Administration of a fusion protein that binds to CD38

Abstract

Disclosed by the present invention is a method for treating cancer (e.g., blood cancer or solid tumor) with a fusion protein that binds to CD38, optionally in combination with an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab).

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 346,784, titled "DOSING OF ANTI-CD38 FUSION PROTEIN," filed on May 27, 2022, and U.S. Provisional Patent Application No. 63 / 488,019, titled "DOSING OF ANTI-CD38 FUSION PROTEIN," filed on May 2, 2023, under 35 U.S.C. § 119(e), and each of these patent applications is hereby incorporated by reference in its entirety.

Background Art

[0002] CD38 is a 46 kDa type II transmembrane glycoprotein. CD38 has a short N-terminal cytoplasmic tail consisting of 20 amino acids, a single transmembrane helix, and a long extracellular domain consisting of 256 amino acids. CD38 is expressed on the surface of many immune cells, including CD4+ and CD8+ T cells, B cells, NK cells, monocytes, and plasma cells, as well as on a significant proportion of normal bone marrow progenitor cells. CD38 is expressed at high levels on various types of cancer cells, such as multiple myeloma cells, and in the majority of cases of T-cell and B-cell acute lymphoblastic leukemia, some acute myeloid leukemias, follicular center cell lymphoma, and T-lymphoblastic lymphoma. CD38 is also expressed on B-cell chronic lymphocytic leukemia (B-CLL) cells. Antibodies targeting CD38 are used in the treatment of cancers and hematological malignancies expressing CD38.

[0003] Interferon, particularly IFN-α, can increase apoptosis and decrease proliferation of certain cancer cells. IFN-α is FDA-approved for the treatment of several cancers, including melanoma, renal cell carcinoma, B-cell lymphoma, multiple myeloma, chronic myeloid leukemia (CML), and hairy cell leukemia. In general, IFN can be directed to cancer cells, for example, by linking IFN to a targeting antibody or a targeting fragment thereof.

[0004] A fusion protein comprising an anti-CD38 antibody fused to IFN-α and the use of that protein in the treatment of cancer are described. SUMMARY OF THE INVENTION

[0005] In some aspects, the present disclosure is a method of treating cancer, the method comprising administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to a hypoattenuated interferon α-2b.

[0006] In some embodiments, the fusion protein that binds to CD38 is administered at 0.1 - 1.5 mg per kg of the subject. In some embodiments, the fusion protein that binds to CD38 is administered at 1 mg per kg of the subject. In some embodiments, the fusion protein that binds to CD38 is administered at 0.75 mg per kg of the subject. In some embodiments, the fusion protein that binds to CD38 is administered at 0.75 - 1.5 mg per kg of the subject.

[0007] In some embodiments, the method comprises administering to the subject a composition comprising 60 - 120 mg of a fusion protein that binds to CD38 (e.g., regardless of the subject's weight). In some embodiments, 80 mg of a fusion protein that binds to CD38 is administered (e.g., regardless of the subject's weight). In some embodiments, 120 mg of a fusion protein that binds to CD38 is administered (e.g., regardless of the subject's weight).

[0008] In some embodiments, the fusion protein that binds to CD38 is administered once every three weeks.

[0009] In some embodiments, the anti-CD38 antibody comprises a heavy-chain complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy-chain complementarity-determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy-chain complementarity-determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light-chain complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light-chain complementarity-determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light-chain complementarity-determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.

[0010] In some embodiments, the anti-CD38 antibody comprises a heavy-chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light-chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD38 antibody comprises a human IgG4 constant region. In some embodiments, according to the EU numbering system, the human IgG4 constant region comprises a proline at position 228. In some embodiments, according to the EU numbering system, the human IgG4 constant region further comprises a tyrosine at position 252, a threonine at position 254, and a glutamic acid at position 256 of the constant region. In some embodiments, the anti-CD38 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the attenuated interferon α-2b comprises mutations T106A and A145D relative to interferon α-2b comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the attenuated interferon α-2b comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the attenuated interferon α-2b is fused to the C-terminus of the heavy chain. In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0011] In some embodiments, the composition further comprises histidine, arginine, sucrose, and polysorbate 80 (PS80). In some embodiments, in the composition, histidine is at a concentration of 50 mM, arginine is at a concentration of 100 mM, sucrose is at a concentration of 50 mg / ml, and PS80 is at a concentration of 0.2 mg / ml. In some embodiments, the composition has a pH of 6.6.

[0012] In some embodiments, the method further comprises administering an immune checkpoint inhibitor to the subject. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor comprises an anti-PD-1 antibody. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, 400 mg of pembrolizumab is administered once every 6 weeks. In some embodiments, 200 mg of pembrolizumab is administered once every 3 weeks.

[0013] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is colorectal cancer, cholangiocarcinoma, bone cancer, gastroesophageal cancer, pancreatic cancer, kidney cancer, melanoma, anal cancer, uterine cancer, liver cancer, sarcoma, breast cancer, bladder cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, or gastric cancer, and optionally, the cancer is metastatic melanoma, metastatic non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, metastatic urothelial cancer, gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, triple-negative breast cancer, high-risk non-muscle-invasive bladder cancer, advanced urothelial cancer, Merkel cell carcinoma, and cutaneous squamous cell carcinoma. In some embodiments, the cancer is a CD38-expressing cancer. In some embodiments, the cancer does not express CD38 (e.g., does not express CD38 when measured experimentally). In some embodiments, the cancer is melanoma. In some embodiments, the subject is human.

[0014] The present invention further provides a method for treating cancer, the method comprising administering a composition comprising a fusion protein that binds to CD38 to a subject in need of treatment, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and administering the fusion protein that binds to CD38 to the subject at a dose of 0.1 to 1.5 mg per kg of the subject once every three weeks, and the subject has been or is being treated with an immune checkpoint inhibitor.

[0015] The present invention further provides a method for treating cancer, the method comprising administering a composition comprising an immune checkpoint inhibitor to a subject in need of treatment, wherein the subject has been or is being treated with a fusion protein that binds to CD38, and the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and administering the fusion protein that binds to CD38 to the subject at a dose of 0.1 to 1.5 mg per kg of the subject once every three weeks.

[0016] The present invention further provides a method for treating cancer, the method comprising administering a composition comprising a fusion protein that binds to CD38 to a subject in need of treatment, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and administering the fusion protein that binds to CD38 to the subject at a dose of 60 to 120 mg once every three weeks, and the subject has been or is being treated with an immune checkpoint inhibitor.

[0017] The present invention further provides a method for treating cancer, the method comprising administering to a subject in need of treatment a composition comprising an immune checkpoint inhibitor, wherein the subject has been treated or has been treated with a fusion protein that binds to CD38, and the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to a attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 60 to 120 mg once every three weeks.

[0018] The present invention further provides a fusion protein that binds to CD38 and is used in a method for treating cancer, the method comprising administering to a subject in need of treatment the fusion protein that binds to CD38 at a dose of 0.1 to 1.5 mg per kg of the subject once every three weeks, and the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to a attenuated interferon α-2b.

[0019] The present invention further provides a fusion protein that binds to CD38 and is used in a method for treating cancer, the method comprising administering to a subject in need of treatment the fusion protein that binds to CD38 at a dose of 60 to 120 mg once every three weeks, and the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to a attenuated interferon α-2b.

[0020] In some embodiments, the subject is further administered an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, 400 mg of pembrolizumab is administered once every six weeks. In some embodiments, 200 mg of pembrolizumab is administered once every three weeks.

[0021] In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the subject is human. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is melanoma.

[0022] In some aspects, the present invention discloses a method for treating multiple myeloma, the method comprising administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to a decoy interferon α-2b, and administering the fusion protein that binds to CD38 to the subject at a dose of 1.5 to 3 mg per kg of the subject, or administering 120 to 240 mg of the fusion protein that binds to CD38 to the subject.

[0023] In some embodiments, the fusion protein that binds to CD38 is administered in an amount of 1.5 to 3 mg per kg of the subject. In some embodiments, the fusion protein that binds to CD38 is administered to the subject in an amount of 120 to 240 mg (regardless of the subject's body weight). In some embodiments, the fusion protein that binds to CD38 is administered once every four weeks. In some embodiments, the method further comprises administering to the subject pomalidomide, carfilzomib, daratumumab, lenalidomide and / or bortezomib.

[0024] In some embodiments, the method comprises administering a fusion protein that binds to CD38 and comprises an anti-CD38 antibody that comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.

[0025] In some embodiments, the fusion protein that binds to CD38 comprises the amino acid sequence of SEQ ID NO: 12.

[0026] In some embodiments, the method further comprises administering an adrenal cortical steroid. In some embodiments, the adrenal cortical steroid is dexamethasone.

[0027] In some embodiments, the method further comprises administering an antihistamine. In some embodiments, the antihistamine is montelukast or diphenhydramine. In some embodiments, the method comprises administering an antihistamine 12 hours before and 1 hour after administering the fusion protein that binds to CD38 to the subject in a first treatment cycle, and administering an antihistamine 1 hour before and 1 hour after administering the fusion protein that binds to CD38 to the subject in treatment cycles after the first treatment cycle.

[0028] In some embodiments, the method further comprises administering an analgesic. In some embodiments, the analgesic is acetaminophen. In some embodiments, the analgesic is an NSAID.

[0029] In some aspects, the present disclosure describes a method of promoting an immune response in a subject, the method comprising administering to the subject a fusion protein that binds to CD38 as described herein. In some embodiments, promoting an immune response in the subject includes promoting an immune response at the site of cancer and / or tumor (e.g., melanoma or multiple myeloma) in the subject.

[0030] The drawings are for illustrative purposes only and not for limitation.

Brief Description of the Drawings

[0031]

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Mode for Carrying Out the Invention

[0032] Throughout this specification and the claims, various terms related to aspects of the present disclosure are used. Unless otherwise indicated, such terms are to be given their ordinary meaning in the relevant technical field. Other terms that are specifically defined are to be interpreted in a manner consistent with the definitions set forth herein.

[0033] As used herein, unless expressly defined otherwise, the singular forms with "a", "an", and "the" include plural referents.

[0034] As used herein, "about" means within 5% of a given value or range, e.g., within 5%, within 4%, within 3%, within 2% or within 1%.

[0035] As used herein, the term "improvement" may, in context, refer to an improvement in the treatment of cancer, an improvement in treatment efficacy, etc., with respect to an improvement in the nature of the treatment or the nature of the subject. For example, an improvement in the treatment efficiency of a fusion protein that binds to CD38 may be positively correlated with the CD38 expression of the tumor cells of the subject. For example, the treatment efficacy of a fusion protein that binds to CD38 may be improved in a subject with higher CD38 expression in the tumor compared to a subject with lower CD38 expression in the tumor. In another example, a fusion protein that binds to CD38, where a particular dose or dosing regimen of the fusion protein administered to the subject results in improved efficacy and / or reduced side effects compared to a different dose or dosing regimen of that fusion protein that binds to CD38, the treatment efficacy may be improved. The term "improvement" may, in context, refer to an improvement over a control when it comes to an improvement in the treatment of cancer, an improvement in treatment efficacy, etc. In some embodiments, the control is the response of the subject to treatment with a placebo. In some embodiments, the control is the response of the subject to standard of care (e.g., standard of care for the subject's cancer and / or tumor). In some embodiments, the control is the average treatment efficacy (e.g., survival time) of a population of patients who have been administered a given medicament (e.g., a fusion protein that binds to CD38). In some embodiments, the control is a baseline (e.g., the state of the patient prior to treatment). In some embodiments, an improvement in treatment efficacy is demonstrated by the survival time of the subject being at least 5% (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more) longer compared to the baseline. In some embodiments, an improvement in treatment efficacy is demonstrated by the survival time of the subject being 5 - 10%, 10 - 20%, 20 - 40%, 60 - 100% or 100 - 200% longer compared to the baseline. In some embodiments, an improvement in treatment efficacy is demonstrated by an increase in the disease remission rate compared to the baseline in one or more subjects.In some embodiments, the improvement in therapeutic efficacy is demonstrated by an increase in the function of immune cells in the subject, for example, by an improvement in the ability of the immune cells in the subject to kill cancer cells.

[0036] As used herein, the term "promote," when used in the context of an immune response, means to stimulate, initiate, increase, or enhance, including release from an inhibitory state. In some embodiments, promoting an immune response includes increasing the expression of cytokines and / or chemokines in the subject (e.g., increasing the expression of a cytokine or chemokine by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more). In some embodiments, promoting an immune response includes activating the signaling of interferon α. In some embodiments, promoting an immune response includes inducing an immune response against the cancer and / or tumor of the subject, or inducing an immune response at the location of the cancer and / or tumor in the subject.

[0037] The present disclosure, in some aspects, relates to a method of treating cancer using a fusion protein that binds to CD38 and comprises an anti-CD38 antibody fused to a hypoactive interferon α-2b protein. In some embodiments, the methods described herein include administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38. In some embodiments, the method further includes administering to the subject an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab).

[0038] In some embodiments, the methods described herein include administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38, wherein the subject has been treated with, or has previously been treated with, an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab).

[0039] In some embodiments, the methods described herein include administering to a subject in need of treatment a composition comprising an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab), wherein the subject has been treated with, or has previously been treated with, a fusion protein that binds to CD38.

[0040] As used herein, "fusion protein that binds to CD38" refers to a fusion protein comprising a CD38-binding domain fused to one or more (e.g., one, two) attenuated interferon α-2b proteins. "Fusion protein" refers to a polypeptide comprising two or more proteinaceous components joined by at least one covalent bond that is a peptide bond, where the peptide bond may or may not involve a carbon atom of a carboxylic acid group or another carbon atom. The term "fused" refers to the act of creating a fusion molecule as described above, e.g., a fusion protein generated from a recombinant fusion of genetic regions that, when translated, produce one proteinaceous molecule. Fusion proteins that bind to CD38 and that may be used in the compositions described herein are described, for example, in U.S. Patent No. 10,544,199, which is incorporated herein by reference. The amino acid sequences of specific anti-CD38 antibodies are shown in Table 1.

[0041] A fusion protein that binds to CD38, wherein the fusion protein used in the methods described herein comprises an anti-CD38 antibody. As used herein, the term "antibody" includes, for example, intact immunoglobulins, antigen-binding portions of immunoglobulins, or antigen-binding proteins related to or derived from immunoglobulins. The structural unit of an intact antibody often contains a tetrameric protein. Each tetramer is typically composed of two pairs of identical polypeptide chains, each pair having one "light" chain (typically with a molecular weight of about 25 kDa) and one "heavy" chain (typically with a molecular weight of about 50-70 kDa). Human immunoglobulin light chains can be classified as having either a kappa or lambda light chain. In some embodiments, the antibodies described herein generally comprise antigen-binding domains (e.g., the heavy and / or light chains of the antibody) based on the IgG class, and there are several subclasses of the IgG class, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. Generally, IgG1 has various allotypes with a polymorphism at position 356 (D or E), and IgG2 has a polymorphism at position 358 (L or M). In the sequences shown herein, the 356D / 358M allotype is used, but any allotype is included in the present invention and can be used in accordance with the present disclosure. For example, any sequence containing an IgG1 Fc domain included in the present invention can have the 356E / 358L allotype instead of the 356D / 358M allotype.

[0042] A fusion protein that binds to CD38, wherein the anti-CD38 antibody of the fusion protein used in the methods described herein comprises a heavy chain comprising a heavy chain variable domain (VH) and a light chain comprising a light chain variable domain (VL). As used herein, a "variable domain" refers to a region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the Vκ (V.kappa) genes that make up the immunoglobulin kappa locus, the Vλ (V.lambda) genes that make up the immunoglobulin lambda locus, and / or the VH genes that make up the immunoglobulin heavy chain locus. In the variable domain, three loops come together for each of the V domains of the heavy and light chains to form an antigen-binding site. Each of those loops is called a complementarity-determining region (hereinafter, "CDR"). In addition, the variable domain is a relatively invariant region called a framework region (FR) consisting of 15 to 30 amino acids, and also includes regions separated by CDRs. Each VH and VL is composed of three CDRs and four FRs, which are arranged in the order of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 from the amino terminus to the carboxy terminus. In some embodiments, an "antibody molecule" refers to a two-chain and multi-chain immunoglobulin protein and glycoprotein. In some embodiments, a fusion protein that binds to CD38, wherein the anti-CD38 antibody of the fusion protein used in the methods described herein is an antibody fragment or antigen-binding fragment of the antibody, such as fragments including Fab, Fab’, F(ab’)2, and Fv.

[0043] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a VH comprising CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3, and a VL comprising CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 5, and CDRL3 having the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a set of six CDRs that includes up to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid modifications relative to the six CDRs of the anti-CD38 antibody shown in Table 1. For example, in some embodiments, the CDRs can be modified in any way, provided that the total number of changes to the set of six CDRs does not exceed 10 amino acid modifications. For example, there could be one change in CDRL1, two changes in CDRH2, and no changes in CDRH3, etc. In some embodiments, each CDR has no more than one amino acid substitution relative to the corresponding CDR of the anti-CD38 antibody shown in Table 1. In some embodiments, amino acid modifications in CDRH3 are avoided.

[0044] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 7 and a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 8.

[0045] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein is a full-length IgG antibody. In such full-length IgG antibodies, each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. In some embodiments, the immunoglobulin molecule is IgG4 or a subclass thereof of the IgG class.

[0046] In some embodiments, the fusion protein that binds to CD38 and the anti-CD38 antibody of the fusion protein used in the methods described herein comprise an IgG4 constant region (e.g., a human IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 14). As used herein, the term "IgG4 constant region" refers to a wild-type IgG4 constant region (e.g., a wild-type human IgG4 constant region) or an IgG4 constant region variant (e.g., a human IgG4 constant region variant), or a fragment thereof. An IgG4 constant region variant (e.g., a human IgG4 constant region variant) that may be used in the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein may, in some embodiments, comprise one or more mutations, e.g., mutations that stabilize its hinge region and / or mutations that reduce the toxicity of the antibody. For example, according to the EU numbering system, the mutation at position 228 of the IgG4 stabilizes the hinge of the IgG4. In some embodiments, according to the EU numbering system, due to the mutation at position 228 of the IgG4 constant region, position 228 becomes proline.

[0047] In some embodiments, the mutation in the IgG4 constant region reduces antibody-dependent cell-mediated cytotoxicity (ADCC). "Antibody-dependent cell-mediated cytotoxicity (ADCC)", as used herein, refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing Fcγ receptor (FcγR) recognize a bound antibody on a target cell and then lyse that target cell. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein contains an IgG4 constant region that reduces ADCC and contains one or more mutations (e.g., mutations at one or more of positions 252, 254, and 256 of the IgG4 constant region according to the EU numbering system) that avoid undesired high levels of cytotoxicity. In some embodiments, according to the EU numbering system, due to the mutation at position 252 of the IgG4 constant region, position 252 becomes tyrosine. In some embodiments, according to the EU numbering system, due to the mutation at position 254 of the IgG4 constant region, position 254 becomes threonine. In some embodiments, according to the EU numbering system, due to the mutation at position 256 of the IgG4 constant region, position 256 becomes glutamate.

[0048] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein contains an IgG4 constant region that contains a mutation at position 228 of the IgG4 constant region according to the EU numbering system. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein contains an IgG4 constant region that contains the amino acid sequence of SEQ ID NO: 15.

[0049] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a heavy chain comprising a VH and a human IgG4 constant region, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7 and the IgG4 constant region comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 9.

[0050] In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a light chain comprising a VL and a kappa light chain constant region, wherein the VL comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-CD38 antibody of the fusion protein that binds to CD38 and is used in the methods described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 10.

[0051] In some embodiments, the fusion protein that binds to CD38 and is used in the methods described herein further comprises an anti-CD38 antibody (e.g., the anti-CD38 antibodies shown in Table 1) fused to a hypoactive interferon α-2b protein (e.g., the hypoactive interferon α-2b protein is fused to the heavy chain of the anti-CD38 antibody). Interferon-α-2b can have its biological activity attenuated, and it has been observed that such attenuation is mediated through binding of the interferon to interferon receptors on the cell surface by introducing specific amino acid changes into its protein sequence. In some embodiments, the hypoactive interferon α-2b protein comprises a mutation that reduces potency (e.g., A145D) and / or a mutation that eliminates O-linked glycosylation of the interferon α-2b protein (e.g., T106A). The hypoactive interferon molecule can be fused to an antibody that specifically binds to CD38 (e.g., an anti-CD38 antibody) as described herein, such that the anti-CD38 antibody can serve as a vehicle for delivering the hypoactive interferon to CD38-positive cells, thereby reducing the activity of off-target interferon due to the hypoactive interferon molecule.

[0052] In some embodiments, the attenuated interferon α-2b protein is fused to the heavy chain of an anti-CD38 antibody. In some embodiments, the attenuated interferon α-2b protein is fused to the C-terminus of the heavy chain of an anti-CD38 antibody. Thus, in some embodiments, a fusion protein that binds to CD38 and is used in the methods described herein comprises a heavy chain and a light chain, wherein the heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon α-2b protein, and the light chain is the light chain of that anti-CD38 antibody. In some embodiments, a fusion protein that binds to CD38 and is used in the methods described herein comprises two heavy chains and two light chains, wherein each heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon α-2b protein, and each light chain is the light chain of that anti-CD38 antibody.

[0053] In some embodiments, the attenuated interferon α-2b comprises the mutations T106A and A145D relative to wild-type human interferon α-2b (e.g., human interferon α-2b comprising the amino acid sequence of SEQ ID NO: 11). In some embodiments, the attenuated interferon α-2b comprises the amino acids of SEQ ID NO: 12. In some embodiments, the attenuated interferon α-2b comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acids of SEQ ID NO: 12.

[0054] In some embodiments, the fusion protein that binds to CD38 and is used in the methods described herein comprises a heavy chain having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acids of SEQ ID NO: 13, and a light chain having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acids of SEQ ID NO: 10. In some embodiments, the fusion protein that binds to CD38 and is used in the methods described herein comprises the amino acids of SEQ ID NO: 13 and a light chain comprising the amino acids of SEQ ID NO: 10. In some embodiments, the fusion protein that binds to CD38 and is used in the methods described herein comprises two heavy chains and two light chains, each heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and each light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0055]

Table 1-1

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[0057]

Table 1-3

[0058] In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.1 to 15 mg per kg of subject (e.g., 0.1 to 15 mg, 0.5 to 15 mg, 1 to 15 mg, 2 to 15 mg, 3 to 15 mg, 4 to 15 mg, 5 to 15 mg, 6 to 15 mg, 7 to 15 mg, 8 to 15 mg, 9 to 15 mg, 10 to 15 mg, 11 to 15 mg, 12 to 15 mg, 13 to 15 mg, 14 to 15 mg, 0.1 to 14 mg, 0.5 to 14 mg, 1 to 14 mg, 2 to 14 mg, 3 to 14 mg, 4 to 14 mg, 5 to 14 mg, 6 to 14 mg, 7 to 14 mg, 8 to 14 mg, 9 to 14 mg, 10 to 14 mg, 11 to 14 mg, 12 to 14 mg, 13 to 14 mg, 0.1 to 13 mg, 0.5 to 13 mg, 1 to 13 mg, 2 to 13 mg, 3 to 13 mg, 4 to 13 mg, 5 to 13 mg, 6 to 13 mg, 7 to 13 mg, 8 to 13 mg, 9 to 13 mg, 10 to 13 mg, 11 to 13 mg, 12 to 13 mg, 0.1 to 12 mg, 0.5 to 12 mg, 1 to 5 mg, 2 to 12 mg, 3 to 12 mg, 4 to 12 mg, 5 to 12 mg, 6 to 12 mg, 7 to 12 mg, 8 to 12 mg, 9 to 12 mg, 10 to 12 mg, 11 to 12 mg, 0.1 to 11 mg, 0.5 to 11 mg, 1 to 11 mg, 2 to 11 mg, 3 to 11 mg, 4 to 11 mg, 5 to 11 mg, 6 to 11 mg, 7 to 11 mg, 8 to 11 mg, 9 to 11 mg, 10 to 11 mg, 0.1 to 10 mg, 0.5 to 10 mg, 1 to 10 mg, 2 to 10 mg, 3 to 10 mg, 4 to 10 mg, 5 to 10 mg, 6 to 10 mg, 7 to 10 mg, 8 to 10 mg, 9 to 10 mg, 0.1 to 9 mg, 0.5 to 9 mg, 1 to 9 mg, 2 to 9 mg, 2 to 9 mg, 3 to 9 mg, 4 to 9 mg, 5 to 9 mg, 6 to 9 mg, 7 to 9 mg, 8 to 9 mg, 0.1 to 8 mg, 0.5 to 8 mg, 1 to 8 mg, 2 to 8 mg, 3 to 8 mg, 4 to 8 mg, 5 to 8 mg, 6 to 8 mg, 7 to 8 mg, 0.1 to 7 mg, 0.5 to 7 mg, 1 to 7 mg, 2 to 7 mg, 3 to 7 mg, 4 to 7 mg, 5 to 7 mg or 6 to 7 mg) per kg of subject. In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.1 mg, 0.2 mg, 0.4 mg, 0.75 mg, 1 mg, 1.5 mg, 3 mg, 6 mg, 9 mg, 12 mg, 14 mg or 15 mg per kg of subject.In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.1 to 6 mg per kg of subject (e.g., 0.1 to 6 mg, 0.5 to 6 mg, 1 to 6 mg, 2 to 6 mg, 3 to 6 mg, 4 to 6 mg, 5 to 6 mg, 0.1 to 5 mg, 0.5 to 5 mg, 1 to 5 mg, 2 to 5 mg, 3 to 5 mg, 4 to 5 mg, 0.1 to 4 mg, 0.5 to 4 mg, 1 to 4 mg, 2 to 4 mg, 3 to 4 mg, 0.1 to 3 mg, 0.5 to 3 mg, 1 to 3 mg, 2 to 3 mg, 0.1 to 2 mg, 0.5 to 2 mg, 1 to 2 mg, 0.1 to 1 mg or 0.5 to 1 mg per kg of subject). In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.1 mg, 0.2 mg, 0.4 mg, 0.75 mg, 1 mg, 1.5 mg, 3 mg or 6 mg per kg of subject. In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.1 to 1.5 mg per kg of subject (e.g., 0.1 to 1.5 mg, 0.3 to 1.4 mg, 0.5 to 1.3 mg, 0.7 to 1.2 mg or 0.9 to 1.1 mg per kg of subject). In some embodiments, in the methods described herein, the fusion protein that binds to CD38 is administered at 0.5 to 2 mg per kg of subject (e.g., 0.5 to 2 mg, 0.6 to 1.8 mg, 0.7 to 1.6 mg, 0.8 to 1.4 mg, 0.9 to 1.2 mg per kg of subject). In some embodiments, the fusion protein that binds to CD38 is administered at about 1 mg per kg of subject. In some embodiments, the fusion protein that binds to CD38 is administered at about 0.75 mg per kg of subject.

[0059] In some embodiments, the fusion protein that binds to CD38 is administered at a dose that increases over time (e.g., a gradually increasing dose). In some embodiments, the dose of the fusion protein that binds to CD38 is increased in at least one cycle of a multiple-cycle administration regimen (e.g., the dose is increased in cycle 3 out of 6 cycles). In some embodiments, the dose of the fusion protein that binds to CD38 is increased between consecutive cycles of the administration regimen, for example, 0.001 mg / kg (cycle 1), 0.01 mg / kg (cycle 2), 0.1 mg / kg (cycle 3), 0.75 mg / kg (cycle 4), 1.5 mg / kg (cycle 5), 3 mg / kg (cycle 6), 6 mg / kg (cycle 7), 9 mg / kg (cycle 8), and 14 mg / kg (cycle 9). In some embodiments, the dose of the fusion protein that binds to CD38 is increased over time, for example, 0.001 mg / kg, 0.01 mg / kg, 0.1 mg / kg, 0.75 mg / kg, 1.5 mg / kg, 3 mg / kg, 6 mg / kg, 9 mg / kg, and 14 mg / kg. In some embodiments, the fusion protein that binds to CD38 is administered to the subject at a dose of 60-120 mg (e.g., 60-120 mg, 60-100 mg, 60-80 mg, 80-120 mg, 80-100 mg, or 100-120 mg) (e.g., regardless of the subject's body weight). In some embodiments, the fusion protein that binds to CD38 is administered to the subject at a dose of 80-120 mg (e.g., 80 mg, 90 mg, 100 mg, 110 mg, or 120 mg) (e.g., regardless of the subject's body weight). In some embodiments, the fusion protein that binds to CD38 is administered to the subject at a dose of about 80 mg (e.g., regardless of the subject's body weight). In some embodiments, the fusion protein that binds to CD38 is administered to the subject at a dose of about 120 mg (e.g., regardless of the subject's body weight). In some embodiments, the fusion protein that binds to CD38 is administered at a dose of 120-250 mg or 200-260 mg. In some embodiments, the fusion protein that binds to CD38 is administered at a maximum dose of 240 mg (e.g., regardless of the subject's body weight).In some embodiments, the fusion protein that binds to CD38 is administered at a dose of 240 mg.

[0060] In some embodiments, in any one of the methods described herein, the fusion protein that binds to CD38 is administered once every 1 to 4 weeks (e.g., once a week, once every two weeks, once every three weeks, or once every four weeks). In some embodiments, the fusion protein that binds to CD38 is administered once per cycle. One cycle may be 1 week (1-week cycle), 2 weeks (2-week cycle), 3 weeks (3-week cycle), or 4 weeks (4-week cycle). In some embodiments, the cycle is a 3-week cycle or a 4-week cycle. In some embodiments, the fusion protein that binds to CD38 is administered once per cycle, over 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, or 15 cycles. In some embodiments, the fusion protein that binds to CD38 is administered once per cycle, over 1 to 12 cycles. In some embodiments, in any one of the methods described herein, the fusion protein that binds to CD38 is administered once every three weeks. In some embodiments, in any one of the methods described herein, the fusion protein that binds to CD38 is administered once every three weeks, over a period (e.g., up to 1 year, 2 years, 3 years, 4 years, 5 years or more). In some embodiments, in any one of the methods described herein, the fusion protein that binds to CD38 is administered once every three weeks, over the remaining lifetime of the patient.

[0061] In some embodiments, the method includes monitoring a subject (e.g., monitoring the efficacy and / or side effects of treatment) to determine how many cycles to administer the fusion protein that binds to CD38. In some embodiments, the method monitors side effects of the subject (e.g., neutropenia lasting more than 7 consecutive days, thrombocytopenia lasting more than 14 consecutive days, and nausea / vomiting lasting more than 48 hours), and if a harmful side effect is observed in the subject, it includes stopping, delaying, or reducing treatment with the fusion protein that binds to CD38. In some embodiments, the method monitors intolerable side effects of the subject, and if an intolerable side effect is observed in the subject, it includes stopping, delaying, or reducing treatment with the fusion protein that binds to CD38.

[0062] In some embodiments, an increase in the expression of CD38 on cancer cells and / or the immune cells of a subject after administration of the fusion protein that binds to CD38 is associated with an improvement in the efficacy of cancer treatment (e.g., improvement in patient survival rate). In some embodiments, the expression of CD38 on cancer cells is not associated with or has a weak association with the efficacy of the fusion protein that binds to CD38. In some embodiments, the efficacy of the fusion protein that binds to CD38 is independent of the expression of CD38 on myeloma cells and immune cells in the bone marrow. In some embodiments, administration of the fusion protein that binds to CD38 increases the number of natural killer cells in the blood of the subject. In some embodiments, administration of the fusion protein that binds to CD38 activates immune cells (e.g., T cells) of the subject.

[0063] In some embodiments, the improvement of immune activity in a subject (e.g., the expression of neopterin, the expression of complement, the expression of cytokines / chemokines, and the expression of immune-related genes) is associated with the administration of a fusion protein that binds to CD38. In some embodiments, after the administration of a fusion protein that binds to CD38, the improvement of immune activity in a subject (e.g., the expression of neopterin, the expression of complement, the expression of cytokines / chemokines, and the expression of immune-related genes) is associated with the improvement of the effectiveness of cancer treatment (e.g., the improvement of patient survival rate). In some embodiments, the administration of a fusion protein that binds to CD38 increases the expression of cytokines / chemokines. In some embodiments, the administration of a fusion protein that binds to CD38 increases the expression of cytokines / chemokines by at least 2-fold (e.g., at least 3-fold, at least 5-fold, or at least 10-fold). In some embodiments, the administration of a fusion protein that binds to CD38 increases the expression of one or more of the genes IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2, and this increase may indicate an interferon response in the subject (Harari et al., Human Molecular Genetics 24.11 (2015): 3192-3205). In some embodiments, the administration of a fusion protein that binds to CD38 increases the expression of at least 5 of the genes IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2.In some embodiments, administration of a fusion protein that binds to CD38 increases the expression of at least 10 genes, namely IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2. In some embodiments, administration of a fusion protein that binds to CD38 increases the expression of at least 15 genes, namely IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2. In some embodiments, administration of a fusion protein that binds to CD38 increases the expression of at least 20 genes, namely IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2. In some embodiments, administration of a fusion protein that binds to CD38 increases the expression of the genes IFI44L, RSAD2, IFI27, OAS3, IFIT1, IFI44, EPSTI1, HERC5, OAS1, MX1, OAS2, USP18, SPATS2L, IFIT3, OASL, DDX60, LY6E, IFI6, LAMP3, RTP4, HERC6, SERPING1, CMPK2, CXCL10, and IFIT2.

[0064] In some embodiments, improvement of immune cell activity in a subject after administration of a fusion protein that binds to CD38 is associated with improvement in the effectiveness of cancer treatment (e.g., improvement in patient survival rate). In some embodiments, administration of a fusion protein that binds to CD38 to a subject increases the concentration of an antibody against the fusion protein that binds to CD38. In some embodiments, in a subject during administration of a fusion protein that binds to CD38 (e.g., over one or more cycles of administration), the rate at which the concentration of an antibody against the fusion protein that binds to CD38 increases is associated with the effectiveness of cancer treatment. For example, in a subject, the slower the rate of increase in the concentration of an antibody against the fusion protein that binds to CD38, the higher the effectiveness in cancer treatment can be associated compared to when the rate of increase in the concentration of an antibody against the fusion protein that binds to CD38 is fast. In some embodiments, in a subject, the baseline concentration of an antibody against the fusion protein that binds to CD38 can indicate the effectiveness of the fusion protein that binds to CD38 in cancer treatment. For example, in a subject, the lower the baseline concentration of an antibody against the fusion protein that binds to CD38, the higher the effectiveness in cancer treatment can be associated compared to when the baseline concentration of an antibody against the fusion protein that binds to CD38 is high.

[0065] In some embodiments, during and / or after administration of a composition comprising a fusion protein that binds to CD38, a measurable state of minimal residual disease (MRD) in a subject is monitored. MRD may refer to evidence (e.g., detection of cancer cells or cancer DNA in the subject) that cancer (e.g., multiple myeloma or melanoma) persists or recurs in a subject after cancer treatment (e.g., administration of a fusion protein that binds to CD38 or tumor resection). MRD can be detected using any suitable method, including, but not limited to, quantitative polymerase chain reaction (qPCR), flow cytometry, or next-generation sequencing. A negative MRD status may indicate that in the subject, MRD is either absent or not detectable above a threshold. For example, when MRD is not detected at a detection sensitivity of 10 -5 or 10 -6 , the MRD status of the subject can be determined to be negative. In some embodiments, in a subject who has achieved a complete response (e.g., all signs of cancer have disappeared in response to treatment) to treatment with a fusion protein that binds to CD38, when MRD is not detected at a sensitivity of 10 -5 , the MRD status is determined to be negative. In some embodiments, during an administration cycle of a composition comprising a fusion protein that binds to CD38, the rate at which the MRD status becomes negative is measured. In some embodiments, in a subject who has shown a complete response to a composition comprising a fusion protein that binds to CD38, the period during which the MRD status is negative is monitored. In some embodiments, when a subject is being administered a composition comprising a fusion protein that binds to CD38 and is also receiving treatment with an anti-PD-1 antibody, the period during which the MRD status is negative is longer compared to a subject who is being administered a composition comprising a fusion protein that binds to CD38 but not an anti-PD-1 antibody. In some embodiments, the period during which the MRD status is negative is at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years or more.

[0066] In some embodiments, in any one of the methods described herein, the dose of the fusion protein that binds to CD38 is administered (e.g., intravenously) over 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours or more. In some embodiments, the dose of the fusion protein that binds to CD38 is administered for at least 0.5 hours, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours. In some embodiments, the dose of the fusion protein that binds to CD38 is administered over 0.5 - 7 hours, 1 - 7 hours, 2 - 7 hours, 3 - 7 hours, 4 - 7 hours, 5 - 7 hours, 6 - 7 hours or more. In some embodiments, the dose of the fusion protein that binds to CD38 is administered over 0.5 - 4 hours. In some embodiments, the dose of the fusion protein that binds to CD38 is administered over 7 hours or less. In some embodiments, a dose of the fusion protein that binds to CD38 and is 6 mg / kg or less is administered over 1 hour. In some embodiments, a dose of the fusion protein that binds to CD38 and is less than 6 mg / kg (per kg of subject) is administered over 1 hour. In some embodiments, a dose of the fusion protein that binds to CD38 and is 6 mg / kg or more (per kg of subject) is administered over 2 hours. In some embodiments, a dose of the fusion protein that binds to CD38 and is more than 6 mg / kg (per kg of subject) is administered over 2 hours.

[0067] In some embodiments, any one of the methods described herein comprises administering to a subject refractory to standard cancer therapy (e.g., standard therapy for multiple myeloma) or having relapsed after such therapy, a fusion protein that binds to CD38. In some embodiments, the subject is refractory to one or more of an anti-CD38 antibody (e.g., daratumumab or isatuximab), CAR-T cell therapy, anti-BCMA therapy, immunomodulatory agent (IMiD) therapy, proteasome inhibitor therapy, or elotuzumab. In some embodiments, the subject is refractory to the last line of prior treatment.

[0068] In some embodiments, any one of the methods described herein further comprises administering an adrenocortical steroid to a subject. In some embodiments, the adrenocortical steroid is cortisone, prednisone, methylprednisolone, prednisolone, methylprednisolone, dexamethasone, betamethasone, or hydrocortisone. In some embodiments, the adrenocortical steroid is dexamethasone. In some embodiments, the method comprises administering 10 - 50 mg, 10 - 40 mg, 10 - 30 mg, 10 - 20 mg, 20 - 50 mg, 30 - 50 mg, or 35 - 45 mg of dexamethasone to the subject. In some embodiments, the method comprises administering 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of dexamethasone to the subject. In some embodiments, the method comprises administering 40 mg of dexamethasone to a subject who is less than 75 years old. In some embodiments, the method comprises administering 20 mg of dexamethasone to a subject who is 75 years old or older. In some embodiments, the method comprises administering 20 mg of dexamethasone to the subject. In some embodiments, the adrenocortical steroid is methylprednisolone. In some embodiments, the method comprises administering 50 - 150 mg, 50 - 140 mg, 50 - 130 mg, 50 - 120 mg, 75 - 150 mg, 75 - 125 mg, or 90 - 110 mg of methylprednisolone to the subject. In some embodiments, the method comprises administering 50 mg, 75 mg, 90 mg, 95 mg, 100 mg, 105 mg, 115 mg, 125 mg, or 150 mg of methylprednisolone to the subject. In some embodiments, the method comprises administering 100 mg of methylprednisolone to the subject. In some embodiments, when no significant infusion-related reaction (IRR) is observed in the subject, the dose of the adrenocortical steroid may be reduced by half (e.g., from 100 mg of methylprednisolone to 50 mg of methylprednisolone, or from 20 mg of dexamethasone to 10 mg of dexamethasone).In some embodiments, when no significant infusion-related reaction (IRR) is observed in a subject after administering a fusion protein that binds to CD38 three times (i.e., three doses), the dose of the steroid may be reduced by half for the remaining administrations (e.g., from administration 4 to the last administration).

[0069] In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) twice a week. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) once a week. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) once every two weeks. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) once every three weeks. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) together with a fusion protein that binds to CD38. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) to the subject before administering a fusion protein that binds to CD38 to the subject. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) 1 to 2 hours before administering a fusion protein that binds to CD38. In some embodiments, the method includes administering an adrenocortical steroid (e.g., dexamethasone or methylprednisolone) to fight inflammation as needed (e.g., according to a physician's judgment).

[0070] In some embodiments, the method further comprises administering an antihistamine. In some embodiments, the antihistamine is montelukast or diphenhydramine. In some embodiments, 10 - 70 mg, 20 - 60 mg, 25 - 50 mg, 20 - 30 mg or 45 - 55 mg of diphenhydramine (or an equivalent amount of montelukast) is administered to the subject. In some embodiments, 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast) is administered to the subject. In some embodiments, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 45 mg, 50 mg or 55 mg of diphenhydramine (or an equivalent amount of montelukast) is administered to the subject. In some embodiments, 10 mg of montelukast is administered to the subject (e.g., when the subject is intolerant to diphenhydramine or diphenhydramine is not effective for the subject). In some embodiments, the method comprises administering an antihistamine to the subject before and after administering a fusion protein that binds to CD38 to the subject. In some embodiments, the antihistamine is administered 10 - 14 hours before and 0.5 - 3 hours after administering a fusion protein that binds to CD38 to the subject. In some embodiments, the antihistamine is administered 12 hours before and 1 hour after administering a fusion protein that binds to CD38 to the subject. In some embodiments, in the first treatment cycle, the antihistamine is administered 12 hours before and 1 hour after administering a fusion protein that binds to CD38 to the subject, and in cycles after the first cycle (e.g., cycles 2 - 12), the antihistamine is administered 1 hour before and 1 hour after administering a fusion protein that binds to CD38 to the subject. In some embodiments, in the first treatment cycle, the antihistamine is administered 12 hours before and 1 hour after administering a fusion protein that binds to CD38 to the subject, and in cycles after the first cycle (e.g., cycles 2 - 12), the antihistamine is administered 1 hour before administering a fusion protein that binds to CD38 to the subject.

[0071] In some embodiments, the method further comprises administering (or co-administering) an analgesic. In some embodiments, the method comprises administering acetaminophen, which is an analgesic. In some embodiments, acetaminophen is administered to the subject at 500-1200 mg, 600-1200 mg, 700-1200 mg, 800-1200 mg, 900-1200 mg, 500-1100 mg, 500-1000 mg, 500-900 mg, 500-800 mg, 500-700 mg, 500-600 mg. In some embodiments, acetaminophen is administered to the subject at 650-1000 mg. In some embodiments, acetaminophen is administered to the subject at 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg. In some embodiments, acetaminophen is administered to the subject 1-2 hours before administering the fusion protein that binds to CD38. In some embodiments, 650-1000 mg of acetaminophen is administered to the subject 1-2 hours before administering the fusion protein that binds to CD38 to that subject.

[0072] In some embodiments, the method further comprises administering to the subject a non-steroidal anti-inflammatory drug (NSAID) as an analgesic. In some embodiments, the NSAID is aspirin, ibuprofen, naproxen or celecoxib. In some embodiments, aspirin is administered to the subject at 350-650 mg. In some embodiments, ibuprofen is administered to the subject at 200-600 mg. In some embodiments, ibuprofen is administered to the subject at 200-600 mg. In some embodiments, naproxen is administered to the subject at 275-550 mg. In some embodiments, celecoxib is administered to the subject at 100-400 mg.

[0073] In some embodiments, any one of the methods described herein further comprises administering an immune checkpoint inhibitor to a subject. As used herein, the term "immune checkpoint inhibitor" refers to a molecule that globally or partially reduces, inhibits, blocks, or modulates one or more checkpoint proteins. The immune system has multiple inhibitory pathways that function to maintain self-tolerance and regulate the immune response. In T cells, the degree and quality of the response are initiated through antigen recognition by the T cell receptor and are regulated by immune checkpoint proteins that balance co-stimulatory and inhibitory signals. Checkpoint proteins regulate the activation or function of T cells. Checkpoint proteins include, but are not limited to, CTLA-4 and its ligands CD80 and CD86, PD-1 and its ligands PDL1 and PDL2 (Pardoll, Nature Reviews Cancer 12:252-264, 2012), lymphocyte activation gene-3 (LAG-3), such as B7 (e.g., B7-H3 and B7-H4), and TIM3. These proteins are involved in co-stimulatory or inhibitory interactions of the T cell response. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and extent of the physiological immune response. Immune checkpoint inhibitors include, but are not limited to, antibodies or molecules derived from antibodies.

[0074] In some embodiments, the immune checkpoint inhibitor used in any one of the described methods includes an inhibitor against programmed cell death 1 (PD-1). PD-1 restricts the activity of T cells in peripheral tissues during the inflammatory response to infection and to limit autoimmunity. In the mixed lymphocyte reaction, blocking PD-1 in vitro enhances T cell proliferation and cytokine production in response to challenge with a given antigen target or allogeneic cells. A strong correlation was seen between PD-1 expression and efficacy in the state of blocking PD-1 (Pardoll, Nature Reviews Cancer, 12:252-264, 2012). Examples of PD-1 blockers are described in U.S. Patent Nos. 7,488,802, 8,008,449, 8,168,757, and International Publications WO2008 / 156712, WO2010 / 089411, WO2010 / 036959, WO2011 / 159877, and WO2011 / 082400.

[0075] In some embodiments, the PD-1 inhibitor used in any one of the methods described herein is an anti-PD-1 antibody. Non-limiting examples of anti-PD-1 antibodies that can be used in accordance with the present disclosure include pembrolizumab, nivolumab, pidilizumab, and semiprilumab.

[0076] In some embodiments, any one of the methods described herein further comprises administering to a subject an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) together with (e.g., in the same composition) or as a separate administration (e.g., before or after administration of the fusion protein that binds to CD38) a fusion protein that binds to CD38. In some embodiments, the immune checkpoint inhibitor is administered according to a separate dosing schedule from the dosing schedule of the fusion protein that binds to CD38.

[0077] In some embodiments, in any one of the methods described herein, an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) is administered to the subject once every 6 weeks at a dose of 400 mg (e.g., regardless of the subject's body weight). In some embodiments, in any one of the methods described herein, an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) is administered to the subject once every 3 weeks at a dose of 200 mg (e.g., regardless of the subject's body weight).

[0078] In some embodiments, the method described herein comprises administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38 at a dose of 0.1 to 1.5 mg per kg of the subject (e.g., 0.75 mg / kg or 1 mg / kg) once every 3 weeks, and further administering to the subject an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 400 mg once every 6 weeks. In some embodiments, the administration period is at most 2 years. In some embodiments, the method further comprises administering an adrenocortical steroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or NSAID).

[0079] In some embodiments, the methods described herein involve administering to a subject in need thereof (e.g., a subject with melanoma), a composition comprising a fusion protein that binds to CD38, at a dose of 0.1 to 1.5 mg / kg (e.g., 0.75 mg / kg or 1 mg / kg) per kg of the subject, once every three weeks, and further administering to the subject, (e.g., regardless of the subject's weight), an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 200 mg, once every three weeks. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenocortical steroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or NSAID).

[0080] In some embodiments, the methods described herein involve administering to a subject in need of treatment, (e.g., regardless of the subject's weight), a composition comprising 80 mg of a fusion protein that binds to CD38, once every three weeks, and further administering to the subject, (e.g., regardless of the subject's weight), an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 400 mg, once every six weeks. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenocortical steroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or NSAID).

[0081] In some embodiments, the methods described herein involve administering to a subject in need of treatment, a composition comprising a fusion protein that binds to CD38 (e.g., regardless of the subject's weight), once every three weeks at a dose of 120 mg, and further administering to the subject, once every three weeks at a dose of 200 mg, an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) (e.g., regardless of the subject's weight). In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenocortical steroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0082] In some embodiments, the methods described herein involve administering to a subject in need of treatment, a composition comprising a fusion protein that binds to CD38, once every three weeks at a dose of 0.1 to 1.5 mg / kg (e.g., 0.75 mg / kg or 1 mg / kg) per kg of the subject, wherein the subject is or has been treated with an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 400 mg once every six weeks. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenocortical steroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0083] In some embodiments, the method described herein comprises administering to a subject in need of treatment a composition comprising a fusion protein that binds to CD38, at a dose of 0.1 to 1.5 mg per kg of the subject (e.g., 0.75 mg / kg or 1 mg / kg), once every three weeks, wherein the subject has been or is being treated with an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 200 mg, once every three weeks (e.g., regardless of the subject's weight). In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenal corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0084] In some embodiments, the method described herein comprises administering to a subject in need of treatment a composition comprising 80 mg of a fusion protein that binds to CD38, once every three weeks, wherein the subject has been or is being treated with an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 400 mg, once every six weeks (e.g., regardless of the subject's weight). In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenal corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0085] In some embodiments, the methods described herein involve administering to a subject in need of treatment a composition comprising 120 mg of a fusion protein that binds to CD38 once every three weeks (e.g., regardless of the subject's weight), wherein the subject is being or has been treated with an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 200 mg once every three weeks. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenal corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0086] In some embodiments, the methods described herein involve administering to a subject in need of treatment an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 400 mg once every six weeks, wherein the subject is being or has been treated with a composition comprising a fusion protein that binds to CD38 at a dose of 0.1 to 1.5 mg per kg of subject (e.g., 0.75 mg / kg or 1 mg / kg) once every three weeks. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering an adrenal corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0087] In some embodiments, the methods described herein involve administering to a subject in need of treatment an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab), regardless of the subject's weight, at a dose of 200 mg once every three weeks, wherein the subject has been or is being treated once every three weeks with a composition comprising a fusion protein that binds to CD38 at a dose of 0.1 to 1.5 mg per kg of the subject (e.g., 0.75 mg / kg or 1 mg / kg). In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering a corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0088] In some embodiments, the methods described herein involve administering to a subject in need of treatment an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab), regardless of the subject's weight, at a dose of 400 mg once every six weeks, wherein the subject has been or is being treated once every three weeks with a composition comprising 80 mg of a fusion protein that binds to CD38. In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering a corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0089] In some embodiments, the methods described herein involve administering an immune checkpoint inhibitor (e.g., a PD-1 inhibitor such as pembrolizumab) at a dose of 200 mg once every three weeks to a subject in need of treatment (e.g., regardless of the subject's weight), wherein the subject has been or is being treated once every three weeks with a composition containing 120 mg of a fusion protein that binds to CD38 (e.g., regardless of the subject's weight). In some embodiments, the administration period is up to two years. In some embodiments, the method further comprises administering a corticosteroid (e.g., dexamethasone) and an antihistamine (e.g., diphenhydramine) as described herein. In some embodiments, the method further comprises administering at least one analgesic (e.g., acetaminophen or an NSAID).

[0090] In some embodiments, the method involves administering to a subject with a solid tumor (e.g., melanoma) (1) a fusion protein that binds to CD38 at 0.2 - 1.5 mg per kg of the subject, (2) pembrolizumab, (3) methylprednisolone or dexamethasone, (4) acetaminophen or an NSAID, and (5) diphenhydramine or montelukast.

[0091] In some embodiments, the method involves administering to a subject with a solid tumor (e.g., melanoma) (1) a fusion protein that binds to CD38 at 0.2 - 1.5 mg per kg of the subject, (2) 100 - 500 mg of pembrolizumab, (3) 50 - 100 mg of methylprednisolone or 10 - 20 mg of dexamethasone, (4) 650 - 1000 mg of acetaminophen, and (5) 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast). In some embodiments, the fusion protein that binds to CD38 is administered to a subject with a solid tumor (e.g., melanoma) once every three weeks. In some embodiments, pembrolizumab is administered to a subject with a solid tumor (e.g., melanoma) once every six weeks.

[0092] In some embodiments, the method comprises administering to a subject having a solid tumor (e.g., melanoma): (1) a fusion protein that binds to CD38 at 0.2 to 1.5 mg per kg of subject; (2) pembrolizumab at 400 mg; (3) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (4) acetaminophen at 650 to 1000 mg; and (5) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount).

[0093] In some embodiments, the method comprises administering to a subject having a solid tumor (e.g., melanoma): (1) a fusion protein that binds to CD38 at 1 mg per kg of subject; (2) pembrolizumab at 400 mg; (3) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (4) acetaminophen at 650 to 1000 mg; and (5) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount).

[0094] In some embodiments, the method comprises administering to a subject having a solid tumor (e.g., melanoma): (1) a fusion protein that binds to CD38 at 1 mg per kg of subject; (2) pembrolizumab at 400 mg; (3) methylprednisolone at 50 to 100 mg; (4) acetaminophen at 650 to 1000 mg; and (5) diphenhydramine at 25 to 50 mg.

[0095] In some embodiments, the method comprises administering to a subject having a solid tumor (e.g., melanoma): (1) a fusion protein that binds to CD38 at 1 mg per kg of subject; (2) pembrolizumab at 400 mg; (3) dexamethasone at 10 to 20 mg; (4) acetaminophen at 650 to 1000 mg; and (5) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount).

[0096] In some embodiments, the method comprises administering to a subject having a solid tumor (e.g., melanoma): (1) a fusion protein that binds to CD38 at a dose of 1 mg per kg of the subject, wherein the fusion protein that binds to CD38 is administered once every three weeks (e.g., on the first day of a three-week cycle); (2) pembrolizumab at a dose of 400 mg, wherein the pembrolizumab is administered once every six weeks; (3) dexamethasone at a dose of 10 - 20 mg or methylprednisolone at a dose of 50 - 100 mg, wherein the dexamethasone or methylprednisolone is administered 1 - 2 hours before administering the fusion protein that binds to CD38; (4) acetaminophen at a dose of 650 - 1000 mg, wherein the acetaminophen is administered 1 - 2 hours before administering the fusion protein that binds to CD38; and (5) diphenhydramine at a dose of 25 - 50 mg (or montelukast in an equivalent amount), wherein in the first treatment cycle, the diphenhydramine (or equivalent montelukast) is administered 12 hours before and 1 hour after administering the fusion protein that binds to CD38 to the subject, and in cycles after the first cycle (e.g., cycles 2 - 12), the diphenhydramine (or equivalent montelukast) is administered 1 hour before administering the fusion protein that binds to CD38 to the subject. In some embodiments, the fusion protein that binds to CD38 comprises an anti-CD38 antibody comprising a heavy chain complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity-determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity-determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity-determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity-determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the method comprises treating a subject having cancer (e.g., cutaneous melanoma).

[0097] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) a fusion protein that binds to CD38 at 1.5 to 3 mg per kg of subject; (2) methylprednisolone, dexamethasone; (3) acetaminophen or NSAID; and (4) diphenhydramine (or an equivalent amount of montelukast).

[0098] In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at 1.5 to 3 mg per kg of subject, or administering to the subject a fusion protein that binds to CD38 in a dose of 120 to 240 mg. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3 mg per kg of subject. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 in a dose of 120 mg, 160 mg, 190 mg, 210 mg, or 240 mg. In some embodiments, administering a fusion protein that binds to CD38 to a subject having multiple myeloma is performed every four weeks.

[0099] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) a fusion protein that binds to CD38 at 1.5 to 3 mg per kg of subject; (2) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (3) acetaminophen at 650 to 1000 mg; and (4) diphenhydramine at 25 to 50 mg (or an equivalent amount of montelukast).

[0100] In some embodiments, the method comprises administering to a subject with multiple myeloma: (1) a fusion protein that binds to CD38 in an amount of 1.5 to 3 mg per kg of the subject; (2) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (3) acetaminophen at 650 to 1000 mg; and (4) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount).

[0101] In some embodiments, the method comprises administering to a subject with multiple myeloma: (1) a fusion protein that binds to CD38 in an amount of 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3 mg per kg of the subject; (2) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (3) acetaminophen at 650 to 1000 mg; and (4) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount).

[0102] In some embodiments, the method comprises administering to a subject with multiple myeloma: (1) a fusion protein that binds to CD38 in an amount of 1.5 mg per kg of the subject; (2) methylprednisolone at 50 to 100 mg or dexamethasone at 10 to 20 mg; (3) acetaminophen at 650 to 1000 mg; and (4) diphenhydramine at 25 to 50 mg (or montelukast in an equivalent amount). In some embodiments, administering at least 1.5 mg per kg of the subject with multiple myeloma of the fusion protein that binds to CD38 achieves therapeutic efficacy. In some embodiments, administering at least 1.0 mg per kg of the subject with multiple myeloma of the fusion protein that binds to CD38 achieves therapeutic efficacy. In some embodiments, administering more than 0.75 mg per kg of the subject with multiple myeloma of the fusion protein that binds to CD38 achieves therapeutic efficacy.

[0103] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) a fusion protein that binds to CD38 at 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3 mg per kg of subject; (2) methylprednisolone at 50 - 100 mg or dexamethasone at 10 - 20 mg; (3) acetaminophen at 650 - 1000 mg; and (4) diphenhydramine at 25 - 50 mg (or montelukast in an equivalent amount).

[0104] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) a fusion protein that binds to CD38 at 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3 mg per kg of the subject (the fusion protein that binds to CD38 is administered once every 4 weeks (e.g., on day 1 of a 4-week cycle)); (2) dexamethasone at 10 - 20 mg or methylprednisolone at 50 - 100 mg (the dexamethasone or methylprednisolone is administered 1 - 2 hours before administering the fusion protein that binds to CD38); (3) acetaminophen at 650 - 1000 mg (the acetaminophen is administered 1 - 2 hours before administering the fusion protein that binds to CD38); and (4) diphenhydramine at 25 - 50 mg (or montelukast in an equivalent amount) (in the first treatment cycle, the diphenhydramine (or equivalent montelukast) is administered 12 hours before and 1 hour after administering the fusion protein to the subject, and in cycles after the first cycle (e.g., cycles 2 - 12), the diphenhydramine (or equivalent montelukast) is administered 1 hour before administering the fusion protein to the subject). In some embodiments, the fusion protein that binds to CD38 comprises an anti-CD38 antibody comprising a heavy chain complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity-determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity-determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity-determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity-determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.

[0105] In some embodiments, the method comprises administering 120 to 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 60 mg, 80 mg, 120 mg, or 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 120 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering to a subject with multiple myeloma (1) 120 to 240 mg of a fusion protein that binds to CD38, (2) 50 to 100 mg of methylprednisolone or 10 to 20 mg of dexamethasone, (3) 650 to 1000 mg of acetaminophen, and (4) 25 to 50 mg of diphenhydramine (or an equivalent amount of montelukast). In some embodiments, administration to a subject with multiple myeloma is performed every four weeks.

[0106] In some embodiments, the method comprises administering 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, or 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 60 mg, 80 mg, 120 mg, or 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 120 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering 240 mg of a fusion protein that binds to CD38 to a subject with multiple myeloma. In some embodiments, the method comprises administering a fusion protein that binds to CD38 to a subject with multiple myeloma once every four weeks at a certain dosage.

[0107] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, or 240 mg of a fusion protein that binds to CD38, (2) 50 - 100 mg of methylprednisolone or 10 - 20 mg of dexamethasone, (3) 650 - 1000 mg of acetaminophen, and (4) 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast).

[0108] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) 120 mg of a fusion protein that binds to CD38, (2) 50 - 100 mg of methylprednisolone or 10 - 20 mg of dexamethasone, (3) 650 - 1000 mg of acetaminophen, and (4) 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast).

[0109] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) 240 mg of a fusion protein that binds to CD38, (2) 50 - 100 mg of methylprednisolone or 10 - 20 mg of dexamethasone, (3) 650 - 1000 mg of acetaminophen, and (4) 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast).

[0110] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, or 240 mg of a fusion protein that binds to CD38, (2) 50 - 100 mg of methylprednisolone or 10 - 20 mg of dexamethasone, (3) 650 - 1000 mg of acetaminophen, and (4) 25 - 50 mg of diphenhydramine (or an equivalent amount of montelukast).

[0111] In some embodiments, the method comprises administering to a subject having multiple myeloma: (1) a fusion protein that binds to CD38 at 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, and 240 mg (the fusion protein that binds to CD38 is administered once every 4 weeks (e.g., on day 1 of a 4-week cycle)), (2) dexamethasone at 10 - 20 mg or methylprednisolone at 50 - 100 mg (the dexamethasone or methylprednisolone is administered 1 - 2 hours before administering the fusion protein that binds to CD38), (3) acetaminophen at 650 - 1000 mg (the acetaminophen is administered 1 - 2 hours before administering the fusion protein that binds to CD38), and (4) diphenhydramine at 25 - 50 mg (or montelukast in an equivalent amount) (in the first treatment cycle, the diphenhydramine (or equivalent montelukast) is administered 12 hours before and 1 hour after administering the fusion protein that binds to CD38 to the subject; in cycles after the first cycle (e.g., cycles 2 - 12), the diphenhydramine (or equivalent montelukast) is administered 1 hour before administering the fusion protein that binds to CD38 to the subject). In some embodiments, the fusion protein that binds to CD38 comprises an anti-CD38 antibody comprising a heavy-chain complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy-chain complementarity-determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy-chain complementarity-determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light-chain complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light-chain complementarity-determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light-chain complementarity-determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.

[0112] In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at a dose of 1.5 to 6.0 mg per kg of the subject. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at a dose of 3.0 to 6.0 mg per kg of the subject. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at a concentration of 3.0 to 6.0 mg per kg of the subject. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at a dose of 6.0 mg per kg of the subject. In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at a dose of 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, or 5.5 mg per kg of the subject. In some embodiments, administration to a subject having multiple myeloma is performed every four weeks.

[0113] In some embodiments, the method comprises administering to a subject having multiple myeloma a fusion protein that binds to CD38 at 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, or 5.5 mg per kg of the subject, wherein the fusion protein that binds to CD38 is administered once every four weeks (e.g., on day 1 of a four-week cycle), and the fusion protein that binds to CD38 comprises an anti-CD38 antibody comprising a heavy-chain complementarity-determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy-chain complementarity-determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy-chain complementarity-determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light-chain complementarity-determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light-chain complementarity-determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light-chain complementarity-determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the method further comprises administering to the subject a corticosteroid (e.g., dexamethasone). In some embodiments, the method further comprises administering to a subject having multiple myeloma pomalidomide, carfilzomib, daratumumab, lenalidomide, or bortezomib. In some embodiments, when administering carfilzomib, daratumumab, lenalidomide, or bortezomib to a subject having multiple myeloma, 40-100 mg of the fusion protein that binds to CD38 is administered to the subject. In some embodiments, when administering carfilzomib, daratumumab, lenalidomide, or bortezomib to a subject having multiple myeloma, 60 mg, 80 mg, 120 mg, or 240 mg of the fusion protein that binds to CD38 is administered to the subject.

[0114] In some embodiments, a subject with multiple myeloma can tolerate a higher dose of a fusion protein that binds to CD38 compared to a subject with melanoma. In subjects with multiple myeloma, there may be fewer adverse side effects to the fusion protein that binds to CD38 at higher doses compared to subjects with melanoma. In some embodiments, the fusion protein that binds to CD38 has higher therapeutic efficacy at a lower dose in subjects with melanoma compared to subjects with multiple myeloma.

[0115] In some embodiments, a composition comprising a fusion protein that binds to CD38 for use in the methods described herein comprises a buffer (e.g., histidine / histidine-HCl as a buffer), an isotonic agent (e.g., arginine-HCl), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80). The buffer may have stabilizing properties. The isotonic agent may have stabilizing properties. The surfactant may have stabilizing properties.

[0116] In some embodiments, the composition described herein has a pH of 6.0 to 7.0 (e.g., 6.6), contains the fusion protein that binds to CD38 at a concentration of 8 to 12 mg / mL (e.g., 10 mg / ml), contains histidine / histidine-HCl at a concentration of 40 to 60 mM (e.g., 50 mM), contains arginine-HCl at a concentration of 75 to 125 mM (e.g., 100 mM), contains sucrose at a concentration of 30 to 80 mg / ml (e.g., 50 mg / ml), and contains polysorbate 80 at 0.1 to 0.3 mg / ml (e.g., 0.2 mg / ml).

[0117] In some embodiments, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, comprises the fusion protein that binds to CD38 at a concentration of 100 mg / ml or less. In some embodiments, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, comprises the fusion protein that binds to CD38 at a concentration of 8 - 12 mg / ml. For example, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, may comprise the fusion protein that binds to CD38 at a concentration of 8 - 12 mg / ml, 8 - 11.5 mg / ml, 8 - 11 mg / ml, 8 - 10.5 mg / ml, 8 - 10 mg / ml, 8 - 9.5 mg / ml, 8 - 9 mg / ml, 8 - 8.5 mg / ml, 8.5 - 12 mg / ml, 8.5 - 11.5 mg / ml, 8.5 - 11 mg / ml, 8.5 - 10.5 mg / ml, 8.5 - 10 mg / ml, 8.5 - 9.5 mg / ml, 8.5 - 9 mg / ml, 9 - 12 mg / ml, 9 - 11.5 mg / ml, 9 - 11 mg / ml, 9 - 10.5 mg / ml, 9 - 10 mg / ml, 9 - 9.5 mg / ml, 9.5 - 12 mg / ml, 9.5 - 11.5 mg / ml, 9.5 - 11 mg / ml, 9.5 - 10.5 mg / ml, 9.5 - 10 mg / ml, 10 - 12 mg / ml, 10 - 11.5 mg / ml, 10 - 11 mg / ml, 10 - 10.5 mg / ml, 10.5 - 12 mg / ml, 10.5 - 11.5 mg / ml, 10.5 - 11 mg / ml, 11 - 12 mg / ml, 11 - 11.5 mg / ml or 11.5 - 12 mg / ml.In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises the fusion protein that binds to CD38 at a concentration of about 8 mg / ml, about 8.1 mg / ml, about 8.2 mg / ml, about 8.3 mg / ml, about 8.4 mg / ml, about 8.5 mg / ml, about 8.6 mg / ml, about 8.7 mg / ml, about 8.8 mg / ml, about 8.9 mg / ml, about 9 mg / ml, about 9.1 mg / ml, about 9.2 mg / ml, about 9.3 mg / ml, about 9.4 mg / ml, about 9.5 mg / ml, about 9.6 mg / ml, about 9.7 mg / ml, about 9.8 mg / ml, about 9.9 mg / ml, about 10 mg / ml, about 10.1 mg / ml, about 10.2 mg / ml, about 10.3 mg / ml, about 10.4 mg / ml, about 10.5 mg / ml, about 10.6 mg / ml, about 10.7 mg / ml, about 10.8 mg / ml, about 10.9 mg / ml, about 11 mg / ml, about 11.1 mg / ml, about 11.2 mg / ml, about 11.3 mg / ml, about 11.4 mg / ml, about 11.5 mg / ml, about 11.6 mg / ml, about 11.7 mg / ml, about 11.8 mg / ml, about 11.9 mg / ml or about 12 mg / ml. In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises the fusion protein that binds to CD38 at a concentration of about 10 mg / ml.

[0118] In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein has a pH of 5.5 to 7.5. For example, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein may have a pH of 5.5 to 7.5, 5.5 to 7, 5.5 to 6.5, 5.5 to 6, 6 to 7.5, 6 to 7, 6 to 6.5, 6.5 to 7.5, 6.5 to 7, or 7 to 7.5. In some embodiments, the compositions described herein have a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein has a pH of about 6.0 to 7.0 (e.g., 6.0 to 7.0, 6.2 to 7, 6.3 to 6.9, 6.4 to 6.8, or 6.5 to 6.7). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein has a pH of about 6.6.

[0119] A composition comprising a fusion protein that binds to CD38 and is used in the methods as described herein further comprises a buffering agent (e.g., histidine / histidine-HCl as a buffering agent), an isotonicity agent (e.g., arginine-HCl), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80).

[0120] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a buffer comprising histidine and histidine-HCl. In some embodiments, due to the balance between the histidine and histidine-HCl, the final concentration of histidine in the composition is 10 to 120 mM (e.g., 10 to 120 mM, 20 to 110 mM, 30 to 100 mM, 40 to 90 mM, 50 to 80 mM, or 60 to 70 mM). In some embodiments, due to the balance between the histidine and histidine-HCl, the final concentration of histidine in the composition is 12.5 to 107.5 mM. In some embodiments, due to the balance between the histidine and histidine-HCl, the final concentration of histidine in the composition is 15 to 50 mM (e.g., about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM).In some embodiments, due to the balance between the histidine and histidine-HCl, the final concentration of histidine in the composition is about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about 46 mM, about 47 mM, about 48 mM, about 49 mM, about 50 mM, about 51 mM, about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 56 mM, about 57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM, about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about 68 mM, about 69 mM, about 70 mM, about 71 mM, about 72 mM, about 73 mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM, about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about 84 mM, about 85 mM, about 86 mM, about 87 mM, about 88 mM, about 89 mM, about 90 mM, about 91 mM, about 92 mM, about 93 mM, about 94 mM, about 95 mM, about 96 mM, about 97 mM, about 98 mM, about 99 mM, about 100 mM, about 101 mM, about 102 mM, about 103 mM, about 104 mM, about 105 mM, about 106 mM, about 107 mM, about 108 mM, about 109 mM, about 110 mM, about 111 mM, about 112 mM, about 113 mM, about 114 mM, about 115 mM, about 116 mM, about 117 mM, about 118 mM, about 119 mM or about 120 mM of histidine.

[0121] Adjust the relative amounts of histidine and histidine-HCl to maintain the histidine concentration in the composition as described herein, for example, while obtaining a desired pH. In some embodiments, due to the balance between the histidine and histidine-HCl (e.g., when the composition contains a buffer with 7.5 mM concentration of histidine and 7.5 mM concentration of histidine-HCl), the final histidine concentration in the composition is about 15 mM. In some embodiments, due to the balance between the histidine and histidine-HCl (e.g., when the composition contains a buffer with 40 mM concentration of histidine and 10 mM concentration of histidine-HCl), the final histidine concentration in the composition is about 50 mM.

[0122] In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains an isotonic agent comprising arginine-HCl. In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains arginine-HCl at a concentration of 50-125 mM (e.g., 50-125 mM, 60-120 mM, 70-110 mM, 80-100 mM, 75-125 mM, 95-105 mM, or 97.5-102.5 mM). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains arginine-HCl at a concentration of about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, or about 120 mM. In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains arginine-HCl at a concentration of about 100 mM.

[0123] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a stabilizer. In some embodiments, the stabilizer is a sugar. In some embodiments, the stabilizer is sucrose. In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises sucrose at a concentration of 3 to 10% (w / v) (corresponding to 30 to 100 mg / ml).For example, the composition described in this specification may contain sucrose at a concentration of 3 to 10% (w / v) (corresponding to 30 to 100 mg / ml), 3 to 9% (w / v) (corresponding to 30 to 90 mg / ml), 3 to 8% (w / v) (corresponding to 30 to 80 mg / ml), 3 to 7% (w / v) (corresponding to 30 to 70 mg / ml), 3 to 6% (w / v) (corresponding to 30 to 60 mg / ml), 3 to 5% (w / v) (corresponding to 30 to 50 mg / ml), 3 to 4% (w / v) (corresponding to 30 to 40 mg / ml), 3 to 10% (w / v), 3 to 9% (w / v), 3 to 8% (w / v), 3 to 7% (w / v), 3 to 6% (w / v), 3 to 5% (w / v), 3 to 4% (w / v), 4 to 10% (w / v) (corresponding to 40 to 100 mg / ml), 4 to 9% (w / v) (corresponding to 40 to 90 mg / ml), 4 to 8% (w / v) (corresponding to 40 to 80 mg / ml), 4 to 7% (w / v) (corresponding to 40 to 70 mg / ml), 4 to 6% (w / v) (corresponding to 40 to 60 mg / ml), 4 to 5% (w / v) (corresponding to 40 to 50 mg / ml), 5 to 10% (w / v) (corresponding to 50 to 100 mg / ml), 5 to 9% (w / v) (corresponding to 50 to 90 mg / ml), 5 to 8% (w / v) (corresponding to 50 to 80 mg / ml), 5 to 7% (w / v) (corresponding to 50 to 70 mg / ml), 5 to 6% (w / v) (corresponding to 50 to 60 mg / ml), 6 to 10% (w / v) (corresponding to 60 to 100 mg / ml), 6 to 9% (w / v) (corresponding to 60 to 90 mg / ml), 6 to 8% (w / v) (corresponding to 60 to 80 mg / ml), 5 to 7% (w / v) (corresponding to 60 to 70 mg / ml), 7 to 10% (w / v) (corresponding to 70 to 100 mg / ml), 7 to 9% (w / v) (corresponding to 70 to 90 mg / ml), 7 to 8% (w / v) (corresponding to 60 to 80 mg / ml), 8 to 10% (w / v) (corresponding to 80 to 100 mg / ml), 8 to 9% (w / v) (corresponding to 80 to 90 mg / ml), or 9 to 10% (w / v) (corresponding to 90 to 100 mg / ml).

[0124] In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains sucrose at a concentration of about 3% (w / v) (corresponding to 30 mg / mL), about 3.5% (w / v) (corresponding to 35 mg / mL), about 4% (w / v) (corresponding to 40 mg / mL), about 4.5% (w / v) (corresponding to 45 mg / mL), about 5% (w / v) (corresponding to 50 mg / mL), about 5.5% (w / v) (corresponding to 55 mg / mL), about 6% (w / v) (corresponding to 60 mg / mL), about 6.5% (w / v) (corresponding to 65 mg / mL), about 7% (w / v) (corresponding to 70 mg / mL), about 7.5% (w / v) (corresponding to 75 mg / mL), about 8% (w / v) (corresponding to 80 mg / mL), about 8.5% (w / v) (corresponding to 85 mg / mL), about 9 (w / v) (corresponding to 90 mg / mL), about 9.5% (w / v) (corresponding to 95 mg / mL) or about 10% (w / v) (corresponding to 100 mg / ml). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains sucrose at a concentration of about 4% - 8% (w / v) (corresponding to 40 - 80 mg / mL). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains sucrose at a concentration of about 4% - 7% (w / v) (corresponding to 40 - 70 mg / mL). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains sucrose at a concentration of about 4% - 6% (w / v) (corresponding to 40 - 60 mg / mL). In some embodiments, a composition comprising a fusion protein that binds to CD38 and is used in the methods described herein contains sucrose at a concentration of about 4.5% - 5.5% (w / v) (corresponding to 45 - 55 mg / mL).In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises sucrose at a concentration of about 4% (w / v) (corresponding to 40 mg / ml), about 5% (w / v) (corresponding to 50 mg / ml), about 6% (w / v) (corresponding to 60 mg / ml), about 7% (w / v) (corresponding to 70 mg / ml), or about 8% (w / v) (corresponding to 80 mg / ml). In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises sucrose at a concentration of about 5% (w / v) (corresponding to 50 mg / ml).

[0125] In some embodiments, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, comprises a surfactant. In some embodiments, the surfactant is polysorbate. In some embodiments, the surfactant is polysorbate 80 (PS80). In some embodiments, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, comprises PS80 at a concentration of 0.005 to 0.03% (w / v) (corresponding to 0.05 to 0.3 mg / ml). For example, a composition comprising a fusion protein that binds to CD38, which is used in the methods described herein, may comprise PS80 at a concentration of 0.005 to 0.03% (w / v) (corresponding to 0.05 to 0.3 mg / ml), 0.005 to 0.025% (w / v) (corresponding to 0.05 to 0.25 mg / ml), 0.005 to 0.02% (w / v) (corresponding to 0.05 to 0.2 mg / ml), 0.005 to 0.015% (w / v) (corresponding to 0.05 to 0.15 mg / ml), 0.005 to 0.01% (w / v) (corresponding to 0.05 to 0.1 mg / ml), 0.01 to 0.03% (w / v) (corresponding to 0.1 to 0.3 mg / ml), 0.01 to 0.025% (w / v) (corresponding to 0.1 to 0.25 mg / ml), 0.01 to 0.02% (w / v) (corresponding to 0.1 to 0.2 mg / ml), 0.01 to 0.015% (w / v) (corresponding to 0.1 to 0.15 mg / ml), 0.015 to 0.03% (w / v) (corresponding to 0.15 to 0.3 mg / ml), 0.015 to 0.025% (w / v) (corresponding to 0.15 to 0.25 mg / ml), 0.015 to 0.02% (w / v) (corresponding to 0.15 to 0.2 mg / ml), 0.02 to 0.03% (w / v) (corresponding to 0.2 to 0.3 mg / ml), 0.02 to 0.025% (w / v) (corresponding to 0.2 to 0.25 mg / ml), 0.02 to 0.03%, 0.02 to 0.025% or 0.025 to 0.03% (w / v) (corresponding to 0.25 to 0.3 mg / ml).In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises PS80 at a concentration of about 0.007% (w / v) (corresponding to 0.07 mg / mL), 0.008% (w / v) (corresponding to 0.08 mg / mL), 0.009% (w / v) (corresponding to 0.09 mg / mL), 0.01% (w / v) (corresponding to 0.1 mg / mL), 0.011% (w / v) (corresponding to 0.11 mg / mL), 0.012% (w / v) (corresponding to 0.12 mg / mL), 0.013% (w / v) (corresponding to 0.13 mg / mL), 0.014% (w / v) (corresponding to 0.14 mg / mL), 0.015% (w / v) (corresponding to 0.15 mg / mL), 0.016% (w / v) (corresponding to 0.16 mg / mL), 0.017% (w / v) (corresponding to 0.17 mg / mL), 0.018% (w / v) (corresponding to 0.18 mg / mL), 0.019 (w / v) (corresponding to 0.19 mg / mL) or 0.02% (w / v) (corresponding to 0.2 mg / mL). In some embodiments, the compositions described herein comprise PS80 at a concentration of about 0.01% - 0.03% (w / v) (corresponding to 0.1 - 0.3 mg / mL). In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises PS80 at a concentration of about 0.015% - 0.025% (w / v) (corresponding to 0.15 - 0.25 mg / mL). In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises PS80 at a concentration of about 0.02% (w / v) (corresponding to 0.2 mg / ml).

[0126] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a fusion protein that binds to CD38 (e.g., a fusion protein that binds to CD38, such as the fusion proteins shown in Table 1) at a concentration of 8.5 to 11.5 mg / ml (e.g., 10 mg / ml), histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 15 to 60 mM (e.g., 15 mM, 20 mM, 30 mM, 40 mM or 50 mM), arginine-HCl at a concentration of 80 to 120 mM (e.g., 100 mM), sucrose at a concentration of 3 to 8% (w / v) (e.g., 5% (w / v)), PS80 at a concentration of 0.01 to 0.03% (w / v) (e.g., 0.02% (w / v)), and the composition has a pH of 5.5 to 7.5 (e.g., 5.5, 6, 6.5 or 6.6). In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0127] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a fusion protein that binds to CD38 (e.g., a fusion protein that binds to CD38, such as the fusion proteins shown in Table 1) at a concentration of 10 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50 mM, arginine-HCl at a concentration of 100 mM, sucrose at a concentration of 5% (w / v), PS80 at a concentration of 0.02% (w / v), and the composition has a pH of 6.6. In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0128] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a fusion protein that binds to CD38 (e.g., a fusion protein that binds to CD38, such as the fusion proteins shown in Table 1) at a concentration of 10 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 15 mM, arginine-HCl at a concentration of 100 mM, sucrose at a concentration of 5% (w / v), PS80 at a concentration of 0.02% (w / v), and the composition has a pH of 6. In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0129] In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, comprises a fusion protein that binds to CD38 (e.g., a fusion protein that binds to CD38, such as the fusion proteins shown in Table 1) at a concentration of about 30-100 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of about 50-75 mM (e.g., 50 mM), arginine-HCl at a concentration of about 75-150 mM (e.g., 100 mM), sucrose at a concentration of about 3-10% (w / v) (e.g., 5% (w / v)), PS80 at a concentration of about 0.01-0.06% (w / v) (e.g., 0.02% (w / v)), and the composition has a pH of about 6.0-7.0 (e.g., 6.5-6.7). In some embodiments, the fusion protein that binds to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, a composition comprising a fusion protein that binds to CD38, the composition for use in the methods described herein, is an aqueous solution.

[0130] In some embodiments, the compositions described herein (e.g., in aqueous solution form or lyophilized form) are stored in unit dosage form. In some embodiments, the lyophilized form of the compositions described herein is stored for at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years or at least 3 years. In some embodiments, the compositions described herein (e.g., in aqueous solution form or lyophilized form) are stored frozen.

[0131] In some embodiments, the methods described herein are effective for treating cancer in a patient. Treatments may include, for example, inhibiting or reducing the proliferation of CD38-positive cells and / or inducing apoptosis of CD38-positive cells in the cancer.

[0132] The terms "subject" and "patient" are used interchangeably and include any mammal, including companion and farm mammals, rodents including mice, rabbits and rats, and other rodents. Non-human primates, such as cynomolgus monkeys, are more preferred and humans are highly preferred. In some embodiments, the subject is human. In some embodiments, the subject is an adult human (e.g., 18 years of age or older). In some embodiments, the subject is a minor human (e.g., less than 18 years of age).

[0133] The terms "treatment", "treating", "treat" and the like refer to obtaining a desired pharmacological and / or physiological effect. This effect may be prophylactic in terms of completely or partially preventing a disease or its symptoms, or reducing the likelihood of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or the adverse effects resulting from the disease. "Treatment", as used herein, encompasses any treatment of a disease in a mammal, particularly a human, and includes (a) preventing the onset of a disease in a subject who may have a predisposition to the disease but has not yet been diagnosed as having the disease, (b) inhibiting the disease, i.e., arresting its development or progression, and (c) alleviating the disease, i.e., causing regression of the disease and / or alleviating one or more of the symptoms of the disease. "Treatment" is also intended to include the delivery of an agent to effect a pharmacological effect even in the absence of a disease or condition.

[0134] Any one of the methods described in this specification is suitable for the treatment of cancer. In some embodiments, the cancer is a CD38-expressing cancer. In some embodiments, the cancer is not a CD38-expressing cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is a metastatic solid tumor that expresses CD38. Tumors that can be treated include, but are not limited to, colorectal cancer, cholangiocarcinoma, bone cancer, gastroesophageal cancer, pancreatic cancer, renal cancer, melanoma, anal cancer, uterine cancer, liver cancer, sarcoma, breast cancer, bladder cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, or gastric cancer. In some embodiments, the cancer is metastatic melanoma, metastatic non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, metastatic urothelial cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, triple-negative breast cancer, high-risk non-muscle-invasive bladder cancer, advanced urothelial cancer, Merkel cell carcinoma, high-frequency microsatellite instability cancer, and cutaneous squamous cell carcinoma. In some embodiments, the cancer is melanoma (e.g., advanced or metastatic melanoma). In some embodiments, the cancer is advanced non-small cell lung cancer. In some embodiments, the cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is high-risk non-muscle-invasive bladder cancer. In some embodiments, the cancer is advanced urothelial cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is advanced MSI-H / dMMR colorectal cancer. In some embodiments, the cancer is high-frequency microsatellite instability cancer. In some embodiments, the cancer is high-risk early triple-negative breast cancer. In some embodiments, the cancer is advanced triple-negative breast cancer. In some embodiments, the cancer is advanced gastric cancer. In some embodiments, the cancer is advanced cervical cancer. In some embodiments, the cancer is advanced MSI-H / dMMR endometrial cancer. In some embodiments, the cancer is advanced liver cancer. In some embodiments, the cancer is advanced Merkel cell carcinoma. In some embodiments, the cancer is advanced esophageal cancer.In some embodiments, the cancer is squamous cell carcinoma of the skin. In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is Hodgkin lymphoma (e.g., nodular sclerosis Hodgkin lymphoma (NSCH), mixed cellularity Hodgkin lymphoma (MCCHL), lymphocyte-rich Hodgkin lymphoma or lymphocyte-depleted Hodgkin lymphoma). In some embodiments, the lymphoma is non-Hodgkin lymphoma (e.g., T-cell lymphoma, B-cell lymphoma, NK-cell lymphoma or primary cutaneous lymphoma).

Example

[0135] Example 1: An open-label, dose-escalation Phase 1b study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of a fusion protein that binds to CD38, as a single agent and in combination with pembrolizumab, in adult patients with progressive or metastatic solid tumors

[0136] Background CD38 is a multifunctional ectoenzyme involved in cell adhesion and transmembrane signaling. CD38 is overexpressed in various types of tumors and is thought to be involved in tumor cell migration and metastasis. CD38 is a transmembrane glycoprotein of approximately 45 kDa that is expressed by immature hematopoietic cells, downregulated in mature cells, and re-expressed at higher levels by activated lymphocytes, such as T cells, B cells, dendritic cells and natural killer (NK) cells.

[0137] Early myeloid cells are essential for long-term (sustained) bone marrow recovery and do not express CD38, but myeloid lineage committed progenitor cells, B cells in germinal centers, terminally differentiated plasma cells and activated tonsils are CD38+.

[0138] CD38 is expressed in hematopoietic progenitor plasma cells in the bone marrow. In the bone marrow, CD38 functions during homing and apoptosis and is regarded as a marker of progenitor cell commitment. CD38 is seen throughout thymic development in thymic tissue. CD38 is expressed in germinal center B cells in the spleen and lymph nodes and functions in the spleen and lymph nodes to escape apoptosis. CD38 is expressed in T cells, B cells, NK cells, monocyte subsets, platelets, erythrocytes, and hematopoietic progenitor plasma cells and interacts with endothelial cells in these cells. CD38 is expressed in intraepithelial lymphocytes and lamina propria lymphocytes in the intestine and functions in mucosal immunity in the intestine. CD38 is expressed in Purkinje cells, is seen in neurofibrillary changes in the brain, and functions in the memory process in the brain. CD38 is expressed in epithelial cells of the prostate. CD38 is expressed in pancreatic β cells and functions in insulin secretion in the pancreas. CD38 is expressed in osteoclasts in bone tissue and functions in bone resorption in bone tissue. CD38 is expressed in retinal cells of the eye and functions in the visual process in the eye. CD38 is expressed in the sarcolemma of smooth and striated muscle and functions in muscle contraction in these muscles. CD38 is also seen in soluble forms in normal and pathological body fluids.

[0139] A fusion protein that binds to CD38, wherein the fusion protein evaluated in this test is a recombinant humanized immunoglobulin (Ig) G4 monoclonal antibody against CD38 fused to two attenuated interferon-α2b (IFNα2b) molecules. The amino acid sequence of the fusion protein that binds to CD38 is shown in Table 1 (heavy chain of SEQ ID NO: 13 and light chain of SEQ ID NO: 10). The fusion protein that binds to CD38 was prepared in a mammalian cell expression system by recombinant DNA technology and purified by a process including an inactivation step and a removal step of a predetermined virus. Since the CD38 antibody portion of the fusion protein that binds to CD38 induces the attenuated IFNα2b portion into CD38-expressing (CD38+) cells, the local concentration of IFNα2b is increased on the surface of these target cells. In CD38-negative cells, due to the resulting attenuation, the potency is approximately 1 / 130,000 compared to IFNα2b.

[0140] The fusion protein that binds to CD38 has high binding affinity (dissociation constant [K D ) for human and cynomolgus monkey CD38, and its K D is 168 pM for humans and 1.25 nM for cynomolgus monkeys. The fusion protein that binds to CD38 potently inhibits the proliferation of CD38+ multiple myeloma (MM) cells (half-maximal inhibitory concentration [IC50]: 19.9 pM), and its efficacy in CD38-negative cells is approximately 1 / 2500. Since the antibody portion of the fusion protein that binds to CD38 is of the IgG4 isotype (different from the IgG1 isotype of daratumumab), it has limited effector functions to induce antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis, or complement activation against normal CD38+ cells. The fusion protein that binds to CD38, unlike daratumumab, does not regulate the adenosine diphosphate-ribosyl cyclase activity of CD38.

[0141] A promising moiety to conjugate to an anti-CD38 monoclonal antibody (mAb) is interferon-α (IFNα), a cytokine that is currently approved but little used for maintenance therapy of multiple myeloma (MM), metastatic melanoma, follicular lymphoma, or hairy cell leukemia. IFNα has a direct inhibitory effect on some tumors and is a potent stimulator of both the innate and adaptive immune systems.

[0142] However, the systemic toxicity of IFN-α has precluded its use at therapeutically effective doses in the majority of patients. The fusion protein that binds to CD38 is thought to limit the binding of the attenuated IFNα to receptors on CD38 non-expressing cells by reducing its binding affinity for the IFNα receptor. In contrast, when the fusion protein that binds to CD38 binds with high affinity via its CD38-targeting moiety, it is thought to induce activation of the desired on-target interferon (IFN) pathway by increasing the local concentration of the attenuated IFNα on CD38+ target cells.

[0143] By comparison, interferon-α2b (Intron A) binds to the CD38-binding fusion protein and has comparable efficacy on CD38+ cells (IC 50 : 12.3 pM), but is approximately 130,000-fold more potent than the CD38-binding fusion protein on CD38-negative cells (EC 50 [half-maximal effective concentration]: approximately 0.37 pM).

[0144] Among the CD38-binding fusion proteins, a complete and robust anti-tumor response has been previously observed in an MM model after treatment with a fusion protein containing a recombinant humanized immunoglobulin (Ig) G4 monoclonal antibody against CD38 fused to two attenuated interferon-α2b (IFNα2b) molecules in an IFNα-sensitive xenograft model expressing CD38. The anti-tumor activity was driven by the direct anti-proliferative activity of IFNα and the indirect activation of subsets of innate immune cells (including M1 macrophages and NK cells).

[0145] Further studies were conducted to evaluate the activity of a murine cross-reactive surrogate of the CD38-binding fusion protein (i.e., mIgG1 murine Attenukine against murine CD38 [mCD38-mATT]) in a murine tumor model that does not express CD38 and has mild IFNα sensitivity in immunocompetent mice. The data indicate that significant anti-tumor activity was observed with this surrogate compared to the non-targeted mATT control (Figure 1A). In addition, pharmacodynamic analysis revealed significant activation of dendritic cells (as indicated by increased expression of the surface activation markers CD86 (Figure 1B) and CD205 (Figure 1C)). In addition, administration of the CD38-binding fusion protein increased the expression of NKp46 in NK cells (Figure 1D) and Ki67 in T cells (Figure 1E). These results indicate that the CD38-binding fusion protein improved the proliferative capacity of CD8+ T cells after treatment with mCD38-mATT.

[0146] Study design and results A non-blind Phase 1b / 2 trial was designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor response of a fusion protein that binds to CD38, as a single agent (SA) and in combination with pembrolizumab, in patients with progressive or metastatic solid tumors.

[0147] In the Phase 1b trial, patients with progressive / metastatic solid tumors who had no standard treatment options, were intolerant to those therapies, or had refused those therapies were enrolled.

[0148] Each patient had to meet all of the following inclusion criteria to be enrolled in this trial. 1) Adult male or adult female patients 18 years of age or older. 2) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 3) Life expectancy of more than 12 weeks as determined by the principal investigator of the study. 4) Phase 1b dose escalation trial: Eligible patients must have histologically confirmed progressive (recurrent in the local area and not amenable to curative therapy) or metastatic solid tumors. 5) Measurable disease according to mRECIST v1.1. For enrollment in the Phase 1b trial, at least 1 target lesion suitable for biopsy is required. For enrollment in the Phase 2 trial, at least 1 target lesion for efficacy assessment is required. For enrollment in the Phase 2 trial, in all patients (safety lead-in and expansion) in cohorts I and II, and subgroup III melanoma after futility analysis, another lesion suitable for biopsy is required. 6) Phase 1b dose escalation trial: Patients with histologically confirmed locally progressive (recurrent in the local area and not amenable to curative therapy) or metastatic solid tumors.

[0149] Patients who met any of the following exclusion criteria were not enrolled in the trial. 1) Prior to 28 days or 5 half-lives before the administration of the fusion protein that binds to CD38, whichever is the earlier time point (the washout period is 3 weeks if there has been a major surgery in the past, and 2 weeks if there has been prior definitive radiotherapy (including chemoradiotherapy and whole brain radiotherapy)), and within 5 days from the last treatment with stereotactic radiotherapy in the case of symptomatic metastases, the patient was treated with any standard treatment or an anticancer investigational drug. 2.) Toxicity persisted from past treatment that did not improve to Grade 1 or lower according to CTCAE v.5 until prior to the administration of the fusion protein that binds to CD38, except for alopecia, Grade 2 neuropathy, and Grade 2 asthenia / fatigue. 3) Six months before the first administration of the fusion protein that binds to CD38, the patient had a history of any of New York Heart Association Grade III or IV congestive heart failure, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, any ongoing symptomatic cardiac arrhythmia of Grade 2 or higher, pulmonary embolism, symptomatic cerebrovascular event, or any other serious cardiac condition (e.g., symptomatic pericardial effusion or restrictive cardiomyopathy). (Chronic stable atrial fibrillation receiving stable anticoagulation therapy (including low molecular weight heparin) is permitted.) 4) The baseline QTcF was 480 msec or higher (Grade 2 or higher), and there was a history of congenital long QT syndrome or torsades de pointes. 5) There was a history of immune-related AEs related to past treatment with CPI that required treatment discontinuation (Phase 2). 6) A psychiatric / social environment that limits compliance with study requirements and substantially increases the risk of AEs or weakens the ability to provide written informed consent. 7) At the time of administration of the first dose of the fusion protein that binds to CD38, there was a history of uncontrolled brain metastases or metastases that had been previously treated and had received adrenal corticosteroids at a dose of 20 mg / day or higher (in terms of prednisone equivalent) (Note: Excluding patients with carcinomatous meningitis or leptomeningeal disease regardless of clinical stability). 8) The patient is a patient with uveal (ocular) melanoma or mucosal melanoma (Phase 2). 9) An ongoing or active infection.10) There is a known history of HIV infection, or any other related congenital or acquired immunodeficiency. 11) It is known that the hepatitis B (HBV) surface antigen is seropositive, or the amount of hepatitis C virus infection is detectable (Note: Patients who are positive for HBV core antibody can be enrolled, but the amount of hepatitis B virus must be undetectable). 12) It is an autoimmune disease that requires systemic immunosuppressive therapy (Patients with immune-mediated endocrine insufficiency due to past therapy with stable hormone replacement are exceptions). 13) There is a history of severe allergic reaction or anaphylactic reaction to the fusion protein that binds to CD38 or the recombinant protein or excipient used in the pembrolizumab formulation. 14) Female patients who are secreting breast milk and / or breastfeeding during the screening period, or are positive in a serum pregnancy test.

[0150] The dose escalation phase of the fusion protein that binds to CD38 as a single agent was designed to determine the recommended phase II dose (RP2D) of that single agent and the schedule for further testing of the fusion protein that binds to CD38. The RP2D of that single agent may be any maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT) or pharmacologically active dose (PAD) appropriately defined by PK / pharmacodynamic models or exposure-response (ER) analysis.

[0151] Adult patients with progressive / metastatic solid tumors were administered the fusion protein that binds to CD38 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg / kg and was advanced based on the safety data of cycle 1 through a Bayesian flow model using the principle of overdose control. In the escalation phase, 21 patients were administered at 0.1 mg / kg (n = 3), 0.2 mg / kg (n = 3), 0.4 mg / kg (n = 3), 0.75 mg / kg (n = 3), 1.0 mg / kg (n = 3), and 1.5 mg / kg (n = 6), Q3W. The median age of the patients was 63 years (range: 42 - 80 years). 57.1% of the patients were male. 71.4% of the patients had gastrointestinal malignancies. The median number of prior treatment lines was 3 (range: 2 - 7).

[0152] A fusion protein that binds to CD38. In the starting dose cohort of the fusion protein administered at 0.1 mg / kg every 3 weeks (Q3W), at least 3 patients were enrolled. The patients were administered the fusion protein that binds to CD38 at doses of 0.1 mg, 0.2 mg, 0.4 mg, 0.75 mg, or 1.5 mg per kg of the subject's body weight on day 1 of cycle 1 (C1D1, the start of the dose escalation phase (1b)). The patients were treated with multiple cycles of treatment, and each cycle was 21 days. Up to day 1 of cycle 2 (C2D1), the DLT of the patients was evaluated from a safety perspective. In the first cohort consisting of 3 evaluable patients administered at 0.1 mg / kg, when no DLT was observed, a Bayesian logistic regression model (BLRM) guided by the principle of escalation with overdose control (EWOC) was used in the subsequent dose escalation cohorts to estimate the next dose level. More conservative dose escalations, evaluation of intermediate doses, and expansion of existing dose levels were allowed when such measures were necessary for the safety of the patients or to gain a deeper understanding of dose-related toxicity, exposure, or pharmacodynamics. Approximately 30 patients were enrolled until either the MTD and / or PAD was identified.

[0153] Patients diagnosed with various cancers were treated with the fusion protein that binds to CD38 for 1 to 11 cycles according to the type of cancer and disease progression (Figure 2). Among the 14 patients in whom response could be evaluated, 7 patients had the best effect of disease stabilization, including 1 patient with cutaneous melanoma with a 23% reduction in target lesions (Figures 3A and 3B).

[0154] In two patients, dose-limiting toxicity was observed at 1.5 mg / kg in cycle 1. In one patient with baseline bone infiltration, grade 4 thrombocytopenia was seen, and in one patient, grade 3 delirium was seen. Across all doses, patients received a median of 2 treatment cycles (range: 1 - 11 cycles). Treatment-related adverse events (TRAEs) associated with the fusion protein binding to CD38, which were reported in 81% of patients, included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade 3 or higher TRAEs, reported in 42.9% of patients, included neutropenia (9.5%) and hypertension (9.5%). In addition, in most patients, platelet and neutrophil counts transiently decreased and rapidly recovered to baseline by the end of each cycle. No clear relationship was observed between the dose of the fusion protein binding to CD38 and the degree of decrease in platelet and neutrophil counts.

[0155] The pharmacokinetics and immunogenicity in patients were determined by administration of the fusion protein binding to CD38. The serum concentration of the fusion protein binding to CD38 was generally measurable up to 6 hours (0.1 mg / kg), 24 hours (0.2 mg / kg), 48 hours (0.4 mg / kg), and 72 hours (0.75 mg / kg, 1.0 mg / kg, and 1.5 mg / kg) after the end of infusion. The inter-patient AUC variability was moderate to high in all dosing groups. The 0.1 - 1.5 mg / kg dose range had a higher dose-proportional increase in exposure, and there was no accumulation of exposure after administration Q3W. The accumulation ratio of the area under the plasma concentration-time curve (AUC) (i.e., the time curve from time 0 to the last quantifiable concentration) was generally less than 1 across all dose groups. In cycle 1, the geometric half-life ranged from approximately 1 hour (0.1 mg / kg) to 16 hours (1.5 mg / kg). The incidence of anti-drug antibodies after treatment was 100% (Figures 4A and 4B).

[0156] To further characterize the effect of administering a fusion protein that binds to CD38 to patients, we analyzed CD38 receptor occupancy (RO), type I interferon gene signature score, activation of the interferon pathway via systemic cytokine concentrations mediated by interferon α, and the frequency and activation of innate and adaptive immune cells. Dose-dependent saturation of CD38 receptor occupancy was observed (Figure 5A). In addition, administration of the fusion protein that binds to CD38 as a single agent induced the type I IFN gene signature score (Figure 5B). Administration of SA also produced a lineage of cytokines and chemokines mediated by IFNα (Figure 5C). Further analysis showed that treatment with the fusion protein that binds to CD38 resulted in the expression of CD69 in CD8+ T cells (Figure 6A) and the expression of CD69 and granzyme B in NK cells (Figure 6B). Pharmacodynamic data suggest that at 0.2 mg / kg and above, the regulatory peak of the IFN pathway is achieved in peripheral blood and the regulatory period becomes longer with increasing dose.

[0157] Of the 14 patients in whom response could be evaluated, 7 had the best effect of disease stabilization, including 1 patient with cutaneous melanoma who had a 21% decrease in target lesions.

[0158] In conclusion, these results showed that in the fusion protein that binds to CD38, a manageable safety profile was seen in solid tumor patients in the dose range of 0.10 - 1.50 mg / kg. PD data suggest that the regulatory peak of the IFN pathway saturates in peripheral blood at dose levels of 0.2 mg / kg and above, and the regulatory period becomes longer with increasing dose. Of the 14 patients in whom response could be evaluated, 7 had the best effect of disease stabilization, including 1 patient with cutaneous melanoma who had a 21% decrease in target lesions. The recommended phase 2 single-agent dose was determined to be 1.00 mg / kg Q3W, and the pharmacologically active dose range was 0.10 - 1.50 mg / kg Q3W.

[0159] Example 2: Phase 2 dose escalation study In patients with solid tumors, a manageable safety profile was observed in the dose range of 0.1 - 1.5 mg / kg for the fusion protein that binds to CD38. The Phase 2 recommended dose was determined to be 1.0 mg / kg Q3W based on the evaluation of holistic data, and is tested as a single agent and in combination with a checkpoint inhibitor (pembrolizumab) in certain types of tumors. Pembrolizumab is a humanized immunoglobulin G4 (IgG4) mAb that inhibits the interaction with PD-L1 and programmed cell death protein 2 ligand (PD-L2) because of its high specificity for binding to the PD-1 receptor. Preclinical data showed high affinity and potent receptor blocking activity against PD-1. Pembrolizumab has an acceptable clinical safety profile as an intravenous immunotherapy agent for advanced malignancies. Pembrolizumab has been approved for treatment across multiple indications.

[0160] Figure 7 shows the study design of the Phase 2 dose escalation stage. The Phase 2 trial starts with a safety lead-in period for all patients. After the safety lead-in period, patients are divided into three cohorts: (1) patients with unresectable / metastatic cutaneous melanoma who are primary refractory to less than 2 lines of prior therapy including anti-PD1, (2) patients with unresectable / metastatic cutaneous melanoma who are acquired refractory to less than 2 lines of prior therapy including anti-PD1, and (3) patients with unresectable / metastatic cutaneous melanoma who are naive to less than 2 lines of prior therapy including anti-PD1.

[0161] One safety lead-in period is to evaluate safety and tolerability during the DLT evaluation period of Cycle 1 of the fusion protein binding to CD38 and pembrolizumab. In the safety lead-in period, in the first three patients, if no DLT is seen in Cycle 1 of the safety lead-in period when the P2D (1 mg / kg Q3W) of the fusion protein SA binding to CD38 is combined with pembrolizumab 400 mg Q6W, three cohorts of patients will be treated with this combination dosage and regimen. If one DLT is seen in the safety lead-in period in the first three patients, an additional three patients will be enrolled in the combination of the fusion protein binding to CD38, which is the same RP2D (1 mg / kg Q3W) fusion protein, and pembrolizumab 400 mg Q6W. If two or more DLTs are seen in the first three patients with the RP2D (1 mg / kg Q3W) of the fusion protein SA binding to CD38, the registration will be restarted with the combination of the next lower dosage level of the RP2D of the fusion protein binding to CD38 (for example, 0.75 mg / kg Q3W) and pembrolizumab. If the combination of pembrolizumab 400 mg Q6W and the fusion protein binding to CD38 at a dosage one level lower than the RP2D cannot be tolerated, other approved dosing regimens of pembrolizumab (for example, 200 mg Q3W) can be tested in the safety lead-in period.

[0162] Example 3: A Phase 1 / 2 open-label trial to investigate the safety, tolerability, efficacy, pharmacokinetics and immunogenicity of a fusion protein binding to CD38 as a single agent in patients with relapsed refractory multiple myeloma Multiple myeloma (MM) is a plasma cell-derived malignant tumor characterized by bone lesions, hypercalcemia, anemia and renal insufficiency. The 5-year survival rate of patients diagnosed with MM is approximately 45%. MM persists as an incurable disease for the most part due to very complex and diverse cytogenetic and molecular abnormalities. With the discovery, development and approval of proteasome inhibitors (PIs) (such as bortezomib) and immunomodulatory imide drugs (IMiDs), the outcome of MM patients has improved somewhat in the past decade, but those patients become refractory or ineligible to receive bortezomib, and IMiDs have a dismal prognosis.

[0163] Daratumumab, a CD38 antibody, is currently approved for the treatment of MM in many countries. Patients who had received at least 3 prior treatment lines including PI and IMiD, or who were doubly refractory to these agents, were tested with daratumumab. An objective response rate (ORR) of 29% was demonstrated, including a 3% rate of complete response (CR) / stringent complete response (sCR). However, not all patients responded to daratumumab, and many patients ultimately developed progressive disease (PD). The response to daratumumab therapy was significantly associated with the CD38 expression level on tumor cells, and the pretreatment level of CD38 expression on MM cells was significantly higher in patients who achieved at least partial response (PR) compared to those who did not achieve PR. In addition, CD38 expression in these patients decreased in both MM cells localized in the bone marrow and circulating MM cells after the first daratumumab infusion and increased again after daratumumab discontinuation. Therefore, there remains a need for the development of novel targeted therapies that specifically act on the biological phenomena of tumor cells and overcome the limitations regarding CD38 expression levels.

[0164] Target of a fusion protein that binds to CD38 The antigen CD38, which is expressed on the surface of tumor cells, is uniformly and highly expressed on MM cells and is expressed at low levels on various lymphocytes and myeloid cells, as well as on some solid organs. CD38 is highly expressed on the surface of myeloma cells and has lower expression on normal cells, making it a suitable target for delivering drugs (cytokines, radioisotopes, and toxins) to receptor-expressing cells. A promising moiety for conjugation to anti-CD38 monoclonal antibody (mAb) is the cytokine interferon-α (IFN-α), which is currently used by clinicians as a potential option for maintenance therapy in MM, for primary therapy, as well as after autologous and allogeneic stem cell transplantation (SCT). IFN-α has a direct inhibitory effect on some tumors and is a potent stimulator of both the innate and adaptive immune systems. However, the systemic toxicity of IFN-α has precluded its use at therapeutically effective doses in the majority of patients. The fusion protein that binds to CD38 is thought to reduce the binding of IFN-α to non-target CD38-negative cells by decreasing the binding affinity (KD) of IFN-α for its receptor, the interferon α receptor. The fusion protein that binds to CD38 and was evaluated in this study is a recombinant humanized immunoglobulin (Ig) G4 monoclonal antibody against CD38 fused to two attenuated interferon-α2b (IFNα2b) molecules. The amino acid sequences of the fusion protein that binds to CD38 are shown in Table 1 (heavy chain of SEQ ID NO: 13 and light chain of SEQ ID NO: 10).

[0165] When a fusion protein that binds to CD38 binds with high affinity via its CD38-targeting molecule, it is thought to induce the desired on-target activation of the IFN pathway by increasing the local concentration of attenuated IFNα on these CD38+ target cells. In addition, activation of the IFN-α pathway induces upregulation of the levels of CD38 messenger RNA and CD38 protein in malignant cells of patients with B-cell chronic lymphocytic leukemia, and since the fusion protein that binds to CD38 can increase the target expression of CD38 in MM cells and other CD38+ immune cells, it is suggested that the limitations seen with anti-CD38 depletion antibodies, such as daratumumab, are overcome. The fusion protein that binds to CD38 increases CD38 expression on MM cells in vitro, further supporting this hypothesis. CD38 is a multifunctional ectoenzyme involved in cell adhesion and transmembrane signaling. CD38 is overexpressed in hematological malignancies and is thought to be involved in tumor cell migration and metastasis. CD38 has been reported to be highly expressed in 80% of tumor cells derived from MM patients. CD38 is a transmembrane glycoprotein of approximately 45 kDa that is expressed by immature hematopoietic cells, downregulated in mature cells, and re-expressed at even higher levels by activated lymphocytes, such as T cells, B cells, dendritic cells, and natural killer (NK) cells. Early myeloid cells are essential for long-term (sustained) bone marrow recovery and do not express D38, but myeloid-committed progenitor cells, B cells in germinal centers, terminally differentiated plasma cells, and activated tonsils are CD38+.

[0166] Design and initial results of the study A multi-center, open-label, Phase 1 / 2 trial to determine the safety, tolerability, and efficacy of a fusion protein that binds to CD38, as an intravenous (IV) monotherapy and in combination with dexamethasone, in patients with relapsed / refractory multiple myeloma (RRMM). In the Phase 1 trial, the anti-tumor activity of the fusion protein that binds to CD38 against relapsed / refractory multiple myeloma (RRMM) is evaluated in one or more monotherapy schedules. In the Phase 2 trial, including the expanded cohort of Part 2 and the extension cohort of Part 3, the safety profile, anti-myeloma activity, PK, and pharmacodynamics are further firmly estimated to determine whether the maximum tolerated dose (MTD) / biologically optimal dose (OBD) is suitable for future trials. The expanded cohort of Part 2 includes at least one combination cohort of the fusion protein that binds to CD38 and dexamethasone using the same dose and schedule as the fusion protein that binds to CD38. In the extension part of Part 3, the safe and effective dose level of the fusion protein that binds to CD38 is identified. In Part 3, patients are randomly divided 1:1, and the fusion protein that binds to CD38 is administered at 120 mg or 240 mg once every 4 weeks (Q4W), stratified by cytogenetic risk (high risk [(del17, t(4;14) and / or t(14;16)] and standard risk) and type of myeloma (IgA and others).

[0167] Initial results from two patients showed that administration of the fusion protein that binds to CD38 at 6 mg / kg once every 4 weeks (Q4W schedule) exceeded the maximum tolerated dose (MTD). Also, the results showed that administration of the fusion protein that binds to CD38 as a monotherapy at 3 mg / kg on the Q4W schedule was the MTD. Furthermore, when the treatment efficacy of RRMM in patients was observed at 1.5 mg / kg Q4W, no efficacy was seen below 1.5 mg / kg Q4W.

[0168] Administration at a fixed dose is also considered a dosing approach suitable for further clinical development, based on the overall clinical findings and the advantages of fixed-dose administration, including a lower risk of dosing errors and substantially reduced drug wastage. In addition, computer analysis has shown that drug exposure is comparable in patients receiving fixed-dose and weight-adjusted dosing (e.g., mg / kg) (Figures 8A - 8C). Thus, the two doses (Q4W) of 1.5 mg / kg and 3 mg / kg of the fusion protein binding to CD38 are converted to two fixed doses (Q4W) of 120 mg and 240 mg, respectively, based on a median body weight of approximately 80 kg for the evaluation in Part 3.

[0169] Upon consideration, this example describes a therapeutically effective dose of the fusion protein binding to CD38 for the treatment of RRMM.

Claims

1. A pharmaceutical composition for use in a method of treating melanoma, The method comprises administering a composition containing a fusion protein that binds to CD38 to a subject in need of treatment, wherein the fusion protein that binds to CD38 contains an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 0.1 to 1.5 mg per kg of the subject.

2. The pharmaceutical composition according to claim 1, wherein the fusion protein that binds to the CD38 is administered at a dose of 1 mg per 1 kg of the target.

3. The pharmaceutical composition according to claim 1, wherein the fusion protein that binds to the CD38 is administered at a dose of 0.75 mg per 1 kg of the subject.

4. The pharmaceutical composition according to claim 1, wherein the fusion protein that binds to the CD38 is administered at a dose of 0.75 to 1.5 mg per 1 kg of the subject.

5. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering a composition containing 60 to 120 mg of a fusion protein that binds to CD38 to a subject requiring treatment, wherein the fusion protein that binds to CD38 contains an anti-CD38 antibody fused to attenuated interferon α-2b.

6. The pharmaceutical composition according to claim 5, wherein 80 mg of the fusion protein that binds to the CD38 is administered.

7. The pharmaceutical composition according to claim 5, wherein 120 mg of the fusion protein that binds to the CD38 is administered.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein a fusion protein that binds to the CD38 is administered once every three weeks.

9. The pharmaceutical composition according to claim 1 or 5, wherein the anti-CD38 antibody comprises a heavy chain complementarity determination region 1 (CDR-H1) containing the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determination region 2 (CDR-H2) containing the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determination region 3 (CDR-H3) containing the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determination region 1 (CDR-L1) containing the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determination region 2 (CDR-L2) containing the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determination region 3 (CDR-L3) containing the amino acid sequence of SEQ ID NO:

6.

10. The pharmaceutical composition according to claim 1 or 5, wherein the anti-CD38 antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

8.

11. The pharmaceutical composition according to claim 1 or 5, wherein the anti-CD38 antibody comprises the human IgG4 constant region.

12. The pharmaceutical composition according to claim 11, wherein the human IgG4 constant region contains proline at position 228 according to the EU numbering system.

13. The pharmaceutical composition according to claim 12, wherein the human IgG4 constant region further comprises tyrosine at position 252, threonine at position 254, and glutamic acid at position 256, according to the EU numbering system.

14. The pharmaceutical composition according to claim 1 or 5, wherein the anti-CD38 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

15. The pharmaceutical composition according to claim 1 or 5, wherein the weakened interferon α-2b contains the mutations T106A and A145D in interferon α-2b having the amino acid sequence of SEQ ID NO:

11.

16. The pharmaceutical composition according to claim 1 or 5, wherein the weakened interferon α-2b comprises the amino acid sequence of SEQ ID NO:

12.

17. The pharmaceutical composition according to claim 1 or 5, wherein the weakened interferon α-2b is fused to the C-terminus of the heavy chain of the anti-CD38 antibody.

18. The pharmaceutical composition according to claim 17, wherein the fusion protein bound to CD38 comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

19. The pharmaceutical composition according to claim 1 or 5, wherein the composition further comprises histidine, arginine, sucrose, and polysorbate 80 (PS80).

20. The pharmaceutical composition according to claim 19, wherein the histidine is concentrated at a concentration of 50 mM, the arginine at a concentration of 100 mM, the sucrose at a concentration of 50 mg / ml, and the PS80 at a concentration of 0.2 mg / ml.

21. The pharmaceutical composition according to claim 1 or 5, wherein the composition has a pH of 6.

6.

22. The pharmaceutical composition according to claim 1 or 5, further comprising administering an immune checkpoint inhibitor to the subject.

23. The pharmaceutical composition according to claim 22, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

24. The pharmaceutical composition according to claim 23, wherein the PD-1 inhibitor comprises an anti-PD-1 antibody.

25. The pharmaceutical composition according to claim 24, wherein the anti-PD1 antibody is pembrolizumab.

26. The pharmaceutical composition according to claim 25, wherein 400 mg of pembrolizumab is administered once every six weeks.

27. The pharmaceutical composition according to claim 25, wherein pembrolizumab is administered at a dose of 200 mg once every three weeks.

28. The pharmaceutical composition according to claim 1 or 5, wherein the melanoma expresses CD38.

29. The pharmaceutical composition according to claim 1 or 5, wherein the melanoma does not express CD38.

30. The pharmaceutical composition according to claim 1 or 5, wherein the subject is a human.

31. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering a composition comprising a fusion protein that binds to CD38 to a subject requiring treatment, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 0.1 to 1.5 mg per kg of the subject once every three weeks, wherein the subject is currently receiving or has previously received treatment with an immune checkpoint inhibitor.

32. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering a composition comprising an immune checkpoint inhibitor to a subject requiring the treatment, wherein the subject is currently being treated with or has previously been treated with a fusion protein that binds to CD38, the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 0.1 to 1.5 mg per kg of the subject once every three weeks.

33. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering a composition comprising a fusion protein that binds to CD38 to a subject in need of treatment, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 60 to 120 mg once every three weeks, wherein the subject is currently receiving or has previously received treatment with an immune checkpoint inhibitor.

34. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering a composition comprising an immune checkpoint inhibitor to a subject in need of treatment, wherein the subject is currently being treated with or has previously been treated with a fusion protein that binds to CD38, the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 60 to 120 mg once every three weeks.

35. A pharmaceutical composition for use in a method for treating melanoma, The method comprises administering a fusion protein that binds to CD38 to a subject in need of treatment at a dose of 0.1 to 1.5 mg per kg of the subject, once every three weeks, wherein the fusion protein that binds to CD38 contains an anti-CD38 antibody fused to attenuated interferon α-2b.

36. A pharmaceutical composition for use in a method for treating melanoma, wherein the method comprises administering 60 to 120 mg of a CD38-binding fusion protein to a subject in need of treatment once every three weeks, the pharmaceutical composition comprising an anti-CD38 antibody fused to attenuated interferon α-2b.

37. The pharmaceutical composition according to any one of claims 31 to 36, further comprising administering an immune checkpoint inhibitor to the subject.

38. The pharmaceutical composition according to claim 37, wherein the immune checkpoint inhibitor is pembrolizumab.

39. The pharmaceutical composition according to claim 38, comprising administering 400 mg of pembrolizumab once every six weeks.

40. The pharmaceutical composition according to claim 38, wherein pembrolizumab is administered at a dose of 200 mg once every three weeks.

41. The pharmaceutical composition according to any one of claims 31 to 36, wherein the fusion protein bound to CD38 comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

42. The pharmaceutical composition according to any one of claims 31 to 36, wherein the subject is a human.

43. A pharmaceutical composition for use in a method for treating multiple myeloma, wherein the method comprises administering a composition comprising a fusion protein that binds to CD38 to a subject requiring the treatment, wherein the fusion protein that binds to CD38 comprises an anti-CD38 antibody fused to attenuated interferon α-2b, and the fusion protein that binds to CD38 is administered at a dose of 1.5 to 6.0 mg per kg of the subject, or the fusion protein that binds to CD38 is administered at a dose of 120 to 240 mg to the subject.

44. The pharmaceutical composition according to claim 43, wherein the fusion protein that binds to the CD38 is administered in an amount of 1.5 to 6.0 mg per 1 kg of the subject.

45. The pharmaceutical composition according to claim 43, wherein the fusion protein that binds to the CD38 is administered in an amount of 1.5 mg per 1 kg of the subject.

46. The pharmaceutical composition according to claim 43, wherein the fusion protein that binds to the CD38 is administered in an amount of 3.0 mg per 1 kg of the subject.

47. The pharmaceutical composition according to claim 43, wherein the fusion protein that binds to the CD38 is administered in an amount of 4.5 mg per 1 kg of the subject.

48. The pharmaceutical composition according to claim 43, wherein the fusion protein that binds to the CD38 is administered in an amount of 6.0 mg per 1 kg of the subject.

49. The pharmaceutical composition according to claim 43, wherein 120 to 240 mg of a fusion protein bound to the CD38 is administered to the subject.

50. The pharmaceutical composition according to claim 49, wherein 120 mg of the fusion protein that binds to the CD38 is administered to the subject.

51. The pharmaceutical composition according to claim 49, wherein 240 mg of the fusion protein bound to CD38 is administered to the subject.

52. A pharmaceutical composition according to any one of claims 43 to 51, wherein a fusion protein that binds to the CD38 is administered once every four weeks.

53. The pharmaceutical composition according to claim 43, further comprising administering pomalidomide, carfilzomib, daratumumab, lenzilumab, or bortezomib to a subject in need of treatment.

54. The pharmaceutical composition according to claim 43, wherein the anti-CD38 antibody comprises a heavy chain complementarity determination region 1 (CDR-H1) containing the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determination region 2 (CDR-H2) containing the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determination region 3 (CDR-H3) containing the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determination region 1 (CDR-L1) containing the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determination region 2 (CDR-L2) containing the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determination region 3 (CDR-L3) containing the amino acid sequence of SEQ ID NO:

6.

55. The pharmaceutical composition according to claim 43, wherein the weakened interferon α-2b comprises the amino acid sequence of SEQ ID NO:

12.

56. The pharmaceutical composition according to claim 43, wherein the multiple myeloma expresses CD38.

57. The pharmaceutical composition according to claim 43, wherein the multiple myeloma does not express CD38.

58. A pharmaceutical composition according to any one of claims 1, 5, 31-36, or 43, further comprising administering a corticosteroid.

59. The pharmaceutical composition according to claim 58, wherein the adrenocortical steroid is dexamethasone or methylprednisone.

60. A pharmaceutical composition according to any one of claims 1, 5, 31-36, or 43, further comprising administering an antihistamine.

61. The pharmaceutical composition according to claim 60, wherein the antihistamine is montelukast or diphenhydramine.

62. The pharmaceutical composition according to claim 60, comprising: in a first treatment cycle, administering the antihistamine 12 hours before administering the fusion protein that binds to CD38 to the subject and 1 hour after the administration; and in a treatment cycle following the first treatment cycle, administering the antihistamine 1 hour before administering the fusion protein that binds to CD38 to the subject and 1 hour after the administration.

63. A pharmaceutical composition according to any one of claims 1, 5, 31-36, or 43, further comprising administering an analgesic.

64. The pharmaceutical composition according to claim 63, wherein the analgesic agent comprises acetaminophen.

65. The pharmaceutical composition according to claim 63, wherein the analgesic agent comprises an NSAID.

66. The pharmaceutical composition according to any one of claims 1, 5, or 31 to 36, wherein the fusion protein that binds to the CD38 is administered in an amount of 1.0 mg per 1 kg of the subject.

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