1 according to NCICTCAEv5.0 (excluding alopecia). 5. Previous allogeneic stem cell transplantation; autologous stem cell transplantation within 12 weeks before registration, ongoing GVHD (other than grade 1 skin involvement) or GVHD requiring treatment. 6. Major cardiovascular diseases such as symptomatic congestive heart failure (New York Heart Association class III or IV), symptomatic coronary artery disease, myocardial infarction, uncontrollable / unstable arrhythmia, unstable angina within the past 6 months, or QTcF interval prolongation > 470 msec at screening. LVEF < 40% determined by MUGA scan or ECHO. History of deep vein thrombosis or pulmonary embolism, dangerous thromboembolism, or known thrombophilia. Participants must be willing to receive prophylactic treatment for thromboembolic events. 7. Active hepatitis B or C, or known HIV or COVID-19 infection (symptomatic or asymptomatic), or any infectious disease requiring systemic therapy.

[0161] Previous treatment / combination therapy: 1. Previous treatment with immunomodulators such as anti-CD47 or anti-CD19 (other than CAR-T) or thalidomide or lenalidomide. 2. Live vaccines within 4 weeks before randomization and during the trial are prohibited, except for administration of inactivated vaccines. 3. Use of corticosteroids, except for: intranasal, inhaled, ophthalmic drops, topical steroids, or local steroid injections (e.g., intra-articular injection); systemic corticosteroids at a physiological dose of prednisone or equivalent < 10 mg / day.

[0162] The primary evaluation item in the Phase 1b is DLT during the DLT observation period. The analysis of DLT is based on the DLT evaluable set. Summarize and describe the occurrence of DLT and AEs constituting DLT by dose level for participants enrolled in the Phase 1b during the DLT observation period.

[0163] The primary evaluation item for the second phase is the OR according to the Lugano response classification criteria 2014, which is evaluated by the principal investigator of the clinical trial. Participants without tumor evaluation after baseline due to early progression of the disease, participants who received anticancer therapy other than the test intervention before reaching CR or PR, or participants who died for any reason before reaching CR or PR, participants with proven PD, or participants who discontinued tumor evaluation are counted as non-responders in the evaluation of ORR. ORR is calculated using the Clopper-Pearson method with a two-sided 95% CI.

[0164] Exemplary dosing regimens for phases subsequent to the second phase further include the following: Regimen: 600 mg of TTI-622: Administer the treatment in 28-day cycles. Administer lenalidomide until cycle 12, and administer TTI-622 and tafasitamab until disease progression or unacceptable toxicity occurs.

[0165] In cycle 1, administer TTI-622 by IV infusion at a fixed dose of 600 mg on days 1, 8, 15, and 22. Administer tafasitamab by IV infusion at 12 mg / kg on days 1, 4, 8, 15, and 22. Administer lenalidomide orally at 25 mg on days 1 to 21.

[0166] In cycle 2, administer TTI-622 by IV infusion at a fixed dose of 600 mg on days 1, 8, 15, and 22. Administer tafasitamab by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Administer lenalidomide orally at 25 mg on days 1 to 21.

[0167] In cycle 3, administer TTI-622 by IV infusion at a fixed dose of 600 mg on days 1, 8, 15, and 22. Administer tafasitamab by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Administer lenalidomide orally at 25 mg on days 1 to 21.

[0168] In cycles 4 to 12, TTI-622 is administered by IV infusion at a fixed dose of 600 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0169] After cycle 13, TTI-622 is administered by IV infusion at a fixed dose of 600 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15.

[0170] Regimen: 1200 mg TTI-622: Treatment is administered in 28-day cycles. Lenalidomide is administered up to cycle 12, and TTI-622 and tafasitamab are administered until disease progression or unacceptable toxicity occurs.

[0171] In cycle 1, TTI-622 is administered by IV infusion at a fixed dose of 1200 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 4, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0172] In cycle 2, TTI-622 is administered by IV infusion at a fixed dose of 1200 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0173] In cycle 3, TTI-622 is administered by IV infusion at a fixed dose of 1200 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0174] In cycles 4 to 12, TTI-622 is administered by intravenous infusion at a fixed dose of 1200 mg on days 1 and 15. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1 and 15. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0175] After cycle 13, TTI-622 is administered by intravenous infusion at a fixed dose of 1200 mg on days 1 and 15. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1 and 15.

[0176] Regimen: 1800 mg TTI-622: Treatment is administered in 28-day cycles. Lenalidomide is administered up to cycle 12, and TTI-622 and tafasitamab are administered until disease progression or unacceptable toxicity occurs.

[0177] In cycle 1, TTI-622 is administered by intravenous infusion at a fixed dose of 1800 mg on days 1, 8, 15, and 22. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1, 4, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0178] In cycle 2, TTI-622 is administered by intravenous infusion at a fixed dose of 1800 mg on days 1, 8, 15, and 22. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0179] In cycle 3, TTI-622 is administered by intravenous infusion at a fixed dose of 1800 mg on days 1, 8, 15, and 22. Tafasitamab is administered by intravenous infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0180] In cycles 4 to 12, TTI-622 is administered by IV infusion at a fixed dose of 1800 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15. Lenalidomide is orally administered at 25 mg on days 1 to 21.

[0181] After cycle 13, TTI-622 is administered by IV infusion at a fixed dose of 1800 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15.

[0182] Regimen: 2400 mg TTI-622: Treatment is administered in 28-day cycles. Lenalidomide is administered up to cycle 12, and TTI-622 and tafasitamab are administered until disease progression or unacceptable toxicity occurs.

[0183] In cycle 1, TTI-622 is administered by IV infusion at a fixed dose of 2400 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 4, 8, 15, and 22. Lenalidomide is orally administered at 25 mg on days 1 to 21.

[0184] In cycle 2, TTI-622 is administered by IV infusion at a fixed dose of 2400 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is orally administered at 25 mg on days 1 to 21.

[0185] In cycle 3, TTI-622 is administered by IV infusion at a fixed dose of 2400 mg on days 1, 8, 15, and 22. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1, 8, 15, and 22. Lenalidomide is orally administered at 25 mg on days 1 to 21.

[0186] In cycles 4 to 12, TTI-622 is administered by IV infusion at a fixed dose of 2400 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15. Lenalidomide is administered orally at 25 mg on days 1 to 21.

[0187] After cycle 13, TTI-622 is administered by IV infusion at a fixed dose of 2400 mg on days 1 and 15. Tafasitamab is administered by IV infusion at 12 mg / kg on days 1 and 15.

[0188] Optionally, other doses of TTI-622, such as 300 mg, 750 mg, 900 mg, 1350 mg, 1500 mg, 2100 mg, or other fixed TTI-622 doses provided elsewhere in this specification, may be used in the regimens described immediately above.

Claims

1. A combination pharmaceutical for treating cancer in a patient, comprising a SIRPaFc fusion protein and an anti-CD19 antibody, The SIRPaFc fusion protein and the anti-CD19 antibody are administered to the patient simultaneously or sequentially, in a single dosage form or in separate dosage forms. The aforementioned combination drug.

2. The combination pharmaceutical according to claim 1, further comprising an E3 ubiquitin ligase modulator, wherein the SIRPaFc fusion protein, the anti-CD19 antibody, and the E3 ubiquitin ligase modulator are administered to the patient simultaneously or sequentially in a single dosage form or in separate dosage forms.

3. i) the SIRPaFc fusion protein is administered in Q1W or Q2W, and / or ii) the anti-CD19 antibody is administered in Q1W or Q2W, according to claim 1.

4. The combination pharmaceutical according to claim 2, i) the SIRPaFc fusion protein is administered in Q1W or Q2W, and / or ii) the anti-CD19 antibody is administered in Q1W or Q2W, and / or iii) the E3 ubiquitin ligase modulator is administered daily.

5. A combination pharmaceutical for treating cancer in a patient, comprising a SIRPaFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator, The SIRPaFc fusion protein, the anti-CD19 antibody, and the E3 ubiquitin ligase modulator are administered to the patient simultaneously or sequentially, in a single dosage form or in separate dosage forms. The SIRPaFc fusion protein, the anti-CD19 antibody, and the E3 ubiquitin ligase modulator are administered to the patient for at least the first, second, third, and fourth cycles, where, Each cycle is 28 days long. In the first cycle, the SIRPaFc fusion protein was administered on days 1, 8, 15, and 22; the anti-CD19 antibody was administered on days 1, 4, 8, 15, and 22; and the E3 ubiquitin ligase modulator was administered from day 1 to day 21. In the second cycle, the SIRPaFc fusion protein was administered on days 1, 8, 15, and 22; the anti-CD19 antibody was administered on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator was administered from day 1 to day 21. In the third cycle, the SIRPaFc fusion protein was administered on days 1, 8, 15, and 22; the anti-CD19 antibody was administered on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator was administered from day 1 to day 21. In the fourth cycle, the SIRPaFc fusion protein is administered on day 1 and day 15, the anti-CD19 antibody is administered on day 1 and day 15, and the E3 ubiquitin ligase modulator is administered from day 1 to day 21. The aforementioned combination drug.

6. The combination drug according to claim 5, wherein the administration is continued from at least the fifth cycle to a maximum of the twelfth cycle, and in the fifth to the twelfth cycles, the SIRPaFc fusion protein is administered on day 1 and day 15, the anti-CD19 antibody is administered on day 1 and day 15, and the E3 ubiquitin ligase modulator is administered on day 1 to day 21.

7. The combination drug according to claim 6, wherein the administration is continued for at least a 13th cycle, in which the SIRPaFc fusion protein is administered on day 1 and day 15, the anti-CD19 antibody is administered on day 1 and day 15, and the E3 ubiquitin ligase modulator is not administered.

8. The combination drug according to claim 1, wherein the SIRPaFc fusion protein is administered in doses of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or in fixed doses of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg.

9. The combination pharmaceutical according to claim 1, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg.

10. The combination pharmaceutical according to claim 2, wherein the E3 ubiquitin ligase modulator is administered in a dose of 25 mg.

11. A combination pharmaceutical for treating cancer in a patient, comprising a SIRPaFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator, The SIRPaFc fusion protein, the anti-CD19 antibody, and the E3 ubiquitin ligase modulator are administered to the patient simultaneously or sequentially, in a single dosage form or in separate dosage forms. The SIRPaFc fusion protein, the anti-CD19 antibody, and the E3 ubiquitin ligase modulator are administered to the patient for at least the first, second, third, and fourth cycles, where, Each cycle is 28 days long. In the first cycle, the SIRPaFc fusion protein was administered at doses of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at fixed doses of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody was administered at a dose of 12 mg / kg on days 1, 4, 8, 15, and 22; and the E3 ubiquitin ligase modulator was administered at a dose of 25 mg from days 1 to 21. In the second cycle, the SIRPaFc fusion protein was administered at doses of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at fixed doses of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody was administered at a dose of 12 mg / kg on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator was administered at a dose of 25 mg from days 1 to 21. In the third cycle, the SIRPaFc fusion protein is administered at doses of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at fixed doses of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22; the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15, and 22; and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg from days 1 to 21. In the fourth cycle, the SIRPaFc fusion protein is administered at doses of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at fixed doses of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1 and 15; the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15; and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg from days 1 to 21. The aforementioned combination drug.

12. The combination drug according to claim 11, wherein administration is continued from at least the fifth cycle to a maximum of the twelfth cycle, and in the fifth to the twelfth cycle, the SIRPaFc fusion protein is administered on days 1 and 15 at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg; the anti-CD19 antibody is administered on days 1 and 15 at a dose of 12 mg / kg; and the E3 ubiquitin ligase modulator is administered on days 1 to 21 at a dose of 25 mg.

13. The combination drug according to claim 12, wherein the administration is continued for at least 13 cycles, and in the 13th cycle, the SIRPaFc fusion protein is administered on days 1 and 15 at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or at a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg, the anti-CD19 antibody is administered on days 1 and 15 at a dose of 12 mg / kg, and the E3 ubiquitin ligase modulator is not administered.

14. The combination pharmaceutical according to claim 1, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide having the amino acid sequence of SEQ ID NO:

1.

15. The combination pharmaceutical according to claim 1, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide having the amino acid sequence of SEQ ID NO:

2.

16. The combination pharmaceutical according to claim 1, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:

8.

17. The combination pharmaceutical according to claim 1, wherein the SIRPaFc fusion protein comprises a SIRPa polypeptide containing the amino acid sequence of SEQ ID NO: 1, or a variant thereof having one, two, three, four, or five amino acid substitutions compared to the sequence of SEQ ID NO:

1.

18. The combination pharmaceutical according to claim 1, wherein the anti-CD19 antibody comprises a heavy chain variable region including an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 11), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 12), and an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 13), and a light chain variable region including an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 14), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 15), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 16).

19. The aforementioned anti-CD19 antibody The heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSSDKSISSTAYMELSSLRSEDTAMYYYCARGTYYYGTRVFDYWGQGTLVTVSS (Sequence No. 17) and DIV The combination pharmaceutical according to claim 1, comprising the light chain variable region of MTQSPATLSLSPGGERAATLSCRSSKSSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 18).

20. The combination pharmaceutical according to claim 1, wherein the anti-CD19 antibody comprises an Fc domain including an amino acid substitution at position S239 and / or position I332, where the numbering follows the EU index, as in the case of Kabat.

21. The combination drug according to claim 20, wherein the anti-CD19 antibody comprises an Fc domain including an amino acid substitution at S239D and an amino acid substitution at I332E, where the numbering follows the EU index, as in the case of Kabat.

22. The aforementioned anti-CD19 antibody EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGT KYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPPC The heavy chain region of PAPELLGGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSSHEDPEVQFNWYVDGVEVHNHNAKTKPREEQFNSTFRVVSSVLTVVHQDWLNGKEYKCKVSNKALPAPEEEKTISKTKGQPREPQVYTLPPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 19), The light chain region of DIVMTQSPATLSLSPGERAATLSSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (SEQ ID NO: 20) and The combination pharmaceutical according to claim 1, including

23. The combination pharmaceutical according to claim 2, wherein the E3 ubiquitin ligase modulator comprises lenalidomide, pomalidomide, or thalidomide.

24. i) the cancer is CD19-positive, and / or ii) the cancer is CD47-positive, according to any one of claims 1 to 23.

25. The combination pharmaceutical according to any one of claims 1 to 23, wherein the cancer is a hematological malignancy or a solid tumor carcinoma.

26. Use of a SIRPaFc fusion protein or an anti-CD19 antibody in the manufacture of a combination pharmaceutical according to any one of claims 1 to 23.

27. A kit comprising a combination drug and instructions for use according to any one of claims 1 to 23, and optionally comprising one or more additional therapeutic agents.

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