Anti-CD38 fusion protein formulation

Abstract

Compositions are disclosed herein that include a CD38-binding fusion protein, a buffer (e.g., histidine / histidine-HCl buffer), an isotonic agent (e.g., arginine-HCl), a stabilizing substance (e.g., sucrose), and a surfactant (e.g., a polysorbate such as polysorbate 80). In some embodiments, the compositions described herein provide for stable storage of the CD38-binding fusion protein when lyophilized. Also provided is a method of treating cancer (e.g., CD38-positive cancer) using the compositions described herein.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 343,486, titled "ANTI-CD38 FUSION PROTEIN FORMULATION," filed on May 18, 2022, under 35 U.S.C. § 119(e), the entire disclosure of which is hereby incorporated by reference in its entirety.

Background Art

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

[0003] Interferon and especially IFN-α can increase apoptosis and decrease proliferation of certain cancer cells. IFN-α is approved by the FDA for the treatment of multiple cancers, including melanoma, renal cell carcinoma, B cell lymphoma, multiple myeloma, chronic myelogenous leukemia (CML), and hairy cell leukemia. Generally, IFN can be targeted to cancer cells, for example, by conjugating it to a targeting antibody or a targeting fragment thereof.

[0004] A fusion protein containing an anti-CD38 antibody fused to IFN-α, and their use in the treatment of cancer are described.

Summary of the Invention

[0005] In some aspects, the present disclosure relates to a composition comprising a CD38-binding fusion protein, wherein the CD38-binding fusion comprises an anti-CD38 antibody fused to a attenuated interferon α-2b protein. In some embodiments, the composition comprising the CD38-binding fusion protein described herein further comprises a buffer, an isotonic agent, a stabilizing substance, and a surfactant. In some embodiments, the CD38-binding fusion protein described herein remains stable and / or active in the composition (e.g., when stored for a period of months to years). In some embodiments, the composition described herein is an aqueous solution. In some embodiments, the composition described herein is in a lyophilized form. Also provided is a method of using the composition described herein for treating cancer.

[0006] In some aspects, the present application discloses a composition comprising a CD38-binding fusion protein, a buffer, an isotonic agent, a stabilizing substance, and a surfactant, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to an attenuated interferon α-2b.

[0007] 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.

[0008] 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.

[0009] In some embodiments, the anti-CD38 antibody comprises a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises a proline at position 228 according to the EU numbering system. In some embodiments, 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 according to the EU numbering system. 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.

[0010] In some embodiments, the attenuated interferon α-2b comprises mutations of T106A and A145D compared to interferon α-2b comprising the amino acid sequence of SEQ ID NO: 11.

[0011] 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 CD38-binding fusion protein 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.

[0012] In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 8.5 to 100 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 30 to 100 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 30 to 70 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 30 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 40 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 60 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 80 mg / ml.

[0013] In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 8.5 to 11.5 mg / ml. In some embodiments, the composition comprises a CD38-binding fusion protein at a concentration of about 10 mg / ml. In some embodiments, the buffer comprises histidine and histidine-HCl. In some embodiments, the composition comprises total histidine (e.g., histidine + histidine-HCl plus) at a concentration of about 50 to 75 mM. In some embodiments, the composition comprises total histidine at a concentration of about 50 mM. In some embodiments, the isotonicity agent is arginine hydrochloride (HCl). In some embodiments, the composition comprises arginine-HCl at a concentration of about 100 mM.

[0014] In some embodiments, the stabilizing substance is a carbohydrate. In some embodiments, the stabilizing substance is a hexose. In some embodiments, the stabilizing substance is trehalose. In some embodiments, the composition comprises the stabilizing substance at a concentration of about 50 to 100 mg / ml. In some embodiments, the composition comprises the stabilizing substance at a concentration of about 50 mg / ml. In some embodiments, the stabilizing substance is sucrose. In some embodiments, the composition comprises sucrose at a concentration of about 50 mg / ml.

[0015] In some embodiments, the surfactant is polysorbate 80 (PS80). In some embodiments, the composition comprises PS80 at a concentration of about 0.1 to 0.6 mg / ml. In some embodiments, the composition comprises PS80 at a concentration of about 0.2 mg / ml. In some embodiments, the composition has a pH of about 6.0 to 7.0. In some embodiments, the composition has a pH of about 6.5 to 6.7. In some embodiments, the composition has a pH of about 6.6.

[0016] In some aspects, a composition comprising 10 mg / ml of a CD38-binding fusion protein, 50 mM of histidine, 100 mM of arginine, 50 mg / ml of sucrose, and 0.2 mg / ml of polysorbate 80 (PS80), wherein the composition has a pH of 6.6, the CD38-binding fusion protein comprises an anti-CD38 antibody comprising a heavy chain and a light chain, the heavy chain comprises the amino acid sequence of SEQ ID NO: 9 and is fused to a attenuated interferon α-2b comprising the amino acid sequence of SEQ ID NO: 12, the light chain comprises the amino acid sequence of SEQ ID NO: 10, is disclosed herein.

[0017] In some embodiments, a composition comprising a CD38-binding fusion protein at 30-100 mg / ml, histidine at 50-75 mM, arginine at 100-150 mM, sucrose at 50-100 mg / ml, and polysorbate 80 (PS80) at 0.1-0.6 mg / ml, wherein the composition has a pH of 6.0-7.0, the CD38-binding fusion protein comprises an anti-CD38 antibody comprising a heavy chain and a light chain, the heavy chain comprises the amino acid sequence of SEQ ID NO: 9 and is fused to a weakened interferon α-2b comprising the amino acid sequence of SEQ ID NO: 12, and the light chain comprises the amino acid sequence of SEQ ID NO: 10, the composition is described herein. In some embodiments, the composition comprises 40 mg / ml of the CD38-binding fusion protein. In some embodiments, the composition comprises 60 mg / ml of the CD38-binding fusion protein. In some embodiments, the composition comprises 80 mg / ml of the CD38-binding fusion protein.

[0018] In some embodiments, the CD38-binding fusion protein 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 composition is lyophilized. In some embodiments, the composition is in the form of a dosage unit.

[0019] In some aspects, the present application discloses a method of treating CD38-expressing cancer, comprising administering to a subject in need of such treatment an effective amount of the composition described herein. In some embodiments, the CD38-expressing cancer is B-cell lymphoma, multiple myeloma, Waldenström macroglobulinemia, non-Hodgkin lymphoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia. In some embodiments, the CD38-expressing cancer is multiple myeloma. In some embodiments, the multiple myeloma is refractory multiple myeloma. In some embodiments, the subject is human.

[0020] In some embodiments, the method further comprises administering lenalidomide or pomalidomide to the subject. In some embodiments, the composition is for use in a method for treating CD38-expressing cancer in a subject. In some embodiments, the subject is undergoing treatment with lenalidomide or pomalidomide.

[0021] In some embodiments, the methods described herein further comprise administering a CD47 antagonist to the subject. In some embodiments, the subject is undergoing treatment with a CD47 antagonist.

[0022] The drawings are for illustrative purposes only and not for limitation.

Brief Description of the Drawings

[0023]

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Mode for Carrying Out the Invention

[0024] Various terms related to the disclosed embodiments are used throughout this specification and the claims. Such terms shall be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms shall be construed in a manner consistent with the definitions provided herein.

[0025] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0026] In some aspects, the present disclosure relates to a composition comprising a CD38-binding fusion protein, wherein the CD38-binding fusion comprises an anti-CD38 antibody fused to a attenuated interferon α-2b protein. In some embodiments, the composition comprising the CD38-binding fusion protein described herein further comprises a buffer (e.g., histidine / histidine-HCl buffer), an isotonic agent (e.g., arginine-HCl), a stabilizing agent (e.g., sucrose), and a surfactant (e.g., a polysorbate such as polysorbate 80). In some embodiments, the composition described herein has a pH of 6.0 to 7.0 (e.g., 6.6), a concentration of the CD38-binding fusion protein of 8 to 12 mg / ml (e.g., 10 mg / ml), a concentration of histidine / histidine-HCl of 40 to 60 mM (e.g., 50 mM), a concentration of arginine-HCl of 75 to 125 mM (e.g., 100 mM), a concentration of sucrose of 30 to 80 mg / ml (e.g., 50 mg / ml), and a concentration of polysorbate 80 of 0.1 to 0.3 mg / ml (e.g., 0.2 mg / ml). In some embodiments, the CD38-binding fusion protein described herein remains stable and / or active in the composition (e.g., when stored for a period of months to years). In some embodiments, the composition described herein is an aqueous solution. In some embodiments, the composition described herein is in a lyophilized form. Also provided is a method of using the composition described herein for treating cancer.

[0027] "CD38-binding fusion protein", as used herein, refers to a fusion protein comprising a CD38-binding domain fused to a attenuated interferon α-2b protein. "Fusion protein" refers to a polypeptide comprising two or more proteinaceous components associated by at least one covalent bond that is a peptide bond, regardless of whether the peptide bond involves the participation of a carbon atom of the carboxylic acid group or another carbon atom. The term "fused" refers to the action of generating the fused molecules described above (e.g., fusion proteins generated from recombinant fusions of genetic regions that produce a single proteinaceous molecule when translated, etc.). The CD38-binding fusion proteins that can be used in the compositions described herein are those described in the art, such as U.S. Patent No. 10544199B2 (incorporated herein by reference). Examples of the amino acid sequences of anti-CD38 antibodies are provided in Table 1.

[0028] The CD38-binding fusion proteins in the compositions described herein include anti-CD38 antibodies. The term "antibody" as used herein includes, for example, intact immunoglobulins, or antigen-binding portions of immunoglobulins, or antigen-binding proteins related to or derived from immunoglobulins. Intact antibody structural units often include tetrameric proteins. Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). Human immunoglobulin light chains can be classified as having either a κ light chain or a λ light chain. In some embodiments, the antibodies described herein generally include antigen-binding domains (e.g., the heavy and / or light chains of the antibody) based on the IgG class, which has multiple subclasses (including, but not limited to, IgG1, IgG2, IgG3, and IgG4). Generally, IgG1 has different allotypes polymorphic at 356 (D or E), IgG2 and 358 (L or M). The sequences shown herein use the 356D / 358M allotype, but any allotype is included herein and can be used in accordance with the present disclosure. For example, any sequence containing the IgG1 Fc domain included herein can have 356E / 358L replacing the 356D / 358M allotype.

[0029] The anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein comprises a heavy chain comprising a heavy chain variable domain (VH) and a light chain comprising a light chain variable domain (VL). "Variable domain", as used herein, refers to the region of an immunoglobulin comprising one or more Ig domains substantially encoded by any of the genes Vκ (V.kappa), Vλ (V.lambda), and / or VH that construct the immunoglobulin loci of the κ-chain, λ-chain, and heavy chain, respectively. In the variable domain, three loops are gathered for each of the V domains of the heavy and light chains to form an antigen-binding site. Each of the loops is referred to as a complementarity-determining region (hereinafter referred to as "CDR"). Additionally, the variable domain also contains a relatively invariant stretch called the framework region (FR) of 15-30 amino acids separated by the CDRs. Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. In some embodiments, "antibody molecule" refers to double-stranded and multi-chain immunoglobulin proteins and immunoglobulin glycoproteins. In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein is an antibody fragment or an antigen-binding fragment of an antibody (such as Fab, Fab’, F(ab’)2, and Fv fragments).

[0030] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions described herein comprises a set of six CDRs that collectively contain a maximum of 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid modifications compared to the six CDRs of the anti-CD38 antibody provided in Table 1. For example, in some embodiments, the CDRs can be modified in any manner in any combination of the CDRs that are changed, provided that the total number of changes in the set of six CDRs does not exceed 10 amino acid modifications, e.g., 1 change in CDRL1, 2 changes in CDRH2, no change in CDRH3, and the like. In some embodiments, each CDR has no more than a single amino acid substitution compared to the corresponding CDR of the anti-CD38 antibody provided in Table 1. In some embodiments, amino acid modifications in CDRH3 are avoided.

[0031] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions described herein comprises a VH 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 acid sequence of SEQ ID NO: 7 and a VL 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 acid sequence of SEQ ID NO: 8.

[0032] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein is a full-length IgG antibody. In a full-length IgG antibody, each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. In some embodiments, the immunoglobulin molecule is of the IgG class IgG4, or a subclass thereof.

[0033] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein comprises 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. IgG4 constant region variants (e.g., human IgG4 constant region variants) that can be used in the anti-CD38 antibodies of the CD38-binding fusion protein in the compositions described herein may, in some embodiments, contain one or more mutations (e.g., mutations that stabilize the hinge region and / or reduce the toxicity of the antibody). For example, a mutation at position 228 of IgG4 according to the EU numbering system stabilizes the hinge of IgG4. In some embodiments, a mutation at position 228 of the IgG4 constant region according to the EU numbering system results in a proline at position 228.

[0034] In some embodiments, mutations in the IgG4 constant region reduce antibody-dependent cellular 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 an antibody bound on a target cell and subsequently cause lysis of the target cell. In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein comprises an IgG4 constant region with 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 reduce ADCC and avoid undesired high levels of cytotoxicity. In some embodiments, a mutation at position 252 of the IgG4 constant region according to the EU numbering system results in tyrosine at position 252. In some embodiments, a mutation at position 254 of the IgG4 constant region according to the EU numbering system results in threonine at position 254. In some embodiments, a mutation at position 256 of the IgG4 constant region according to the EU numbering system results in glutamate at position 256.

[0035] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein comprises an IgG4 constant region with 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 CD38-binding fusion protein in the compositions described herein comprises an IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 15.

[0036] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions 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.

[0037] In some embodiments, the anti-CD38 antibody of the CD38-binding fusion protein in the compositions described herein comprises a light chain comprising a VL and a κ 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 CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions 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.

[0038] In some embodiments, the CD38-binding fusion protein in the compositions described herein further comprises an anti-CD38 antibody (e.g., an anti-CD38 antibody provided in Table 1) fused to a attenuated interferon α-2b protein (e.g., the attenuated interferon α-2b protein is fused to the heavy chain of the anti-CD38 antibody). It has been observed that interferon α-2b can be attenuated by introducing certain amino acid changes into its protein sequence, its biological activity being mediated through interferon binding to interferon receptors on the cell surface. In some embodiments, the attenuated interferon α-2b protein comprises mutations that reduce its potency (e.g., A145D) and / or remove O-linked glycosylation of the interferon α-2b protein (e.g., T106A). The attenuated 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 serves as a delivery vehicle for the attenuated interferon to CD38-positive cells with the resultant reduction of off-target interferon activity caused by the attenuated interferon molecule.

[0039] In some embodiments, the attenuated interferon α-2b protein is fused to the heavy chain of the anti-CD38 antibody. In some embodiments, the attenuated interferon α-2b protein is fused to the C-terminus of the heavy chain of the anti-CD38 antibody. Thus, in some embodiments, the CD38-binding fusion protein in the compositions described herein comprises a heavy chain and a light chain, the heavy chain comprising the heavy chain of an anti-CD38 antibody fused to an attenuated interferon α-2b protein, and the light chain being the light chain of the anti-CD38 antibody. In some embodiments, the CD38-binding fusion protein in the compositions described herein comprises two heavy chains and two light chains, each heavy chain comprising the heavy chain of an anti-CD38 antibody fused to an attenuated interferon α-2b protein, and the light chains being the light chains of the anti-CD38 antibody, respectively.

[0040] In some embodiments, the attenuated interferon α-2b comprises the mutations T106A and A145D compared to wild-type human interferon α2b (e.g., human interferon α2b 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.

[0041] In some embodiments, the CD38-binding fusion protein in the compositions 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 acids of SEQ ID NO: 13 and 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 acids of SEQ ID NO: 10. In some embodiments, the CD38-binding fusion protein in the compositions 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 CD38-binding fusion protein in the compositions 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.

[0042]

Table 1-1

[0043]

Table 1-2

[0044]

Table 1-3

[0045] In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration not exceeding 100 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 1-100 mg / ml, 5-100 mg / ml, 10-100 mg / ml, 20-100 mg / ml, 30-100 mg / ml, 40-100 mg / ml, 50-100 mg / ml, 60-100 mg / ml, 70-100 mg / ml, 30-80 mg / ml, 40-80 mg / ml, or 40-60 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 25-35 mg / ml, 27.5-32.5 mg / ml, 29-31 mg / ml, or 29.5-30.5 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 35-45 mg / ml, 37.5-42.5 mg / ml, 39-41 mg / ml, or 39.5-40.5 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 55-65 mg / ml, 57.5-62.5 mg / ml, 59-61 mg / ml, or 59.5-60.5 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 75-85 mg / ml, 77.5-82.5 mg / ml, 79-61 mg / ml, or 79.5-80.5 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 30 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 40 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 50 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 60 mg / ml. In some embodiments, the compositions described herein contain a CD38-binding fusion protein at a concentration of 80 mg / ml.In some embodiments, the compositions described herein contain the CD38-binding fusion protein at a concentration of 100 mg / ml. In some embodiments, the compositions described herein contain the CD38-binding fusion protein at a concentration of 8 - 12 mg / ml. For example, the compositions described herein may contain the CD38-binding fusion protein 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, the compositions described herein contain the CD38-binding fusion protein at a concentration of about 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12 mg / ml. In some embodiments, the compositions described herein contain the CD38-binding fusion protein at a concentration of about 10 mg / ml.

[0046] In some embodiments, the compositions described herein have a pH of 5.5 to 7.5. For example, the compositions described herein can 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, 6.0 to 7.0, 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, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, the compositions described herein have a pH of about 6.1 to 7.1 (e.g., 6.1 to 7.1, 6.2 to 7, 6.3 to 6.9, 6.4 to 6.8, or 6.5 to 6.7). In some embodiments, the compositions described herein have a pH of about 6.6.

[0047] The compositions described herein further comprise a buffer (e.g., histidine / histidine-HCl 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 can also have stabilizing properties. The isotonic agent can also have stabilizing properties. The surfactant can also have stabilizing properties.

[0048] In some embodiments, the compositions described herein include a buffer comprising histidine and histidine-HCl. In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of 10-120 mM (e.g., 10-120 mM, 20-110 mM, 30-100 mM, 40-90 mM, 50-80 mM, or 60-70 mM). In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of 12.5-107.5 mM. In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of about 15-75 mM (e.g., 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, or 75 mM). In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of 50-75 mM. In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of 15-50 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, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 mM of histidine.

[0049] The relative amounts of histidine and histidine-HCl can be adjusted, as described herein, to achieve a desired pH, for example, while maintaining the histidine concentration in the composition. In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of about 15 mM (e.g., if the composition includes a buffer containing histidine at a concentration of 7.5 mM and histidine-HCl at a concentration of 7.5 mM). In some embodiments, the histidine and histidine-HCl balance results in a final histidine concentration in the composition of about 50 mM (e.g., if the composition includes a buffer containing histidine at a concentration of 40 mM and histidine-HCl at a concentration of 10 mM).

[0050] In some embodiments, the compositions described herein include an isotonic agent that includes arginine (e.g., arginine-HCl). In some embodiments, the compositions described herein include arginine at a concentration of 50-150 mM (e.g., 50-125 mM, 60-120 mM, 70-110 mM, or 80-100 mM, 75-125 mM, 95-105 mM, or 97.5-102.5 mM). In some embodiments, the compositions described herein include arginine at a concentration of about 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, or 150 mM. In some embodiments, the compositions described herein include arginine at a concentration of 100-150 mM. In some embodiments, the compositions described herein include arginine at a concentration of 100 mM. In some embodiments, the compositions described herein include arginine-HCl at a concentration of 50-150 mM (e.g., 50-125 mM, 60-120 mM, 70-110 mM, or 80-100 mM, 75-125 mM, 95-105 mM, or 97.5-102.5 mM). In some embodiments, the compositions described herein include arginine-HCl at a concentration of about 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, or 150 mM. In some embodiments, the compositions described herein include arginine-HCl at a concentration of 100 mM.

[0051] In some embodiments, the compositions described herein include a stabilizing agent. In some embodiments, the stabilizing agent is a carbohydrate. In some embodiments, the stabilizing agent is a sugar. In some embodiments, the stabilizing agent is a hexose. In some embodiments, the stabilizing agent is trehalose. In some embodiments, the compositions described herein include trehalose at a concentration of 3-10% w / v (equivalent to 30-100 mg / ml). For example, the compositions described herein can include trehalose at a concentration of 3-10% w / v, 3-9% w / v, 3-8% w / v, 3-7% w / v, 3-6% w / v, 3-5% w / v, 3-4% w / v, 3-10% w / v, 3-9% w / v, 3-8% w / v, 3-7% w / v, 3-6% w / v, 3-5% w / v, 3-4% w / v, 4-10% w / v, 4-9% w / v, 4-8% w / v, 4-7% w / v, 4-6% w / v, 4-5% w / v, 5-10% w / v, 5-9% w / v, 5-8% w / v, 5-7% w / v, 5-6% w / v, 6-10% w / v, 6-9% w / v, 6-8% w / v, 6-7% w / v, 7-10% w / v, 7-9% w / v, 7-8% w / v, 8-10% w / v, 8-9% w / v, or 9-10% w / v (equivalent to 30-100 mg / ml, 30-90 mg / ml, 30-80 mg / ml, 30-70 mg / ml, 30-60 mg / ml, 30-50 mg / ml, 30-40 mg / ml, 40-100 mg / ml, 40-90 mg / ml, 40-80 mg / ml, 40-70 mg / ml, 40-60 mg / ml, 40-50 mg / ml, 50-100 mg / ml, 50-90 mg / ml, 50-80 mg / ml, 50-70 mg / ml, 50-60 mg / ml, 60-100 mg / ml, 60-90 mg / ml, 60-80 mg / ml, 60-70 mg / ml, 70-100 mg / ml, 70-90 mg / ml, 70-80 mg / ml, 80-100 mg / ml, 80-90 mg / ml, or 90-100 mg / ml, respectively).In some embodiments, the compositions described herein contain trehalose at a concentration of about 3% w / v (equivalent to 30 mg / ml), 3.5% w / v (equivalent to 35 mg / ml), 4% w / v (equivalent to 40 mg / ml), 4.5% w / v (equivalent to 45 mg / ml), 5% w / v (equivalent to 50 mg / ml), 5.5% w / v (equivalent to 55 mg / ml), 6% w / v (equivalent to 60 mg / ml), 6.5% w / v (equivalent to 65 mg / ml), 7% w / v (equivalent to 70 mg / ml), 7.5% w / v (equivalent to 75 mg / ml), 8% w / v (equivalent to 80 mg / ml), 8.5% w / v (equivalent to 85 mg / ml), 9% w / v (equivalent to 90 mg / ml), 9.5% w / v (equivalent to 95 mg / ml), or 10% w / v (equivalent to 100 mg / ml). In some embodiments, the compositions described herein contain trehalose at a concentration of about 4% - 8% w / v (equivalent to 40 - 80 mg / ml). In some embodiments, the compositions described herein contain trehalose at a concentration of about 4% - 7% w / v (equivalent to 40 - 70 mg / ml). In some embodiments, the compositions described herein contain trehalose at a concentration of about 4% - 6% w / v (equivalent to 40 - 60 mg / ml). In some embodiments, the compositions described herein contain trehalose at a concentration of about 4.5% - 5.5% w / v (equivalent to 45 - 55 mg / ml). In some embodiments, the compositions described herein contain trehalose at a concentration of about 4% w / v, 5% w / v, 6% w / v, 7% w / v, or 8% w / v (equivalent to 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, or 80 mg / ml, respectively). In some embodiments, the compositions described herein contain trehalose at a concentration of about 5 - 10% w / v (equivalent to 50 - 100 mg / ml).

[0052] In some embodiments, the compositions described herein contain trehalose at a concentration of about 5% w / v (equivalent to 50 mg / ml).

[0053] In some embodiments, the stabilizing substance is sucrose. In some embodiments, the compositions described herein contain sucrose at a concentration of 3 to 10% w / v (equivalent to 30 to 100 mg / ml). For example, the compositions described herein may contain sucrose at a concentration of 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, 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, 4 to 9% w / v, 4 to 8% w / v, 4 to 7% w / v, 4 to 6% w / v, 4 to 5% w / v, 5 to 10% w / v, 5 to 9% w / v, 5 to 8% w / v, 5 to 7% w / v, 5 to 6% w / v, 6 to 10% w / v, 6 to 9% w / v, 6 to 8% w / v, 5 to 7% w / v, 7 to 10% w / v, 7 to 9% w / v, 7 to 8% w / v, 8 to 10% w / v, 8 to 9% w / v, or 9 to 10% w / v (equivalent to 30 to 100 mg / ml, 30 to 90 mg / ml, 30 to 80 mg / ml, 30 to 70 mg / ml, 30 to 60 mg / ml, 30 to 50 mg / ml, 30 to 40 mg / ml, 40 to 100 mg / ml, 40 to 90 mg / ml, 40 to 80 mg / ml, 40 to 70 mg / ml, 40 to 60 mg / ml, 40 to 50 mg / ml, 50 to 100 mg / ml, 50 to 90 mg / ml, 50 to 80 mg / ml, 50 to 70 mg / ml, 50 to 60 mg / ml, 60 to 100 mg / ml, 60 to 90 mg / ml, 60 to 80 mg / ml, 60 to 70 mg / ml, 70 to 100 mg / ml, 70 to 90 mg / ml, 60 to 80 mg / ml, 80 to 100 mg / ml, 80 to 90 mg / ml, or 90 to 100 mg / ml, respectively). In some embodiments, the compositions described herein contain sucrose at a concentration of about 5 to 10% w / v (equivalent to 50 to 100 mg / ml).

[0054] In some embodiments, the compositions described herein contain sucrose at a concentration of about 3% w / v (equivalent to 30 mg / ml), 3.5% w / v (equivalent to 35 mg / ml), 4% w / v (equivalent to 40 mg / ml), 4.5% w / v (equivalent to 45 mg / ml), 5% w / v (equivalent to 50 mg / ml), 5.5% w / v (equivalent to 55 mg / ml), 6% w / v (equivalent to 60 mg / ml), 6.5% w / v (equivalent to 65 mg / ml), 7% w / v (equivalent to 70 mg / ml), 7.5% w / v (equivalent to 75 mg / ml), 8% w / v (equivalent to 80 mg / ml), 8.5% w / v (equivalent to 85 mg / ml), 9% w / v (equivalent to 90 mg / ml), 9.5% w / v (equivalent to 95 mg / ml), or 10% w / v (equivalent to 100 mg / ml). In some embodiments, the compositions described herein contain sucrose at a concentration of about 4% - 8% w / v (equivalent to 40 - 80 mg / ml). In some embodiments, the compositions described herein contain sucrose at a concentration of about 4% - 7% w / v (equivalent to 40 - 70 mg / ml). In some embodiments, the compositions described herein contain sucrose at a concentration of about 4% - 6% w / v (equivalent to 40 - 60 mg / ml). In some embodiments, the compositions described herein contain sucrose at a concentration of about 4.5% - 5.5% w / v (equivalent to 45 - 55 mg / ml). In some embodiments, the compositions described herein contain sucrose at a concentration of about 4% w / v, 5% w / v, 6% w / v, 7% w / v, or 8% w / v (equivalent to 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, or 80 mg / ml, respectively). In some embodiments, the compositions described herein contain sucrose at a concentration of about 5% w / v (equivalent to 50 mg / ml).

[0055] In some embodiments, the compositions described herein include a surfactant. In some embodiments, the surfactant is polysorbate. In some embodiments, the surfactant is polysorbate 80 (PS80). In some embodiments, the compositions described herein include PS80 at a concentration of 0.005 - 0.06% w / v (equivalent to 0.05 - 0.6 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.03 - 0.06% w / v (equivalent to 0.3 - 0.6 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.04 - 0.06% w / v (equivalent to 0.4 - 0.6 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.05 - 0.06% w / v (equivalent to 0.5 - 0.6 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.03 - 0.05% w / v (equivalent to 0.3 - 0.5 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.04 - 0.06% w / v (equivalent to 0.3 - 0.4 mg / ml). In some embodiments, the compositions described herein include PS80 at a concentration of 0.03% w / v, 0.035% w / v, 0.04% w / v, 0.045% w / v, 0.05% w / v, 0.055% w / v, or 0.06% w / v. In some embodiments, the compositions described herein include PS80 at a concentration of 0.005 - 0.03% w / v (equivalent to 0.05 - 0.3 mg / ml).For example, the composition described herein may contain PS80 at a concentration of 0.005 - 0.03% w / v, 0.005 - 0.025% w / v, 0.005 - 0.02% w / v, 0.005 - 0.015% w / v, 0.005 - 0.01% w / v, 0.01 - 0.03% w / v, 0.01 - 0.025% w / v, 0.01 - 0.02% w / v, 0.01 - 0.015% w / v, 0.015 - 0.03% w / v, 0.015 - 0.025% w / v, 0.015 - 0.02% w / v, 0.02 - 0.03% w / v, 0.02 - 0.025% w / v, 0.02 - 0.03% w / v, 0.02 - 0.025% w / v, or 0.025 - 0.03% w / v (equivalent to 0.05 - 0.3 mg / ml, 0.05 - 0.25 mg / ml, 0.05 - 0.2 mg / ml, 0.05 - 0.15 mg / ml, 0.05 - 0.1 mg / ml, 0.1 - 0.3 mg / ml, 0.1 - 0.25 mg / ml, 0.1 - 0.2 mg / ml, 0.1 - 0.15 mg / ml, 0.15 - 0.3 mg / ml, 0.15 - 0.25 mg / ml, 0.15 - 0.2 mg / ml, 0.2 - 0.3 mg / ml, 0.2 - 0.25 mg / ml, or 0.25 - 0.3 mg / ml, respectively). In some embodiments, the composition described herein contains PS80 at a concentration of about 0.007% w / v (equivalent to 0.07 mg / ml), 0.008% w / v (equivalent to 0.08 mg / ml), 0.009% w / v (equivalent to 0.09 mg / ml), 0.01% w / v (equivalent to 0.1 mg / ml), 0.011% w / v (equivalent to 0.11 mg / ml), 0.012% w / v (equivalent to 0.12 mg / ml), 0.013% w / v (equivalent to 0.13 mg / ml), 0.014% w / v (equivalent to 0.14 mg / ml), 0.015% w / v (equivalent to 0.15 mg / ml), 0.016% w / v (equivalent to 0.16 mg / ml), 0.017% w / v (equivalent to 0.17 mg / ml), 0.018% w / v (equivalent to 0.18 mg / ml), 0.019% w / v (equivalent to 0.19 mg / ml), or 0.02% w / v (equivalent to 0.2 mg / ml). In some embodiments, the composition described herein contains PS80 at a concentration of about 0.01% - 0.03% w / v (equivalent to 0.1 - 0.3 mg / ml).In some embodiments, the compositions described herein contain PS80 at a concentration of about 0.015% - 0.025% w / v (equivalent to 0.15 - 0.253 mg / ml). In some embodiments, the compositions described herein contain PS80 at a concentration of about 0.02% w / v (equivalent to 0.2 mg / ml).

[0056] In some embodiments, the compositions described herein contain a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 8.5 - 11.5 mg / ml (e.g., 10 mg / ml), histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 15 - 60 mM (e.g., 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM), arginine-HCl at a concentration of 80 - 120 mM (e.g., 100 mM), sucrose at a concentration of 3 - 8% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01 - 0.03% w / v (e.g., 0.02% w / v), and the composition has a pH of 5.5 - 7.5 (e.g., 5.5, 6, 6.5, or 6.6). In some embodiments, the CD38-binding fusion protein 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.

[0057] In some embodiments, the compositions described herein contain a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 30 - 80 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50 - 75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75 - 150 mM (e.g., 100 mM), sucrose at a concentration of 3 - 10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01 - 0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0 - 7.0 (e.g., 6.5 - 6.7). In some embodiments, the CD38-binding fusion protein 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.

[0058] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 40 to 80 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50 to 75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75 to 150 mM (e.g., 100 mM), sucrose at a concentration of 3 to 10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01 to 0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0 to 7.0 (e.g., 6.5 to 6.7). In some embodiments, the CD38-binding fusion protein 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.

[0059] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 30 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50 to 75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75 to 150 mM (e.g., 100 mM), sucrose at a concentration of 3 to 10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01 to 0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0 to 7.0 (e.g., 6.5 to 6.7). In some embodiments, the CD38-binding fusion protein 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.

[0060] In some embodiments, the composition described herein comprises a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 40 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50-75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75-150 mM (e.g., 100 mM), sucrose at a concentration of 3-10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01-0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0-7.0 (e.g., 6.5-6.7). In some embodiments, the CD38-binding fusion protein 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.

[0061] In some embodiments, the composition described herein comprises a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 60 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50-75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75-150 mM (e.g., 100 mM), sucrose at a concentration of 3-10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01-0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0-7.0 (e.g., 6.5-6.7). In some embodiments, the CD38-binding fusion protein 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.

[0062] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 80 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50-75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75-150 mM (e.g., 100 mM), sucrose at a concentration of 3-10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01-0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0-7.0 (e.g., 6.5-6.7). In some embodiments, the CD38-binding fusion protein 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.

[0063] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided in Table 1) at a concentration of 100 mg / ml, histidine (e.g., composed of histidine and histidine-HCl) at a concentration of 50-75 mM (e.g., 50 mM), arginine-HCl at a concentration of 75-150 mM (e.g., 100 mM), sucrose at a concentration of 3-10% w / v (e.g., 5% w / v), and PS80 at a concentration of 0.01-0.06% w / v (e.g., 0.02% w / v), and the composition has a pH of 6.0-7.0 (e.g., 6.5-6.7). In some embodiments, the CD38-binding fusion protein 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.

[0064] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided 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, and PS80 at a concentration of 0.02% w / v, and the composition has a pH of 6.6. In some embodiments, the CD38-binding fusion protein 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.

[0065] In some embodiments, the compositions described herein comprise a CD38-binding fusion protein (e.g., the CD38-binding fusion protein provided 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, and PS80 at a concentration of 0.02% w / v, and the composition has a pH of 6. In some embodiments, the CD38-binding fusion protein 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.

[0066] In some embodiments, the compositions described herein are aqueous solutions. In some embodiments, the present disclosure provides a lyophilized form of the compositions described herein. In some embodiments, the lyophilized form can be stored and reconstituted into an aqueous solution prior to use (e.g., administration to a subject).

[0067] In some embodiments, the compositions described herein (e.g., in the form of an aqueous solution or a 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 the form of an aqueous solution or a lyophilized form) are stored frozen. In some embodiments, the compositions described herein (e.g., in the form of an aqueous solution or a lyophilized form) are stored at room temperature (e.g., 25 - 40 °C). In some embodiments, the compositions described herein (e.g., in the form of an aqueous solution or a lyophilized form) are stored at a temperature below 40 °C.

[0068] In some embodiments, at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of the CD38-binding fusion protein in the compositions described herein remains intact (e.g., not degraded) after storage (e.g., at -30 to 40 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year).

[0069] In some embodiments, less than 5% (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.25%) of the CD38-binding fusion protein in the compositions described herein forms dimers after storage (e.g., at -30 to 40 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year).

[0070] In some embodiments, less than 5% (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.25%) of the CD38-binding fusion protein in the compositions described herein aggregates after storage (e.g., at -30 to 40 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year).

[0071] In some embodiments, the pH of the compositions described herein varies to less than 0.5 (e.g., to less than 0.5, to less than 0.4, or to less than 0.3) after storage (e.g., at -30 to 40 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year).

[0072] In some embodiments, the compositions described herein are in lyophilized form for storage, and the water content of the lyophilized compositions is less than 3% (e.g., less than 3% or less than 2%) after storage (e.g., at -30 to 40 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year). In some embodiments, the compositions described herein retain at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of their activity (e.g., as indicated by a cell-based potency assay) after storage (e.g., at -30 to -15 °C) for at least 3 months (e.g., at least 3 months, at least 6 months, or at least 1 year) compared to the composition before storage.

[0073] In some embodiments, the compositions described herein include a relative percentage (e.g., as determined using cation exchange chromatography) of the main peak of the CD38-binding protein that changes by 10% to less than 20% (e.g., decreases to less than 15%) after storage (e.g., lyophilized storage) at 25 °C for 2 weeks.

[0074] In some embodiments, the compositions described herein have a relative percentage of the main peak of the CD38-binding protein (such as determined using cation exchange chromatography) that changes by 20-30% or less (such as decreases to 25% or less) after storage at 40 °C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to FIG. 1, or the compositions described herein having a pH of 5.8-7.0 (such as a pH of 6.4-6.8), can have these properties.

[0075] In some embodiments, the compositions described herein have a relative percentage of the acidic peak of the CD38-binding protein (such as determined using cation exchange chromatography) that changes by 2.5-7.5% or less (such as decreases to 5% or less) after storage at 25 °C for 2 weeks (such as lyophilized storage). In some embodiments, the compositions described herein have a relative percentage of the acidic peak of the CD38-binding protein (such as determined using cation exchange chromatography) that changes by 10-30% or less (such as decreases to 10% or 30% or less) after storage at 40 °C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to FIG. 1, or the compositions described herein having a pH of 5.8-7.0 (such as a pH of 6.4-6.8), can have these properties.

[0076] In some embodiments, the compositions described herein have a relative percentage of the basic peak of the CD38-binding protein (such as determined using cation exchange chromatography) that changes to 2-20% or less (such as decreases to 10% or less) after storage at 25°C for 2 weeks (such as lyophilized storage). In some embodiments, the compositions described herein have a relative percentage of the basic peak of the CD38-binding protein (such as determined using cation exchange chromatography) that changes to 5-30% or less (such as decreases to 5% or 30% or less) after storage at 40°C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to Figure 1, or the compositions described herein having a pH of 6.0-7.3 (such as a pH of 6.4-6.8), can have these properties.

[0077] In some embodiments, the compositions described herein have a relative percentage of aggregation (such as determined by size exclusion chromatography) that changes to 0.04-0.15% or less (such as decreases to 0.1% or less) after storage at 25°C for 2 weeks (such as lyophilized storage). In some embodiments, the compositions described herein have a relative percentage of aggregation (such as determined by size exclusion chromatography) that changes to 0.3-2% or less (such as decreases to 1.5% or less) after storage at 40°C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to Figure 1, or the compositions described herein having a pH of 5.2-7.0 (such as a pH of 6.4-6.8), can have these properties.

[0078] In some embodiments, the compositions described herein have a relative percentage of low molecular weight molecules (LMW) (such as determined by size exclusion chromatography) that changes to 0.03 to 0.1% or less (such as decreases to 0.06% or less) after storage at 25 °C for 2 weeks (such as lyophilized storage). In some embodiments, the compositions described herein have a relative percentage of low molecular weight molecules (LMW) (such as determined by size exclusion chromatography) that changes to 0.02 to 0.1% or less (such as decreases to 0.07% or less) after storage at 40 °C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to FIG. 1, or the compositions described herein having a pH of 5.4 to 7.3 (such as a pH of 6.4 to 6.8), can have these properties.

[0079] In some embodiments, the compositions described herein have a relative percentage of CD38-binding protein monomers (such as determined by size exclusion chromatography) that changes to 0.01 to 0.2% or less (such as decreases to 0.07% or less) after storage at 25 °C for 2 weeks (such as lyophilized storage). In some embodiments, the compositions described herein have a relative percentage of CD38-binding protein monomers (such as when determined by size exclusion chromatography) that changes to 0.2 to 1.5% or less (such as decreases to 0.6% or 1.3% or less) after storage at 40 °C for 2 weeks (such as lyophilized storage). The compositions described herein with reference to FIG. 1, or the compositions described herein having a pH of 5.0 to 7.0 (such as a pH of 6.4 to 6.8), can have these properties.

[0080] In some embodiments, the compositions described herein have a relative percentage of CD38-binding protein monomer (such as determined by size exclusion chromatography) that changes to 0.2 - 0.5% or less (such as decreases to 0.4% or less) after storage at 2 - 8°C for 4 months (such as lyophilized storage). The compositions described herein, with reference to Table 2, or the compositions described herein having an arginine concentration of 25 - 150 mM (such as 100 mM arginine) and a pH of 6.0 - 7.0 (such as a pH of 6.4 - 6.8), may have these properties.

[0081] In some embodiments, the compositions described herein have a relative percentage of CD38-binding protein monomer (such as determined by size exclusion chromatography) that changes to 0.2 - 0.5% or less (such as decreases to 0.4% or less) after storage at 2 - 8°C for 1 month (such as lyophilized storage). The compositions described herein, with reference to Table 2, or the compositions described herein having an arginine concentration of 25 - 150 mM (such as 25 - 100 mM arginine) and a pH of 6.0 - 7.0 (such as a pH of 6.4 - 6.8), may have these properties.

[0082] In some embodiments, the compositions described herein have a relative percentage of CD38-binding protein monomer (such as determined by size exclusion chromatography) that changes to 2 - 6% or less (such as decreases to 5% or less) after storage at 40°C for 4 months (such as lyophilized storage). The compositions described herein, with reference to Table 2, or the compositions described herein having an arginine concentration of 100 - 150 mM (such as 100 mM arginine) and a pH of 6.0 - 7.0 (such as a pH of 6.4 - 6.8), may have these properties.

[0083] In some aspects, the present disclosure relates to a method of treating cancer in a subject by administering an effective amount of the compositions described herein. In some embodiments, an effective amount of the composition is administered to a cancer patient. In some embodiments, the effective amount is the amount required to treat cancer in the patient. Treatment can include, for example, inhibiting or reducing the proliferation of CD38-positive cells in the cancer and / or inducing apoptosis of CD38-positive cells in the cancer.

[0084] The terms "subject" and "patient" are used interchangeably and include any mammal (including companion mammals and agricultural mammals), and rodents (including mice, rabbits, and rats, and other rodents). Non-human primates (such as cynomolgus monkeys) are more preferred, and humans are most preferred.

[0085] The term "about" means within 5% of a given value or range (e.g., within 5%, 4%, 3%, 2%, or 1%). The terms "treatment", "treating", "treat", and the like refer to obtaining a desired pharmacological and / or physiological effect. The effect can be prophylactic in terms of completely or partially preventing the disease or symptom or reducing the likelihood of the disease or symptom, and / or therapeutic in terms of partial or complete cure of the disease and / or side effects caused by the disease. "Treatment", as used herein, covers any treatment of a disease in a mammal (particularly in a human), including (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., preventing its onset or progression; and (c) alleviating the disease, i.e., causing regression of the disease and / or relieving one or more disease symptoms. "Treatment" is also meant to encompass the delivery of an agent for providing a pharmacological effect even in the absence of a disease or condition.

[0086] An "effective amount" or "therapeutically effective amount" of a composition encompasses an amount of the composition sufficient to provide a beneficial effect to a subject to which the composition is administered. An "effective amount" of a delivery vehicle encompasses an amount sufficient to effectively bind or deliver the composition.

[0087] Any composition described or exemplified herein can be used for the treatment of the disorders described herein. Tumors that can be treated include AIDS-related cancers, acoustic neuromas, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, primary myelofibrosis, alopecia, alveolar soft part sarcoma, anal cancer, angiosarcoma, aplastic anemia, astrocytoma, ataxia telangiectasia, basal cell carcinoma (skin), bladder cancer, bone cancer, bowel cancer, brainstem glioma, brain and CNS tumors, breast cancer, CNS tumors, carcinoid tumors, cervical cancer, childhood brain tumors, childhood cancers, childhood leukemia, childhood soft tissue sarcoma, chondrosarcoma, choriocarcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, desmoplastic small round cell tumor, ductal carcinoma, endocrine cancer, endometrial cancer, epithelioma, esophageal cancer, Ewing sarcoma, extrahepatic bile duct cancer, eye cancer, eye: melanoma, retinoblastoma, fallopian tube cancer, Fanconi anemia, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, genitourinary cancer, germ cell tumor, gestational trophoblastic disease, glioma, gynecologic cancer, hematologic malignancies, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hereditary breast cancer, histiocytosis, Hodgkin disease, human papillomavirus, hydatidiform mole, hypercalcemia, hypopharyngeal cancer, intraocular melanoma, islet tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leiomyosarcoma, leukemia, Li-Fraumeni syndrome, lip cancer, liposarcoma, liver cancer, lung cancer, lymphedema, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, male breast cancer, malignant rhabdoid tumor of the kidney, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic cancer, oral cancer, multiple endocrine neoplasia, mycosis fungoides, myelodysplastic syndrome, multiple myeloma, myeloproliferative syndrome, nasal cancer, nasopharyngeal cancer, nephroblastoma, neuroblastoma, neurofibromatosis, Nijmegen chromosome instability syndrome, non-melanoma skin cancer, non-small cell lung cancer (NSCLC), eye cancer, esophageal cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ostomy ovarian cancer, pancreatic cancer, paranasal sinus cancer, parathyroid cancer, parotid gland cancer, penile cancer, peripheral neuroectodermal tumor, pituitary cancer, polycythemia vera, prostate cancer, rare cancers and associated disorders, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, Rothmund-Thomson syndrome, salivary gland cancer, sarcoma, schwannoma, Sézary syndrome, skin cancer, small cell lung cancer (SCLC), small intestine cancer, soft tissue sarcoma, spinal cord tumor, squamous cell carcinoma (skin), gastric cancer, synovial sarcoma, testicular cancer, thymic cancer, thyroid cancer, transitional cell carcinoma (bladder).Transitional cell carcinoma (renal pelvis / ureter), choriocarcinoma, urethral carcinoma, urinary system cancer, uroplakin, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor are included but not limited to these. In one embodiment, the tumor is selected from the group of multiple myeloma or non-Hodgkin lymphoma.,

[0088] In some embodiments, the method is used for the treatment of multiple myeloma, leukemia or lymphoma in a subject in need of treatment. Such method may further comprise treating the subject with a retinoid (such as all-trans retinoic acid). In some preferred embodiments where the cell surface-associated antigen is CD38, the tumor or cancer may be selected from multiple myeloma, non-Hodgkin lymphoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, or acute myelogenous leukemia.

[0089] The compositions described herein can be used in combination with other drugs and / or in addition to other cancer treatment regimens or modalities (such as radiotherapy or surgery). When a CD38-binding fusion protein is used in combination with a known therapeutic agent, the combination can be administered sequentially (either continuously or interrupted by a period without treatment) or simultaneously, or as a mixture. In the case of cancer, there are numerous known anti-cancer agents that can be used in this context. The combination therapy is also contemplated to cover either treatment with the CD38-binding fusion protein followed by a known treatment, or treatment with a known agent followed by treatment with the CD38-binding fusion protein (such as maintenance therapy). For example, in the treatment of cancer, the CD38-binding fusion protein can be administered in combination with alkylating agents (such as mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide cysplatin, or platinum-containing alkylating-like agents such as cisplatin, carboplatin, and oxaliplatin, etc.), antimetabolites, such as purine analogs or pyrimidine analogs, or antifolates (such as azathioprine and mercaptopurine, etc.), anthracyclines (such as daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, or anthracycline analogs, etc.), plant alkaloids (such as vinca alkaloids or taxanes, such as vincristine, vinblastine, vinorelbine, vindesine, paclitaxel, or docetaxel, etc.), topoisomerase inhibitors (such as type I or type II topoisomerase inhibitors, etc.), podophyllotoxins (such as etoposide or teniposide, etc.), or tyrosine kinase inhibitors (such as imatinib mesylate, nilotinib, or dasatinib, etc.).

[0090] In the case of the treatment of multiple myeloma, the compositions described herein can be administered in combination with other suitable treatment methods, such as the treatment of a subject by administration of autologous hematopoietic stem cell transplantation following induction chemotherapy with or without steroids (such as dexamethasone), proteasome inhibitors (such as bortezomib or carfilzomib), immunomodulatory drugs (such as thalidomide, lenalidomide, or pomalidomide), or other chemotherapeutic agents (such as melphalan hydrochloride or the chemotherapeutic agents listed above).

[0091] In the case of the treatment of Hodgkin lymphoma, the compositions described herein can be administered in combination with current treatment approaches such as ABVD (doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine), Stanford V (doxorubicin, bleomycin, vinblastine, vincristine, mechlorethamine, etoposide, prednisone), or BEACOPP (doxorubicin, bleomycin, vincristine, cyclophosphamide, procarbazine, etoposide, prednisone).

[0092] In the case of non-Hodgkin lymphoma or other lymphomas, the compositions described herein can be administered in combination with current treatment approaches. Examples of approved drugs for non-Hodgkin lymphoma include Abitrexate (methotrexate), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), Amboclorin (chlorambucil), Arranon (nelarabine), bendamustine hydrochloride, Bexxar (tositumomab and iodine I 131Tositumomab), Blenoxane (bleomycin), bleomycin, bortezomib, chlorambucil, Clafen (cyclophosphamide), cyclophosphamide, Cytoxan (cyclophosphamide), denileukin diftitox, DepoCyt (liposomal cytarabine), doxorubicin hydrochloride, DTIC-Dome (dacarbazine), Folex (methotrexate), Folex PFS (methotrexate), Folotyn (pralatrexate), ibritumomab tiuxetan, Istodax (romidepsin), Leukeran (chlorambucil), Linfolizin (chlorambucil), liposomal cytarabine, Matulane (procarbazine hydrochloride), methotrexate, methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), Mozobil (plerixafor), nelarabine, Neosar (cyclophosphamide), Ontak (denileukin diftitox), plerixafor, pralatrexate, Rituxan (rituximab), rituximab, romidepsin, tositumomab and iodine I131 tositumomab, Treanda (bendamustine hydrochloride), Velban (vinblastine sulfate), Velcade (bortezomib), and Velsar (vinblastine sulfate), vinblastine sulfate, Vincasar PFS (vincristine sulfate), vincristine sulfate, vorinostat, Zevalin (ibritumomab tiuxetan), Zolinza (vorinostat) are mentioned.Examples of combinations of drugs used in the treatment of non-Hodgkin lymphoma include CHOP (C = cyclophosphamide, H = doxorubicin hydrochloride (hydroxydaunomycin), O = vincristine sulfate (Oncovin), P = prednisone); COPP (C = cyclophosphamide, O = vincristine sulfate (Oncovin), P = procarbazine hydrochloride, P = prednisone); CVP (C = cyclophosphamide, V = vincristine sulfate, P = prednisone); EPOCH (E = etoposide, P = prednisone, O = vincristine sulfate (Oncovin), C = cyclophosphamide, H = doxorubicin hydrochloride (hydroxydaunomycin)); ICE (I = ifosfamide, C = carboplatin, E = etoposide), and R-CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride (hydroxydaunomycin), O = vincristine sulfate (Oncovin), P = prednisone).

[0093] In some embodiments, as described in U.S. Patent No. 9,636,334, which is hereby incorporated by reference in its entirety, the methods of treating cancer described herein further comprise administering lenalidomide or pomalidomide to a subject.

[0094] The tumor can be B-cell lymphoma, multiple myeloma, early-stage multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, non-Hodgkin lymphoma, chronic myeloid leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia. In some embodiments, the composition comprising the CD38-binding fusion protein described herein is administered separately from lenalidomide or pomalidomide (e.g., lenalidomide or pomalidomide can be formulated separately in different compositions). In some embodiments, the composition comprising the CD38-binding fusion protein described herein is administered to a subject who has already received lenalidomide or pomalidomide treatment. In some embodiments, lenalidomide or pomalidomide is administered to a subject who has already received treatment with the composition comprising the CD38-binding fusion protein described herein.

[0095] In some embodiments, the administration of the composition comprising the CD38-binding fusion protein described herein, and lenalidomide or pomalidomide results in a synergistic effect for treating the tumor. In some embodiments, the synergistic effect can include, without limitation, a decrease in the effective dose for lenalidomide or pomalidomide and / or the composition comprising the CD38-binding fusion protein described herein, an enhancement of the effectiveness in inhibiting tumor growth, and / or an improvement in the survival of the subject.

[0096] In some embodiments, the method of treating cancer described herein further comprises administering to the subject a CD47 antagonist (e.g., an agent that reduces CD47 signaling) as described in PCT Patent Publication No. WO2018014067A1, which is incorporated by reference in its entirety. In some embodiments, the CD47 antagonist is an anti-CD47 antibody. In some embodiments, the method of treating cancer described herein further comprises administering to the subject a CD47 antagonist that inhibits the interaction between CD47 and the SIRPα receptor.

Example

[0097] Example 1: CD38-binding fusion protein composition CD38 is a transmembrane glycoprotein that is highly expressed in many types of immune cell cancers. CD38-binding fusion proteins have been previously developed for the treatment of CD38-expressing immune cell cancers. CD38-binding fusion proteins include anti-CD38 antibodies and attenuated interferon α-2b proteins. The anti-CD38 antibody delivers the attenuated interferon α-2b protein to CD38-expressing cancers (e.g., multiple myeloma), and the protein in turn induces apoptosis and / or reduction of proliferation of CD38-expressing cells, thus limiting disease progression.

[0098] The determination of protein drug formulations is a challenging part of protein drug development. Protein drug formulations protect and maintain the stability of protein drugs so that the protein drugs can be safely administered to patients. Protein drug formulations can be difficult to predict for a given protein drug. This is because small changes in the environment of the protein drug (e.g., changes in temperature, pH, or salt concentration) can denature, degrade, and / or aggregate the protein drug, which can reduce therapeutic efficacy and pose safety concerns for patients. Furthermore, different protein drugs have different and variable properties (e.g., different sizes, shapes, thermodynamic properties, and activities), which makes it difficult to predict whether a given formulation will be sufficient to maintain the stability and activity of the protein drug based on formulations of other protein drugs.

[0099] The composition was developed for the storage and clinical use of the CD38-binding fusion protein. The compositions tested contained a CD38-binding fusion protein containing the sequences provided in Table 1, a histidine buffer, an arginine tonicity agent, a sucrose stabilizing substance, and a PS80 surfactant. Experiments were conducted with these varying amounts of components at multiple temperatures, multiple pHs, and different storage conditions and times. These compositions were lyophilized for storage and reconstituted for testing. The goal of these experiments was to identify the concentration ranges of each component of the composition such that the quality attributes of the composition (e.g., aggregation, subvisible particle formation, turbidity, etc.) were clinically acceptable and showed little or no change. Quality attributes to be quantified included the concentration, potency, aggregation, relative ionic abundance, and dimerization over time of the CD38-binding fusion protein, as well as the subvisible particle formation, turbidity, and pH stability of the composition over time.

[0100] Quality attributes were quantified as follows. CD38-binding fusion protein concentration was determined using ultraviolet spectrophotometry by SoloVPE or absorption at 280 nm. Monomer, aggregation, and dimerization of the CD38-binding fusion protein were quantified using size exclusion chromatography (SEC). The charge profile (main peak, acidic peak, and basic peak) of the CD38-binding fusion protein was quantified using cation exchange chromatography (CEX). Formation of subvisible particles was measured using microflow imaging (MFI) particle analysis. MFI quantifies both the relative number of particles and their relative size. Aggregation and degradation of the CD38-binding fusion protein were measured by turbidity. The potency of the CD38-binding fusion protein was quantified in a cell-based potency assay. The cell-based potency assay measures in vitro cell growth arrest in multiple myeloma. Specifically, the multiple myeloma cell line H929 was subcloned to produce a subclonal H929 cell line, which was used as the cell line for the assay. The subclonal H929 cell line is identical to the parental cell line when evaluated by short tandem repeat analysis. The anti-CD38 moiety of the therapeutic substance binds to subclonal H929 cells expressing the CD38 antigen on the cell surface. The attenuated interferon α moiety of the therapeutic substance then accesses the interferon receptor and activates the receptor. Both anti-CD38 binding and interferon receptor activation are required for a sustained cell growth arrest response, leading to a reduction in intracellular ATP concentration. Cellular ATP concentration is detected using luminescence output. The assay is performed using a series of concentrations of the CD38-binding fusion protein (TS) and reference standard (RS) of the test samples in Table 1. Relative potency (%RP) is calculated from the ratio of the EC50 values of RS and TS. The reportable value (RV) is the mean %RP.

[0101] Using experiments, the pH stability of the CD38-binding fusion protein containing the sequences provided in Table 1 at 1 mg / ml was determined in a solution containing 2.34 mM citrate, 5 mM phosphate-Na buffer, and 50 mM NaCl. Six different pH levels: pH 5.2, 5.51, 5.93, 6.37, 6.8, and 7.23 were tested. Measurements were taken at 25 °C after 2 weeks and at 40 °C after 2 weeks during the preparation of the composition. The pH stability of the CD38-binding fusion protein was first determined by measuring the relative percentages of the main peak, acidic peak, and basic peak of the CD38 fusion-binding protein in solutions of different pH (Figures 1A - 1C). The goal was to identify the pH levels at which the changes in the relative percentages of the main peak, acidic peak, and basic peak were relatively small. From the results, it is shown that pH 6.37 and pH 6.8 have similar proportions of main peak, acidic peak, and basic peak compared to the other pHs tested. Aggregation of the CD38-binding fusion protein was also measured across pH levels (Figure 1D).

[0102] The results show that approximately the same amount of aggregation remains at the start and at 25°C after two weeks, regardless of the pH. However, an increase in aggregation was observed to start at pH 6.37 at 40°C after two weeks. Degradation of the CD38 fusion protein was also measured at different pH levels (Figure 1E). The results show that the LMW (measured by size exclusion chromatography) was relatively stable across all pH, time, and temperature tested. Finally, the concentration of the CD38 fusion protein was measured across different pH levels (Figure 1F). The results show that the amount of CD38-binding fusion protein in the composition was relatively stable across all pH tested, and decreased slightly under the conditions of 40°C for two weeks at pH 6.8 and 7.23. The stability of the CD38-binding fusion protein at pH 5.1, 5.5, 6.1, 6.5, 7.1, 7.5, and 10 was also determined using calorimetry (Figure 2 shows data for pH 5.1, 6.5, and 10). The following melting temperatures of the CD38-binding fusion protein were measured: pH 5.1 (65.79°C), pH 5.5 (66.05°C), pH 6.1 (66.27°C), pH 6.5 (66.4°C), pH 7.1 (66.37°C), pH 7.5 (66.17°C), and pH 10 (66.15°C). Overall, these results suggest that, generally, an increase in pH increases the stability of the CD38-binding fusion protein from pH 5.1 to pH 6.5. The results suggest that the CD38-binding fusion protein is stable from pH 6.5 to 7.1 and decreases slightly after pH 7.5.

[0103] Experiments were also conducted to determine the amount of arginine required to reduce precipitation of the CD38-binding fusion protein. The initial compositions included 10 mM histidine buffer, 9.3%, 7.5%, or 2.10% trehalose dihydrate, 0.02% PS80, and 0 mM, 25 mM, 100 mM arginine-HCl, and had pHs of 6.00, 6.25, 6.50, 6.75, and 7.00 (see Table 2). Precipitation was measured after storage at 2 - 8°C for 5 days, 1 month, and 4 months, or at 40°C for 1 month and 4 months. The results suggested that an increase in arginine-HCl from 0 mM to 25 mM concentration generally decreased precipitation up to 1 month of storage. Further increase in arginine-HCl concentration to 100 mM reduced precipitation after 4 months of storage at 40°C. These results suggest that if arginine HCl is at a concentration of about 100 mM in the composition, aggregation can be minimized with storage at 2 - 40°C for at least 4 months. These results also suggest that if arginine HCl is at a concentration of 25 - 100 mM in the composition, aggregation can be minimized with storage at 2 - 8°C for at least 4 months.

[0104] Next, experiments were conducted to determine the effect of varying the CD38-binding fusion protein concentration (5 - 10 mg / ml), histidine buffer concentration (12.5 - 107.5 mM), % sucrose (4 - 8% w / v), arginine-HCl (50 - 125 mM), polysorbate (PS) type (PS20 vs PS80), the ratio of CD38-binding fusion protein to PS (0.5 - 2.0), and pH (5.5 - 6.5) (see Table 3 for the compositions tested). The compositions were stored at 30°C. The results are summarized in Table 4. From the results, it was shown that the CD38-binding fusion protein (5 - 10 mg / ml), % sucrose (4 - 8% w / v), arginine-HCl (50 - 125 mM), and polysorbate (PS) type (PS20 vs PS80) had no effect on the turbidity of the composition, the basic peak concentration of the CD38-binding fusion protein, the acidic peak concentration of the CD38-binding fusion protein, the higher-order aggregation of the CD38-binding fusion protein, and the dimerization of the CD38-binding fusion protein (Table 4). No effect, low effect, and high effect are defined in the legend of Table 4.

[0105] An increase in histidine concentration slightly decreased the turbidity, slightly decreased the concentration of the basic peak of the CD38-binding fusion protein, and slightly increased the concentration of the acidic peak of the CD38-binding fusion protein (Figure 3). From these results, it is suggested that higher histidine concentrations enhance better composition turbidity than lower histidine concentrations, but the maximum amount of histidine based on the maximum dose of the CD38-binding fusion protein should not exceed about 50 mM. An increase in the molar ratio of CD38-binding fusion protein to PS slightly increased the turbidity, slightly increased the concentration of the basic peak of the CD38-binding fusion protein, and slightly decreased the concentration of the acidic peak of the CD38-binding fusion protein (Figure 3). From these results, it is suggested that a lower ratio of CD38-binding fusion protein to PS improves the turbidity. An increase in pH decreased the turbidity, decreased the concentration of the basic peak of the CD38-binding fusion protein, and increased the concentration of the acidic peak of the CD38-binding fusion protein (Figure 3). From these results, it is suggested that a composition at high pH (pH 6.5) is more preferable than a composition at low pH (pH 5.5) because the turbidity is improved and the concentration of the basic CD38-binding fusion protein is decreased.

[0106] Additional experiments were conducted to determine whether varying the CD38-binding fusion protein (5 - 15 mg / ml), histidine buffer concentration (40 - 60 mM), molar ratio of CD38-binding fusion protein to PS80 (0.5 - 1.5), and pH (5.8 - 6.8) (see Table 5 for the compositions tested) affected the composition's quality attributes: size and concentration (MFI) of subvisible particles, turbidity, concentration of the main peak of the CD38-binding fusion protein, concentration of the basic peak of the CD38-binding fusion protein, concentration of the acidic peak of the CD38-binding fusion protein, and aggregation. The compositions were stored at 30 °C and tested at 2-week and 4-week storage. The results are summarized in Table 6. From the results, it is shown that the CD38-binding fusion protein concentration, histidine buffer concentration, pH, and polysorbate 80 / CD38-binding fusion protein ratio of the compositions have little or no effect on particle size and concentration or aggregation within the tested ranges (Figure 4). An increase in the CD38-binding fusion protein concentration (5 - 25 mg / ml) has little or no effect on the main CD38-binding fusion protein, basic CD38-binding fusion protein, acidic CD38-binding fusion protein, and aggregation of the CD38-binding fusion protein (Figure 4). Overall, this suggests that a lower CD38-binding fusion protein concentration (less than 11 mg / ml) is preferred for the composition.

[0107] An increase in the histidine buffer concentration of the composition (40 - 60 mM) has little or no effect on the main peak of the CD38-binding fusion protein, basic peak of the CD38-binding fusion protein, acidic peak of the CD38-binding fusion protein, and aggregation of the CD38-binding fusion protein (Figure 4). Overall, these results suggest that a histidine buffer concentration of 40 - 60 mM is preferred for the composition.

[0108] An increase in the pH of the composition (6.2 - 7.1) slightly increases and then slightly decreases the concentration of the main peak of the CD38-binding fusion protein, decreases the concentration of the basic peak of the CD38-binding fusion protein, increases the concentration of the acidic peak of the CD38-binding fusion protein, and has a negligible effect on the aggregation of the CD38-binding fusion protein (Figure 4). Overall, these results suggest that a pH range of 6.3 - 6.9 is suitable for the composition.

[0109] An increase in the molar ratio of polysorbate 80 / CD38-binding fusion protein in the composition (0.5 - 1.5) has little or no effect on the concentration of the main peak of the CD38-binding fusion protein, the concentration of the basic peak of the CD38-binding fusion protein, the concentration of the acidic peak of the CD38-binding fusion protein, and the aggregation of the CD38-binding fusion protein (Figure 4). Overall, these results suggest that a molar ratio of PS80 to CD38-binding fusion protein of 0.5 - 1.5 is suitable for the composition.

[0110] Further experiments were performed to measure the pH stability of the composition when the concentrations of histidine, histidine / HCl, or arginine-HCl were varied by up to ±2%. The basic composition contained 10 mg / ml of the CD38-binding fusion protein, 40 mM of histidine, 10 mM of histidine-HCl, 5% (w / v) of sucrose, 100 mM of arginine-HCl, 0.007% (w / v) of PS80, and a pH of 6.6. The results showed that the pH changed by less than 0.02 after a change in the concentration of histidine, histidine / HCl, or arginine-HCl by up to ±2% (Figure 5).

[0111] Further experiments were conducted to determine how the percentage of PS80 in the composition affected the formation of visible light CD38-binding fusion protein and subvisible particles under mechanical stress conditions. The CD38-binding fusion protein composition contained 10 mg / ml of the CD38-binding fusion protein containing the sequences provided in Table 1, 50 mM histidine, 5.0% (w / v) sucrose, 100 mM arginine-HCl, pH 6.6, and 0.005%, 0.007%, 0.01%, or 0.02% PS80 (Table 7). Stress was induced by shaking the samples at room temperature for a period of 120 hours. Visual inspections for the formation of visible particles were performed at 0, 2, 4, 6, 8, 24, 48, and 120 hours. From the results, it was shown that the absence of PS80 caused large-scale foaming of the composition. From the results, it was also shown that the 0.007% PS80 composition had very small particles after 24 hours of shaking, but the visible particle turbidity was better compared to the 0.005% PS80 composition at the same time point. Additionally, the compositions with 0.01% PS80 and 0.02% PS80 had no change in visible particle formation after the initial inspection at 0 hours.

[0112] The effect of PS80 on subvisible particle formation was also quantified using MFI. In these experiments, the CD38-binding fusion protein composition was 10 mg / ml of the CD38-binding fusion protein containing the sequences provided in Table 1, 50 mM histidine, 5.0% (w / v) sucrose, 100 mM arginine-HCl, pH 6.6, and 0.005%, 0.007%, 0.01%, or 0.02% PS80 (Table 8). The compositions were shaken for 5 days prior to MFI analysis. MFI was used to count particles with lengths of 2 - 10 μm, ≥10 μm, and ≥25 μm. From the results, it was shown that an increase in PS80 concentration generally decreased the number of particles of all sizes, with the exception that the 0.01% PS80 composition had fewer 2 - 10 μm particles than the 0.02% PS80 composition.

[0113]

Table 2

[0114]

Table 3

[0115]

Table 4

[0116]

Table 5

[0117]

Table 6

[0118]

Table 7-1

[0119]

Table 7-2

[0120]

Table 8

[0121] Example 2: Stability of CD38-binding fusion protein composition (CD38-binding fusion protein) The lyophilized composition can be formulated as a 10 mg / ml protein in 50 mM histidine / hydrochloric acid histidine at pH 6.6, 5% (w / v) sucrose, 100 mM arginine hydrochloride, and 0.02% (w / v) polysorbate 80 and stored for an extended period at 5 ± 3°C. The quality attributes of this formulation were evaluated for stability under long-term storage conditions (5 ± 3°C), accelerated storage conditions (25 ± 2°C), and stress storage conditions (40 ± 2°C). The test methods used in the study were selected to assess the purity, potency, and other quality attributes of the drug product. The tests included appearance (lyophilized cake and reconstituted liquid), turbidity and color (reconstituted liquid), reconstitution time, size exclusion chromatography (SE-UPLC), imaging capillary isoelectric focusing (icIEF), potency, protein concentration, pH, moisture content, and additional characterization methods for subvisible particle (SVP) analysis by microflow imaging (MFI) and PS80 content determination.

[0122] The long-term (5°C ± 3°C) stability data for Lot 1, Lot 2, and Lot 3 meet the acceptance criteria without any significant changes or trends in general characteristics, content, purity, and impurities, as well as microbiological characteristics up to 12 months, 6 months, and 1 month, respectively. A degradation rate analysis model was used to determine the shelf life of the CD38-binding fusion protein composition. From the degradation rate model (95% confidence interval), SEC (% main peak), reduced CE-SDS (% H+L), non-reduced CE-SDS (% IgG), and icIEF (% area of major isoform, % acidic peak, % basic peak) are shown to remain within the acceptance criteria of Specification SPEC-0014566 over 24 months under long-term storage conditions of 5°C ± 3°C (data not shown).

[0123] An assay was performed and the potency was also measured. From the results of the cell-based potency assay, it is shown that after storage at 5°C ± 3°C, the CD38-binding fusion protein composition protein decreases by 10% or less over 12 months of storage (Figure 6). The potency was analyzed using a degradation rate analysis model in JMP to determine the expected shelf life of the CD38 fusion protein composition. Based on the degradation rate model (with 95% confidence interval), this CD38 fusion protein composition will remain within the acceptance criteria for potency over 24 months under long-term storage conditions of 5°C ± 3°C.

[0124] The stability data under accelerated (25°C ± 2°C / 60% RH (relative humidity) ± 5% RH) conditions for Lot 1, Lot 2, and Lot 3 meet the acceptance criteria without any significant changes or trends so far for all quality attributes tested up to the 6-month and 1-month time points respectively. However, at the 3-month time point for Lot 2, a relative potency value of 146% was reported, which does not meet the long-term acceptance criteria limits of 60% - 140%. However, at the subsequent 6-month time point, the relative potency results are within the long-term specifications, and thus the potency result at the 3-month time point is considered a single event and the potency data at future time points will be closely monitored. Furthermore, all other physicochemical property attributes did not show a trend at the 6-month time point under accelerated conditions.

[0125] The stability data under stress (40 ± 2°C / 75 ± 5% RH (relative humidity)) conditions for Lot 1, Lot 2, and Lot 3 meet the long-term acceptance criteria so far for all quality attributes tested up to the 3-month and 1-month time points respectively. Based on the development stability data under stress conditions, there was a slight decreasing trend for the icIEF% main peak area value under stress conditions and a corresponding increase in the % basic species peak area. The relative potency result for Lot 2 at the 3-month time point was 154%, which is outside the long-term acceptance criteria range, similar to the result obtained for this lot at the 3-month accelerated conditions discussed above.

[0126] Overall, these experiments demonstrate that the CD38-binding fusion protein composition is demonstrated to be stable for at least 12 months of storage at 5°C ± 3°C and is modeled to be stable for 24 months.

Claims

1. A composition comprising a CD38-binding fusion protein, a buffer, an isotonic agent, a stabilizing agent, and a surfactant, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to attenuated interferon α-2b. 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. A composition wherein the attenuated interferon α-2b contains the amino acid sequence of SEQ ID NO:

12.

2. The composition according to claim 1, wherein the attenuated interferon α-2b is fused to the C-terminus of the heavy chain.

3. The composition according to claim 1 or 2, wherein the composition contains the CD38-binding fusion protein at a concentration of 30 to 100 mg / ml.

4. The composition according to claim 1 or 2, wherein the composition contains the CD38-binding fusion protein at a concentration of 8.5 to 11.5 mg / ml.

5. The composition according to claim 4, wherein the composition contains the CD38-binding fusion protein at a concentration of about 10 mg / ml.

6. The buffer comprises histidine and histidine-HCl. The isotonic agent is arginine-HCl. The stabilizing substance is hexose, trehalose, or sucrose. The surfactant is polysorbate 80 (PS80) and / or, The composition has a pH of 6.0 to 7.

0. The composition according to any one of claims 1 to 5.

7. The buffer comprises histidine and histidine-HCl, The isotonic agent is arginine-HCl. The stabilizing substance is hexose, trehalose, or sucrose. The surfactant is polysorbate 80 (PS80), and The composition has a pH of 6.0 to 7.

0. The composition according to any one of claims 1 to 5.

8. The composition according to claim 6 or 7, wherein the composition contains total histidine at a concentration of 50 to 75 mM.

9. The composition according to any one of claims 6 to 8, wherein the composition comprises arginine-HCl at a concentration of 100 to 150 mM.

10. The composition according to any one of claims 6 to 9, wherein the composition contains the stabilizing substance at a concentration of 50 to 100 mg / ml.

11. The composition according to any one of claims 10, wherein the stabilizing substance is sucrose.

12. The composition according to any one of claims 6 to 11, wherein the composition comprises PS80 at a concentration of 0.1 to 0.6 mg / ml.

13. The composition according to any one of claims 6 to 12, wherein the composition has a pH of 6.5 to 6.

7.

14. The composition according to any one of claims 6 to 13, wherein the composition has a pH of 6.

6.

15. A composition comprising 10 mg / ml of CD38-binding fusion protein, 50 mM histidine, 100 mM arginine, 50 mg / ml of sucrose, and 0.2 mg / ml of polysorbate 80 (PS80), wherein the composition has a pH of 6.6, and the CD38-binding fusion protein comprises an anti-CD38 antibody including a heavy chain and a light chain, the heavy chain is fused to attenuated interferon α-2b including the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 12, and the light chain includes the amino acid sequence of SEQ ID NO:

10.

16. A composition comprising 30 to 100 mg / ml of CD38-binding fusion protein, 50 to 75 mM histidine, 100 to 150 mM arginine, 50 to 100 mg / ml of sucrose, and 0.1 to 0.6 mg / ml of polysorbate 80 (PS80), wherein the composition has a pH of 6.0 to 7.0, the CD38-binding fusion protein comprises an anti-CD38 antibody including a heavy chain and a light chain, the heavy chain is fused to attenuated interferon α-2b including the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 12, and the light chain includes the amino acid sequence of SEQ ID NO:

10.

17. The composition according to any one of claims 1 to 16, wherein the CD38-binding fusion protein 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.

18. The composition according to claim 16 or 17, comprising 50 mM histidine, 100 mM arginine, 50 mg / ml sucrose, and 0.2 mg / ml polysorbate 80 (PS80), wherein the composition has a pH of 6.

6.

19. A method for treating CD38-expressing cancer in a human subject, comprising administering an effective amount of the composition according to any one of claims 1 to 18 to a subject in need of the treatment.

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