Subcutaneous administration of anti-CD38 antibodies

Abstract

This provides effective treatment methods for cancer, including autoimmune diseases and blood disorders. [Solution] A method for treating a disease in a subject, the method comprising subcutaneously administering a sufficient amount of isolated human anti-CD38 antibody to the subject, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region having a specific amino acid sequence and a variable light (VL) chain region having another specific amino acid sequence and comprising CDR1, CDR2, and CDR3, the disease is one for which binding to CD38 is indicated, and the antibody is administered in a dosage of 45 to 1,800 milligrams.

Description

[Technical Field]

[0001] Cross-Reference to Related Applications The present application claims the benefit of U.S. Provisional Application No. 62 / 649,489, filed on March 28, 2018, which is incorporated herein by reference in its entirety.

[0002] Disclosed are methods and compositions for administering an isolated anti-CD38 antibody via subcutaneous (SC) administration. [Background Art]

[0003] CD38 (also known as cyclic ADP ribose hydrolase) is a type II transmembrane glycoprotein having a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 is a member of a group of related membrane-bound or soluble enzymes, including CD157 and Aplysia ADPR cyclase. This family of enzymes has the unique ability to convert NAD to cyclic ADP-ribose or nicotinic acid adenine dinucleotide phosphate. CD38 is Ca 2+ mobilization, and signal transduction via tyrosine phosphorylation of a number of signaling molecules including phospholipase Cγ, ZAP-70, syk, and c-cbl. Based on these observations, CD38 is a key signaling molecule in the maturation and activation of lymphoid cells during their normal development. Among hematopoietic cells, various functional effects including lymphocyte proliferation, cytokine release, regulation of development and survival of B cells and myeloid cells, and induction of maturation of dendritic cells (DC) have been attributed to CD38-mediated signal transduction.

[0004] CD38 is expressed on immature hematopoietic cells, is down-regulated in mature hematopoietic cells, and is re-expressed at high levels in activated lymphocytes and plasma cells. For example, high expression of CD38 is observed in activated B cells, plasma cells, activated CD4+ T cells, activated CD8+ T cells, NK cells, NKT cells, mature DCs, and activated monocytes (see, e.g., U.S. Patent No. 8,362,211).

[0005] The presence of autoantibodies against CD38 has been associated with several diseases including diabetes mellitus, chronic autoimmune thyroiditis, and Graves' disease (see Antonelli et al. (2001) Clin. Exp. Immunol. 126: 426-431, Mallone et al. (2001) Diabetes 50: 752, and Antonelli et al. (2004) J. Endocrinol. Invest. 27: 695-707).

[0006] Increased expression of CD38 has been reported in various diseases including autoimmune diseases and cancer. Such diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and ulcerative colitis (UC). In patients with RA, an increased number of plasma cells are observed in joint tissues compared to controls. In patients with SLE, an increased number of plasmablasts are observed in peripheral blood in patients with more active disease. Current CD20-based B cell depletion therapies such as rituximab effectively deplete CD20+ B cells, but cannot directly and effectively deplete plasma cells or plasmablasts because these cells do not express CD20. Consistent with this concept, patients with RA or SLE who have high levels of plasma cells or plasmablasts are unlikely to obtain substantial clinical benefit from CD20-based therapies. Therefore, therapeutic agents targeting CD38, which is highly expressed on plasma cells and plasmablasts as well as NK cells and activated T cells, may provide effective treatment for RA and SLE, as well as other diseases characterized by CD38 expression.

[0007] In particular, increased CD38 expression has been reported in various hematopoietic diseases and cell lines derived therefrom, and has been described as a negative prognostic marker in hematological malignancies. Such diseases include, but are not limited to, multiple myeloma (MM), chronic lymphoblastic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) including B-cell acute lymphoblastic leukemia, B-cell and T-cell acute lymphoblastic leukemia (ALL), acute lymphoblastic leukemia, Waldenström macroglobulinemia, mantle cell lymphoma, prolymphocytic / myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), follicular lymphoma, NK-cell leukemia, plasma cell leukemia, non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), T-cell lymphoma (TCL), hairy cell leukemia (HCL), and Hodgkin lymphoma (HL). Furthermore, CD38 expression is a prognostic indicator for patients with conditions such as B-CLL (Durig et al. (2002) Leukemia 16:30-35, and Morabito et al. (2001) Leukemia Res. 25:927-932) and acute myeloid leukemia (Keyhani et al. (1999) Leukemia Res. 24:153-159). Therefore, CD38 provides a useful target in the treatment of hematopoietic disorders.

[0008] Several anti-CD38 antibodies are currently undergoing clinical trials for the treatment of CD38-related cancers. However, all prior-technical therapeutic antibodies against CD38 bind to red blood cells (RBCs) and platelets, leading to higher required dosages due to unproductive binding to RBCs. CD38 is expressed on RBCs at approximately 1000 times lower levels than on myeloma cells (deWeers et al. (2011) J.Immunol. 186(3):1840-1848), but there are approximately 36,000 RBCs per myeloma cell in the blood of patients with active MM (multiple myeloma) (Witzig et al. (1993) Cancer 72(1):108-113). Therefore, 36 times more CD38 molecules are expressed on RBCs than on tumor cells. Consequently, current treatments using anti-CD38 antibodies require high doses to achieve efficacy overcoming RBC binding, thus necessitating intravenous administration. For example, daratumumab (anti-CD38 IgG1 mAb, DARZALEX®, FDA approved and marketed by Janssen Oncology) requires very high doses (≥16 mg / kg) and an intensive regimen (8 times weekly, 8 times every other week, then monthly) to achieve optimal antitumor activity (Xu et al. (2017) Clin. Pharmacol. Ther. 101(6):721-724).

[0009] Therefore, treatment with anti-CD38 antibodies that bind to RBCs currently focuses on intravenous administration because high volumes of antibody are required to achieve therapeutic efficacy, and such large volumes are unsuitable for subcutaneous administration. For example, daratumumab requires ≥16 mg / kg (e.g., approximately 1120 mg for a 70 kg patient) to reach target saturation, and therefore cannot be administered at low volumes. The highest known subcutaneous formulation concentration is 200 mg / ml (Cimzia®, also known as cetrizumab pegol). Using the highest known subcutaneous formulation concentration of 200 mg / ml, the minimum predicted injection volume of daratumumab would be 5.6–11.2 mL, which is a very large volume for subcutaneous administration. Considering these volume and concentration limitations, daratumumab must be administered subcutaneously in 15 ml volumes with hyaluronidase to aid in dispersion and absorption.

[0010] Another anti-CD-38 antibody, isatuximab (marketed by Sanofi Genzyme and currently in Phase 3 clinical trials), was administered at 10 mg / kg and 20 mg / kg in Phase 3 trials, which corresponds to 700-1400 mg for a 70 kg patient. Again, using the highest known subcutaneous formulation concentration of 200 mg / mL, the predicted injection volume of isatuximab would be 3.5-14 mL.

[0011] In addition to requiring higher doses and volumes, current clinically available anti-CD38 antibodies target red blood cells (RBCs) and platelets, which can lead to serious side effects such as hemolytic anemia (a condition in which RBCs are destroyed more rapidly than they can be replenished). In an open-label, single-arm trial, isatuximab was administered intravenously to a total of 97 patients at 3 mg / kg every two weeks (Q2W, n=23), 10 mg / kg for two cycles of Q2W followed by Q4W (n=25), 10 mg / kg for Q2W (n=24), and 20 mg / kg weekly for four cycles (1 cycle), followed by Q2W (n=25). The most common severe (grade 3 / 4) adverse event was anemia, which affected 24% of patients (see http: / / www.onclive.com / conference-coverage / asco-2016 / isatuximab-monotherapy-effective-for-heavily-pretreated-myeloma, the 2016 ASCO Annual Meeting, and Richter et al. (2016) J. Clin. Oncol. 34 (suppl):abstr 8005). In addition to severe anemia, thrombocytopenia and neutropenia are also common severe adverse events (22.9%, 18.4%, and 18.4%, respectively; Dimopolos et al. (2018) Blood 132 (suppl. 1):ASH abstract 155 / oral presentation). Similarly, decreased blood cell counts (WBC, RBC, and platelets), anemia, and thrombocytopenia are well-known serious side effects of daratumumab. In one daratumumab trial, 45% of all patients experienced anemia (19% of which were grade 3), and 48% experienced thrombocytopenia (10% of which were grade 3, and 8% of which were grade 4) (see, for example, Darzalex (daratumumab) prescribing information, Horsham, Pennsylvania: Janssen Biotech, Inc. 2018, and the review article Costello (2017) Ther. Adv. Hematol. 8(1):28-37). Furthermore, intravenous administration of therapeutic monoclonal antibodies can lead to severe infusion-related reactions (IRRs). Common IRRs include, but are not limited to, nasal congestion, cough, allergic rhinitis, throat irritation, dyspnea, chills, nausea, hypoxia, and hypertension (Usmani et al.). (2016)Blood 128(1):37-44). With daratumumab, 48% of patients experienced an IRR with the first dose of the drug (Usmani et al. (2016)Blood 128(1):37-44), of which 3% experienced a severe IRR (Darzalex (daratumumab) prescribing information). Horsham, Pennsylvania: Janssen Biotech, Inc 2018). Similarly, IRR was reported in 40.4% of patients who received isatuximab, of which 4.6% were reported as severe (Dimopoulos et al.). (2018)Blood 132:(suppl 1)ASH abstract 155 / oral presentation). Therefore, patients being treated with isatuximab or daratumumab must be carefully monitored for these life-threatening side effects and other serious side effects.

[0012] AB79 has high affinity (Kd = 6.1 × 10⁻¹⁰). -10 M) is a fully human immunoglobulin IgG1 monoclonal antibody that specifically binds to CD38. AB79 inhibits the growth of tumor cells expressing CD38 through cell depletion mediated by antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). AB79 also reduces the levels of plasma cells and plasmablasts in the blood isolated from healthy subjects and patients with systemic lupus erythematosus (SLE) (PCT application PCT / US2017 / 042128). In healthy cynomolgus monkeys, the efficiency of depletion for each cell type was positively correlated with the level of CD38 expression and the AB79 dose level (PCT application PCT / US2017 / 042128). Furthermore, AB79 demonstrated anti-inflammatory and disease-modifying activity in a monkey model of rheumatoid arthritis (US8,362,211).

[0013] Given that many CD38 antibodies in clinical practice bind to red blood cells (RBCs) and are therefore unsuitable for subcutaneous administration, and that this can lead to dangerous side effects, there remains a need in this field for safer, more convenient, and more effective subcutaneous antibody preparations for the treatment of diseases in which CD38 binding is indicated, such as autoimmune diseases and hematological forms of cancer. [Overview of the project]

[0014] This specification provides a method for treating diseases for which binding to CD38 is indicated, such as autoimmune diseases and hematological cancers, which involves subcutaneous administration of an isolated anti-CD38 antibody.

[0015] In one embodiment, the present invention provides a method for treating a disease in which binding to CD38 is indicated in a subject, the method comprising the step of subcutaneously administering to a subject having a disease in which binding to CD38 is indicated a therapeutically effective amount sufficient to treat the disease, the anti-CD38 antibody comprising a variable heavy (VH) chain region having a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5, or variants of those sequences having up to three amino acid changes, and a variable light (VL) chain region having a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, or variants of those sequences having up to three amino acid changes, the anti-CD38 antibody is administered in doses of 45 to 1,800 milligrams.

[0016] In another embodiment, the present invention provides a method for treating a disease in which binding to CD38 is indicated in a subject, the method comprising the step of subcutaneously administering to a subject having a disease in which binding to CD38 is indicated a therapeutically effective amount sufficient to treat the disease, the anti-CD38 antibody comprising a VH chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, or variants of those sequences having up to three amino acid substitutions, and a VL chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, or variants of those sequences having up to three amino acid substitutions, the anti-CD38 antibody is administered in doses of 45 to 1,800 milligrams.

[0017] In another embodiment, the present invention provides a method for treating a disease in which binding to CD38 is indicated in a subject, the method comprising the step of subcutaneously administering to a subject having a disease in which binding to CD38 is indicated a therapeutically effective amount sufficient to treat the disease, the anti-CD38 antibody comprising a VH chain region including CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a VL chain region including CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, the anti-CD38 antibody is administered in doses of 45 to 1,800 milligrams.

[0018] In one embodiment, anti-CD38 antibodies as described herein do not cause hemolytic anemia or thrombocytopenia.

[0019] In one embodiment, administration of an anti-CD38 antibody therapy results in a rate of less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of one or more grade 3 or 4 treatment-related adverse events (TRAEs) or treatment-induced adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, neutropenia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia. This results in an incidence of less than 4%, less than 3%, less than 2%, or less than 1%. TEAEs are adverse events observed or diagnosed up to approximately 30 days after the last dose of the drug, regardless of the cause. TEAEs may have any underlying disease or treatment-related causes that are unrelated to the anti-CD38 antibody or may be specifically related to the anti-CD38 antibody. Preferably, administration of an anti-CD38 antibody may result in an incidence of less than 30% of one or more Grade 3 or 4 treatment-induced adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia.

[0020] In one embodiment, administration of an anti-CD38 antibody therapy results in an incidence of less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of one or more grade 3 or 4 treatment-related adverse events (TRAEs) selected from the group consisting of anemia, hemolytic anemia, neutropenia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia. A TRAE is an adverse event that the treating physician considers to have a possible causal relationship between the drug used for treatment and the adverse event. Therefore, TRAEs are considered to be specifically associated with anti-CD38 antibodies. Preferably, administration of an anti-CD38 antibody may result in an incidence of less than 30% of one or more grade 3 or 4 TRAEs selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia.

[0021] In one embodiment, administration of anti-CD38 antibody therapy results in the depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of RBCs.

[0022] In one embodiment, administration of anti-CD38 antibody therapy results in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of platelets.

[0023] In one embodiment, the disease is an autoimmune disease or cancer.

[0024] In one embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis (UC), systemic light chain amyloidosis, and graft-versus-host disease.

[0025] In one embodiment, hematological cancers are selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

[0026] In one aspect, blood cancer is multiple myeloma.

[0027] In another aspect, the autoimmune disease is systemic light chain amyloidosis.

[0028] In one embodiment, the VH chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 9, and the VL chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 10. The sequence is included. Preferably, the VH chain region may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 10.

[0029] Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 80% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 85% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 90% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 97% sequence identity with SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 97% sequence identity with SEQ ID NO: 10.Preferably, the VH chain may include CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 10.

[0030] In one embodiment, the VH chain region has the amino acid sequence of SEQ ID NO: 9 or a variant thereof having up to three amino acid substitutions, and the VL chain region has the amino acid sequence of SEQ ID NO: 10 or a variant thereof having up to three amino acid substitutions.

[0031] In one embodiment, the VH chain region has the amino acid sequence of SEQ ID NO: 9, and the VL chain region has the amino acid sequence of SEQ ID NO: 10.

[0032] In one embodiment, the VH chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 11, and the VL chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 11, and the VL chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 11, and the VL chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 12. The chain includes a column. Preferably, the VH chain may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 12.

[0033] Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 80% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 85% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 85% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 90% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 90% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 97% sequence identity with SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 97% sequence identity with SEQ ID NO: 12.Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 11, and the VL chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 12.

[0034] In one embodiment, the anti-CD38 antibody comprises a variant thereof having the heavy chain amino acid sequence of SEQ ID NO: 11 or up to three amino acid substitutions, and a variant thereof having the light chain amino acid sequence of SEQ ID NO: 12 or up to three amino acid substitutions.

[0035] In one embodiment, the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO: 12.

[0036] In one embodiment, the therapeutically effective dose is a dosage of 45 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 1,200 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 600 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 135 milligrams. Preferably, the therapeutically effective dose may be a dosage of 135 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 135 to 1,200 milligrams. Preferably, the therapeutically effective dose may be 135 to 600 milligrams. This can be the dosage. Preferably, the therapeutically effective dose may be a dosage of 600 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 600 to 1,200 milligrams. Preferably, the therapeutically effective dose may be a dosage of 1,200 to 1,800 milligrams.

[0037] In one embodiment, the human anti-CD38 antibody is administered in the form of a pharmaceutically acceptable composition.

[0038] In another embodiment, the present invention provides a method for treating a hematological malignancy in a subject, the method comprising the step of subcutaneously administering to a subject having hematological malignancy a therapeutically effective amount sufficient to treat the hematological malignancy, the anti-CD38 antibody comprising a VH chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, or variants of those sequences having up to three amino acid changes, and a VL chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, or variants of those sequences having up to three amino acid changes, the antibody being administered in doses of 45 to 1,800 milligrams.

[0039] In another embodiment, the present invention provides a method for treating a hematological malignancy in a subject, the method comprising the step of subcutaneously administering to a subject having hematological malignancy a therapeutically effective amount sufficient to treat the hematological malignancy, wherein the anti-CD38 antibody comprises a VH chain region including CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, or variants of those sequences having up to three amino acid substitutions, and a VL chain region including CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, or variants of those sequences having up to three amino acid substitutions, and the anti-CD38 antibody is administered in doses of 45 to 1,800 milligrams.

[0040] In another embodiment, the present invention provides a method for treating a hematological malignancy in a subject, the method comprising the step of subcutaneously administering to a subject having hematological malignancy a therapeutically effective amount sufficient to treat the hematological malignancy, wherein the anti-CD38 antibody comprises a VH chain region including CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a VL chain region including CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, and the anti-CD38 antibody is administered in doses of 45 to 1,800 milligrams.

[0041] In one embodiment, anti-CD38 antibodies do not cause hemolytic anemia or thrombocytopenia.

[0042] In one embodiment, administration of an anti-CD38 antibody results in an incidence of less than 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, or 1% of one or more grade 3 or 4 treatment-related adverse events (TRAEs) or TEAEs selected from the group consisting of anemia including hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia. Preferably, administration of an anti-CD38 antibody may result in an incidence of less than 30% of one or more grade 3 or 4 treatment-related adverse events or TEAEs selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia.

[0043] In one embodiment, administration of anti-CD38 antibody is used to address the depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of RBCs. It brings about.

[0044] In one embodiment, administration of an anti-CD38 antibody results in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of platelets.

[0045] In one embodiment, hematological cancers are selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

[0046] In one aspect, blood cancer is multiple myeloma.

[0047] In one embodiment, the VH chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 9, and the VL chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9, and the VL chain region may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 9, and the VL chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 9, and the VL chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 10.

[0048] Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 80% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 85% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 90% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO: 10. Preferably, the VH chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of the sequence may have at least 97% sequence identity with SEQ ID NO: 9, and the VL chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of the VL sequence may have at least 97% sequence identity with SEQ ID NO: 10. Preferably, the VH chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of the sequence may have at least 97% sequence identity with SEQ ID NO: 10. 3. The CDR sequence may include sequences as defined by SEQ ID NO: 4 and SEQ ID NO: 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 9; the VL chain may include sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 10.

[0049] In one embodiment, the VH chain region has the amino acid sequence of SEQ ID NO: 9 or a variant thereof having up to three amino acid substitutions, and the VL chain region has the amino acid sequence of SEQ ID NO: 10 or a variant thereof having up to three amino acid substitutions.

[0050] In one embodiment, the VH chain region has the amino acid sequence of SEQ ID NO: 9, and the VL chain region has the amino acid sequence of SEQ ID NO: 10.

[0051] In one embodiment, the VH chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 11, and the VL chain region includes an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 11, and the VL chain region may include an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 11, and the VL chain region may include an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and the VL chain region may include an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 12.

[0052] Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 80% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 85% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 85% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 90% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 90% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO: 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NOs. 3, 4, and 5, the remainder of which may have at least 97% sequence identity with SEQ ID NO. 11, and the VL chain may include a CDR sequence as defined by SEQ ID NOs. 6, 7, and 8, the remainder of which may have at least 97% sequence identity with SEQ ID NO. 12. Preferably, the VH chain The VL chain may include CDR sequences as defined by SEQ ID NOs. 3, 4, and 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO. 11, and the VL chain may include CDR sequences as defined by SEQ ID NOs. 6, 7, and 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO. 12.

[0053] In one embodiment, the VH chain region has the amino acid sequence of SEQ ID NO: 11 or a variant thereof having up to three amino acid substitutions, and the VL chain region has the amino acid sequence of SEQ ID NO: 12 or a variant thereof having up to three amino acid substitutions.

[0054] In one embodiment, the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO: 12.

[0055] In one embodiment, the therapeutically effective dose is a dosage of 45 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 1,200 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 600 milligrams. Preferably, the therapeutically effective dose may be a dosage of 45 to 135 milligrams. Preferably, the therapeutically effective dose may be a dosage of 135 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 135 to 1,200 milligrams. Preferably, the therapeutically effective dose may be a dosage of 135 to 600 milligrams. Preferably, the therapeutically effective dose may be a dosage of 600 to 1,800 milligrams. Preferably, the therapeutically effective dose may be a dosage of 600 to 1,200 milligrams. Preferably, the therapeutically effective dose may be 1,200 to 1,800 milligrams.

[0056] In one embodiment, the human anti-CD38 antibody is administered in the form of a pharmaceutically acceptable composition. Preferably, the pharmaceutically acceptable composition may be suitable for subcutaneous administration.

[0057] In another embodiment, the present invention provides a unit dosage form comprising an isolated antibody comprising an amino acid sequence of a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 9 and an amino acid sequence of a light chain variable region having at least 80% sequence identity to SEQ ID NO: 10, wherein the isolated antibody is conjugated to CD38, and the unit dosage form is formulated for subcutaneous administration at doses of 45 to 1,800 milligrams of the antibody. Preferably, the VH chain region may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 9, and the VL chain region may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 9, and the VL chain region may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9, and the VL chain region may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 9, and the VL chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 10. Preferably, the VH chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 9, and the VL chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 10.

[0058] Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of the sequence may have at least 85% sequence identity with SEQ ID NO: 9, and the VL chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of the VL sequence may have at least 85% sequence identity with SEQ ID NO: 10. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and sequence The VL chain may contain a CDR sequence as defined by sequence number 5, the remainder of which may have at least 85% sequence identity with sequence number 9; the VL chain may contain a CDR sequence as defined by sequence numbers 6, 7, and 8, the remainder of which may have at least 85% sequence identity with sequence number 10. Preferably, the VH chain may contain a CDR sequence as defined by sequence numbers 3, 4, and 5, the remainder of which may have at least 90% sequence identity with sequence number 9; the VL chain may contain a CDR sequence as defined by sequence numbers 6, 7, and 8, the remainder of which may have at least 90% sequence identity with sequence number 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs. 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO. 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs. 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO. 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs. 3, 4, and 5, with the remainder of these sequences having at least 97% sequence identity to SEQ ID NO. 9, and the VL chain may include CDR sequences as defined by SEQ ID NOs. 6, 7, and 8, with the remainder of the VL sequence having at least 97% sequence identity to SEQ ID NO. 10. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 9, and the VL chain may include CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 10.

[0059] Preferably, the present invention may provide a unit dosage form comprising an isolated antibody having the amino acid sequence of the heavy chain variable region of SEQ ID NO: 9 or a variant thereof having up to three amino acid substitutions, and the amino acid sequence of the light chain variable region of SEQ ID NO: 10 or a variant thereof having up to three amino acid substitutions, wherein the isolated antibody is conjugated to CD38, and the unit dosage form is formulated for subcutaneous administration at doses of 45 to 1,800 milligrams of the antibody.

[0060] In another embodiment, the present invention provides a unit dosage form comprising an isolated antibody having the amino acid sequence of the heavy chain variable region of SEQ ID NO: 9 and the amino acid sequence of the light chain variable region of SEQ ID NO: 10, wherein the isolated antibody binds to CD38 and does not significantly bind to human erythrocytes, and the unit dosage form is formulated for subcutaneous administration at doses of 45 to 1,800 milligrams of the antibody.

[0061] In one embodiment, the heavy chain contains an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 11, and the light chain contains an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 11, and the VL chain region may contain an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 80% sequence identity with SEQ ID NO: 11, and the VL chain may be defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8 The VH chain may include a CDR sequence such as that defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the VL chain may have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the VH chain may include a CDR sequence such as that defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL chain may have at least 85% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include a CDR sequence such as that defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the VL chain may have at least 90% sequence identity with SEQ ID NO: 11. Preferably, the VL chain may include a CDR sequence such as that defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL chain may have at least 90% sequence identity with SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 95% sequence identity to SEQ ID NO: 11; the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 95% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, with the remainder of these sequences having at least 97% sequence identity to SEQ ID NO: 11; the VL chain may include CDR sequences as defined by SEQ ID NOs: 6, 7, and 8, with the remainder of the VL sequence having at least 97% sequence identity to SEQ ID NO: 12. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 11, and the VL chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, the remainder of which may have at least 99% sequence identity with SEQ ID NO: 12.

[0062] Preferably, the heavy chain may include the amino acid sequence of SEQ ID NO: 11 or a variant thereof having up to three amino acid substitutions, and the light chain may include the amino acid sequence of SEQ ID NO: 12 having up to three amino acid substitutions.

[0063] In one embodiment, the heavy chain may include the amino acid sequence of SEQ ID NO: 11, and the light chain may include the amino acid sequence of SEQ ID NO: 12.

[0064] In one embodiment, the unit dosage form is formulated for subcutaneous administration of the antibody in the treatment of hematological cancers selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

[0065] In one aspect, blood cancer is multiple myeloma.

[0066] In one embodiment, anti-CD38 antibodies do not cause hemolytic anemia or thrombocytopenia.

[0067] In one embodiment, the anti-CD38 antibody results in the depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of RBCs.

[0068] In one embodiment, anti-CD38 antibodies cause depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1% of platelets.

[0069] In one embodiment, a human anti-CD38 antibody for use in therapy is provided, the antibody does not cause significant levels of red blood cell and / or platelet depletion after administration. Preferably, the human anti-CD38 antibody can be administered subcutaneously. Preferably, the antibody is administered in doses of 45-1,800 mg. It can be administered in regram doses.

[0070] In one embodiment, a human anti-CD38 antibody for use in therapy is provided, which does not cause significant levels of red blood cell and / or platelet depletion after administration, and which is administered subcutaneously in doses of 45 to 1,800 milligrams. Preferably, a human anti-CD38 antibody that does not cause significant levels of red blood cell and / or platelet depletion after administration may be an anti-CD38 antibody as defined herein.

[0071] In one embodiment, a unit dosage form is provided comprising an isolated antibody that does not cause significant levels of red blood cell and / or platelet depletion after administration, wherein the isolated antibody binds to CD38 and does not bind to human red blood cells, and the unit dosage form is formulated for subcutaneous administration at doses of 45 to 1,800 milligrams of the antibody.

[0072] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in therapy, and the human anti-CD38 antibody is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody is administered subcutaneously.

[0073] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of a disease in which binding to CD38 is indicated, and the human anti-CD38 antibody is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody is administered subcutaneously.

[0074] In many embodiments, the dosage of anti-CD38 antibody administered as described herein is a weekly dose.

[0075] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in therapy, and the human anti-CD38 antibody is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody is administered subcutaneously.

[0076] Preferably, the human anti-CD38 antibody may be administered in doses ranging from 45 to 1,800 milligrams of antibody. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration and administered in doses ranging from 45 to 1,800 milligrams of antibody.

[0077] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of cancer. Preferably, the cancer may be a hematological malignancy.

[0078] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of hematological malignancies, and the human anti-CD38 antibody is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody can be administered subcutaneously.

[0079] Preferably, the human anti-CD38 antibody may be administered in doses ranging from 45 to 1,800 milligrams of antibody. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration and administered in doses ranging from 45 to 1,800 milligrams of antibody.

[0080] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of hematological malignancies, the human anti-CD38 antibody being formulated for subcutaneous administration, and the human anti-CD38 antibody being administered in doses ranging from 45 to 1,800 milligrams of antibody. Preferably, the human anti-CD38 antibody may be administered subcutaneously.

[0081] Preferably, the hematological cancer may be multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, or Burkitt lymphoma. Preferably, the hematological cancer may be multiple myeloma.

[0082] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of an autoimmune disease.

[0083] In one embodiment, a human anti-CD38 antibody, as defined herein, is provided for use in the treatment of an autoimmune disease, wherein the human anti-CD38 antibody is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody can be administered subcutaneously.

[0084] Preferably, the human anti-CD38 antibody may be administered in doses ranging from 45 to 1,800 milligrams of antibody. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody may be formulated for subcutaneous administration and administered in doses ranging from 45 to 1,800 milligrams of antibody.

[0085] Preferably, the autoimmune disease may be systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, systemic light chain amyloidosis, or graft-versus-host disease.

[0086] In one embodiment, a pharmaceutical composition is provided comprising an isolated human anti-CD38 antibody as defined herein.

[0087] In one embodiment, a pharmaceutical composition comprising a unit dosage form according to the present invention is provided.

[0088] In one embodiment, a pharmaceutical composition according to the present invention is provided for use in therapy.

[0089] In one embodiment, a pharmaceutical composition according to the present invention is provided for use in the treatment of a disease in which binding to CD38 is indicated.

[0090] In one embodiment, a pharmaceutical composition according to the present invention is provided for use in the treatment of an autoimmune disease. Preferably, the autoimmune disease may be systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis (UC), systemic light chain amyloidosis, or graft-versus-host disease. Preferably, the autoimmune disease may be systemic lupus erythematosus (SLE). Preferably, the autoimmune disease may be rheumatoid arthritis (RA). Preferably, the autoimmune disease may be inflammatory bowel disease (IBD). Preferably, the autoimmune disease may be ulcerative colitis (UC). Preferably, the autoimmune disease may be graft-versus-host disease.

[0091] In another embodiment, pharmaceutical compositions according to the present invention are provided for use in the treatment of cancer. Preferably, the cancer may be a hematological cancer. Preferably, the hematological cancer may be multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B cell lymphoma, or Burkitt lymphoma. Preferably, the hematological cancer may be multiple myeloma. Preferably, the hematological cancer may be chronic lymphoblastic leukemia. Preferably, the hematological cancer may be chronic lymphocytic leukemia. Preferably, the hematological cancer may be plasma cell leukemia. Preferably, the hematological cancer may be acute myeloid leukemia. Preferably, the hematological cancer may be chronic myeloid leukemia. Preferably, the hematological cancer may be B cell lymphoma. Preferably, the hematological cancer may be Burkitt lymphoma.

[0092] In one embodiment, isolation as defined herein for the manufacture of a pharmaceutical product for the treatment of a disease The use of a human anti-CD38 antibody is provided.

[0093] In another embodiment, the use of unit dosage forms according to the present invention is provided for the manufacture of pharmaceuticals for the treatment of diseases.

[0094] Preferably, the disease may be one for which binding to CD38 is indicated.

[0095] Preferably, the disease may be an autoimmune disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis (UC), systemic light chain amyloidosis, or graft-versus-host disease.

[0096] Preferably, the disease may be cancer. Preferably, the cancer may be a hematological cancer such as multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, or Burkitt lymphoma.

[0097] Preferably, the pharmaceutical product can be formulated for subcutaneous administration.

[0098] Preferably, the pharmaceutical can be formulated to provide a dosage of 45 to 1,800 milligrams of antibody.

[0099] Preferably, the pharmaceutical product is formulated for subcutaneous administration and may contain a dosage of 45 to 1,800 milligrams of antibody.

[0100] These and other embodiments, features and potential advantages will become apparent with reference to the following description and drawings.

[0101] The object and features of the present invention can be better understood by referring to the drawings described below. [Brief explanation of the drawing]

[0102] [Figure 1] The table below shows the antibodies used in flow cytometry analysis in the PD study. [Figure 2] The PK data for the SC-treated group is shown. Anti-drug antibodies (ADAs) were detected by a validated qualitative electrochemiluminescence (ECL) assay. The incidence increased over time and affected PK when it reached a specific threshold titer of approximately 1000 (approximately log(7)). [Figure 3]This document presents PK data and models for AB79 in cynomolgus monkeys (cyno). Panels A and B show raw PK data from eight monkey studies. (Panel A) First 7 days after initial administration. (Panel B) Entire observation period. Doses are color-coded, and SC data are omitted (Figure 2). Panel C illustrates the final PK model structure, including targeted-mediated pharmacokinetics (TMDD) marked in blue boxes. VC represents the volume of the central compartment where AB79 concentration is observed (marked by concentration). VP represents the volume of the peripheral compartment. Total R represents the compartments of the antibody-bound and unbound receptor CD38. KSYN and KDEG represent the rate constants for the generation and degradation of the receptor, respectively, and KINT represents the rate constant for internal transfer (complex elimination rate). KSS is a steady-state constant defined as KSS = (KOFF + KINT) / KON, where KOFF is the dissociation and KON is the binding rate constant. Panels D-F show a superposition of linear two-compartment model predictions (median, 95% prediction interval) without the TMDD component and observed data for three minimum doses (Study 8). Note that the time scales differ between panels D, E, and F. [Figure 4] The effects of AB79 treatment on RBCs during the two days following drug administration and the total lymphocyte count on the first day following drug administration in Study 7 are shown. [Figure 5] The effects of ADA in a 13-week toxicological study are shown. For evaluation, refer to the final population PK model (Figure 1, Table 4). The following goodness-of-fit (GOF) plots, stratified by dose and route of administration, are presented (Keizer et al. (2013) CPT Pharmacometrics Syst. Pharmacol. 2:e50): (1) Conditionally weighted residuals (CWRES) versus time, (2) Observed concentration versus population model prediction, (3) CWRES versus population model prediction, and (4) Observed concentration versus individual model prediction. [Figure 6A] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6B]The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6C] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6D] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6E] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6F] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6G] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6H] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6I] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 6J] The GOF plots for the final population PK model, stratified by dose and route of administration (IV-red, SC-blue), are shown. [Figure 7]This report compares CD38 expression on the surface of human and monkey NK cells, B cells, and T cells. Flow cytometry measurements are standardized, and signals are reported as molecules of equivalent soluble fluorescence (MOEF) exhibiting the same level of fluorescence intensity. Human and monkey blood lymphocytes bind to similar levels of AB79. Direct comparisons of CD38 expression levels on monkey NK cells (CD3-, CD159a+), B cells (CD3-, CD20+), and T cells (CD3+), as well as on human NK cells (CD3-, CD16 / CD56+), B cells (CD3-, CD19+), and T cells (CD3+) were evaluated by flow cytometry. The median fluorescence intensity (MFI) of AB79 staining for each cell population was converted to MOEF units using a standardized curve created with Rainbow Beads (Spherotech, Lake Forest, IL). The data presented are from three individuals of each species, and the MOEF ± SD for each cell type is shown. Differences in CD38 expression exist among blood lymphocytes, with the level of AB79 binding (MOEF) being highest in NK cells > B cells > T cells. The AB79 binding pattern is similar in monkey-derived blood cells, but the level of AB79 binding / CD38 expression is lower. [Figure 8] This shows the inter- and intra-individual variability of T cell, B cell, and NK cell count data in placebo-treated animals. [Figure 9] The graph shows the pre-treatment NK cell, B cell, and T cell counts (cell count per μL) stratified by study (top panel) or sex (bottom panel). [Figure 10]The graphs show AB79-dependent NK cell, B cell, and T cell depletion. The presented graphs focus on changes that occurred within the first 7 days after treatment with the initial dose of AB79. This allowed for the pooling of data from single-dose and multi-dose studies on weekly or bi-weekly dosing schedules. Graphs A-C show the individual minimum cell number of NK cells (i.e., maximum PD effect), the individual cell number 7 days after the initial dose, and the mean cell depletion profile and PK-PD model structure for each dose, respectively. Graphs E-F show the same information for B cells, and graphs G-I show the same information for T cells. [Figure 11] This shows simulated human PK, as well as NK cell, B cell, and T cell depletion profiles for AB79. Five PK and cell depletion profiles were simulated for single IV and SC dosing based on scaled monkey PK and PK-PD models (0.0003–1 mg / kg). The plot on the left shows data after IV administration, and the plot on the right shows data after SC administration. The first row of plots displays the PK profile. The lower limit of quantification (LLOQ) of 0.05 μg / mL is indicated by a horizontal dashed line. The lowest dose of PK was completely superimposed on noise, and only at a dose of 0.03 mg / kg did PK reach a level above LLOQ. [Figure 12] This document outlines the design for a single-dose escalation study (toxicology study) of AB79 in healthy volunteers. A total of 6 IV and 4 SC cohorts of 74 subjects were randomized and administered a single dose of AB79. After each cohort, extensive blinded safety, PK, and PD data were reviewed before dose escalation. To avoid potential immunosuppression in healthy volunteers, target cell depletion was included as a discontinuation criterion. Each subject was followed for 92 days after administration. [Figure 13A] GOF plots for PK-PD models stratified by administration route (IV-red, SC-blue) are shown (NK cells). [Figure 13B] GOF plots for PK-PD models stratified by administration route (IV-red, SC-blue) are shown (B cells). [Figure 13C] GOF plots for PK-PD models stratified by administration route (IV-red, SC-blue) are shown (T cells). [Figure 14] This study demonstrates that AB79 mediates cell depletion through antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Comparison of CD38 receptor count and susceptibility to ADCC and CDC in human B-lineage cell lines. Cell lines with increased CD38 expression were susceptible to ADCC. No ADCC was observed in human lymphoblast cell lines (MV-4-11) that do not express CD38, or in Chinese hamster ovary cell lines transfected with CD157, a molecule closely related to CD38 (data not shown). EC50, 50% effective concentration; nd, not performed; SD, standard deviation. [Figure 15] This study demonstrates that AB79 mediates the depletion of monkey lymphocytes. When quantified using Flow-Count® fluorospheres (Beckman-Coulter) by flow cytometry, AB79 dose-dependently depleted serum NK cells > B cells > T cells in female cynomolgus monkeys (n=4 / dose group) after a single IV dose of AB79. Samples were collected pre-treatment (-1 week), day 1: pre-administration, and 15, 30, 1, 4, 8, 24, 48, 96, and 168 hours post-administration, day 10, day 15, day 22, day 29, day 36, day 43, day 50, and day 57. For clarity, only two weeks of data are shown. The mean cell count was calculated at each time point, and this was used to calculate the percentage relative to the baseline count. [Figure 16]This study demonstrates that the human tetanus toxoid (TTd) recall response is reduced by AB79 treatment. CB17 / SCID mice were treated with anti-asialoGM1 to eliminate NK cells, and then given 25 × 10⁶ human peripheral blood lymphocytes. After 7–10 days, serum samples were collected for evaluation of human Ig, and Ig levels were used as the basis for randomization. Mice were given TTd to induce a recall response and treated with the indicated antibody twice a week for 10 days. Three days after the last treatment, serum was collected and analyzed for anti-TTd antibody. AB79 dose-dependently suppressed the TTd recall response. AB79 reduced the recall response to a degree similar to that of rituxan (Rtx) (isotype (iso)), Rtx, and AB79 (all at 10 mg / kg). [Figure 17] This study demonstrates that AB79 does not induce cytokine induction. AB79 (soluble) did not increase IL-6 levels after 24-hour incubation in PBMCs collected from four different subjects. In contrast, IgG1 isotype-controlled PHA (positive control) increased cytokine levels in all subjects, demonstrating the cells' ability to produce IL-6. Similar results were observed in PBMCs stimulated for 48 hours, as well as when IL-2, IL-4, IL-10, GM-CSF, IFNγ, and TNFα were tested (data not shown). [Figure 18A] Figure 18B shows the setup for dry bonding, wet bonding, and solubility experiments (modified from Stebbings et al. (2007) J.Immunol. 179:3325-3331). [Figure 18B]This demonstrates that AB79 does not possess agonist activity. AB79 was highly concentrated when added to wells in solution, either by evaporation of the liquid (dry bonding), in contrast to bonding AB79 to wells in solution (wet bonding), or by direct addition to PBMC (soluble). Under all tested conditions, AB79 did not stimulate IL-6 or IL-2, IL-4, IL-8, IL-10, GM-CSF, IFNγ, or TNFα after 24 hours. IL-8 was constitutively produced by PBMC and was not altered by any of the treatments (data not shown). [Figure 19] This shows the evaluation of AB79 binding to cynomolgus monkey CD45+ lymphocytes. Binding of AB79 to CD45+ lymphocytes in unlysed cynomolgus monkey whole blood is shown. CD45+ lymphocytes were gated, and then binding of AB79 (black histogram) or isotype control (red histogram) was evaluated. AB79 binding was detected on a subset of lymphocytes, as illustrated by the percentage of cells to the right of the red dashed line. Binding of isotype control lymphocytes was hardly observed to nowhere. [Figure 20A] The average observed Cmax and pre-medication trough (ng / ml) levels (cycle 1 and cycle 2) are shown. The Cmax (ng / ml) for Ab79 is also shown. [Figure 20B] The mean observed Cmax and pre-medication trough (ng / ml) levels (cycle 1 and cycle 2) are shown. The concentration of Ab79 (ng / ml) is also shown. [Figure 21] This shows that subcutaneously administered Ab79 reduced plasmablast levels in the blood in a dose-dependent manner. [Figure 22] This shows that subcutaneously administered Ab79 reduced plasmablast levels in bone marrow aspirate in a dose-dependent manner. [Figure 23] This shows that subcutaneously administered Ab79 reduced plasma cell levels in bone marrow aspirate in a dose-dependent manner. [Figure 24] This shows the levels of NK cells in the peripheral blood of healthy subjects after a single dose of AB79 via subcutaneous saccharin (SC). [Figure 25]This shows the levels of plasmablasts, monocytes, B cells, T cells, and NK cells in peripheral blood from healthy subjects after a placebo-controlled, placebo-controlled, or single injection of 0.1, 0.3, or 0.6 mg / kg-1 of AB79(SC).

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[0103] The present invention relates to a method for treating CD-38-related diseases by subcutaneous administration of an anti-CD38 antibody.

[0104] In the vascular systems of patients with active disease, approximately 36 times more CD38 molecules are expressed on red blood cells (RBCs) than on myeloma cells. Therefore, off-target expression of CD38 may need to be saturated before, for example, an unbound antibody can pass through the bone marrow and saturate the CD38 expressed on myeloma cells. This may explain why other anti-CD38 antibodies in the art, such as daratumumab and isatuximab, which bind strongly to RBCs and platelets, may require high-dose systemic administration to achieve efficacy.

[0105] AB79, daratumumab, isatuximab, and MOR202 are IgG1s that primarily kill tumors through antibody-dependent cell-mediated cytotoxicity (ADCC). This mechanism requires effector cells, such as NK cells, to bind to antibodies on target cells, form lytic synapses, and secrete cytotoxic substances in a concentrated manner. The frequency of these effector cells in the blood is orders of magnitude lower than that of RBCs and platelets. For example, the ratio of RBCs to NK cells in the blood is 20,000:1. As a result, the effector activity of daratumumab, isatuximab, and MOR202 is reduced because the effector cells primarily bind to anti-CD-38 antibodies bound to RBCs and platelets, thus diverting them from the tumor and preventing the formation of lytic synapses with the tumor, thereby lowering ADCC efficiency.

[0106] Treatment of patients with anti-CD38 antibodies that bind to RBCs and platelets can result in life-threatening side effects. For example, one study reported several serious treatment-related adverse events (TEAEs) in patients with relapsed or refractory multiple myeloma treated with MOR202 (see, e.g., Raab et al. (2015) Blood 126:3035). The most common TEAEs of any grade were anemia (15 patients, 34%), fatigue (14 patients, 32%), infusion-related reactions (IRRs) and leukopenia (13 patients each, 30%), lymphopenia and nausea (11 patients each, 25%). Grade ≥3 TEAEs were reported in 28 patients (64%), the most common of which were lymphopenia (8 patients, 18%) and leukopenia (5 patients, 11%). This included %, and hypertension (4 patients, 9%). IRRs mainly occurred during the initial infusion, and all were grade 1-2 except for one patient (grade 3). Infections were commonly reported (26 patients, 59%), but the majority of cases were not considered treatment-related. MOR202 is used clinically only via IV infusion.

[0107] Other Morphosys antibodies targeting CD38 are known (see, for example, WO2006 / 125640, which discloses four human antibodies MOR03077, MOR03079, MOR03080, and MOR03100, as well as two mouse antibodies OKT10 and IB4). These prior art antibodies are inferior to the antibody intended for use in the present invention (e.g., AB79) for various reasons. MOR03080 binds to human CD38 and cynomolgus monkey CD38, but has low affinity for human CD38 (Biacore K D (=27.5nm). OKT10 binds to human CD38 and cynomolgus monkey CD38, but its affinity for human CD38 is low / moderate (Biacore K D =8.28nm). MOR03079 has high affinity (Biacore K DIt binds to human CD38 at a wavelength of 2.4 nm, but does not bind to cynomolgus monkey CD38. MOR03100 and MOR03077 have moderate to low affinity (Biacore K D (These antibodies bind to human CD38 at 10 nm and 56 nm, respectively.) In comparison, the antibody used in this invention (e.g., AB79) has a high affinity for human CD38 (Biacore K D It binds to human and cynomolgus monkey CD38 at a wavelength of 5.4 nm. Furthermore, prior art antibodies exhibit insufficient ADCC and CDC activity.

[0108] A more efficient advantage of ADCC is that anti-CD38 therapeutic agents can be delivered as low-dose injections. If the antibody for use in this invention (e.g., AB79) is formulated at a concentration of 100 mg / mL, an effective dose for an 80 kg myeloma patient may be administered as a single subcutaneous injection of <1.0 mL. In contrast, an effective dose of daratumumab or isatuximab delivered to this patient in an equivalent form (i.e., 100 mg / mL) would require an administration of 12.8 mL or 8–16 mL, respectively.

[0109] The anti-CD38 method and unit dosage described herein provide a therapeutically effective dose of subcutaneous anti-CD38 antibody, thereby providing unexpected benefits and preventing the side effects, inconveniences, and costs associated with high-dose systemic anti-CD38 antibody therapy.

[0110] The present invention provides a method and unit dosage form for subcutaneously administering a therapeutically effective amount of isolated anti-CD38 antibody to patients in need, for the treatment of diseases for which binding to CD38 is indicated, including hematological malignancies. In some embodiments, the antibody for subcutaneous administration comprises a heavy chain variable region containing SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto) and a light chain variable region containing SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto). The anti-CD38 antibodies provided herein can be therapeutically effective when administered subcutaneously.

[0111] Another advantage of the anti-CD38 antibody of the present invention is that, unlike some other anti-CD38 antibodies in clinical practice, the anti-CD38 antibody of the present invention (e.g., AB79) can bind to cynomolgus monkey (cyno) CD38, providing a useful animal model for preclinical evaluation of drug administration, toxicity, efficacy, etc.

[0112] Another advantage of the anti-CD38 antibodies of the present invention is that they can be used to screen for other antibodies that may be useful in the methods and unit doses of the present invention, as they compete for binding to CD-38 at the same epitope.

[0113] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have meanings generally understood by those skilled in the art. The meaning and scope of such terms shall be clear. However, in the event of any potential ambiguity, the definitions provided herein shall prevail over any dictionary or supplementary definitions. Furthermore, unless the context requires otherwise, singular terms shall include plural forms, and plural terms shall include singular forms. The term “or” shall include “and / or” unless otherwise specified. Furthermore, the use of the terms “including,” “includes,” or “included” is not limited. Terms such as “element” and “component” shall, unless otherwise specifically specified, include both elements and components containing one unit, and elements and components containing more than one subunit.

[0114] In general, the nomenclatures and techniques used in relation to cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein, as well as nucleic acid chemistry and hybridization, as described herein, are well known and commonly used in the art. The methods and techniques of the present invention are generally carried out in accordance with conventional methods well known in the art, unless otherwise indicated, and as described in the various general and more specific references referenced and discussed throughout this specification. Enzyme reactions and purification techniques are carried out in accordance with the manufacturer's specifications, as commonly performed in the art, or as described herein. The nomenclatures and testing procedures and techniques used in relation to analytical chemistry, synthetic organic chemistry, and medicinal chemistry and pharmaceutical chemistry described herein are well known and commonly used in the art. Standard techniques are used for chemical synthesis, chemical analysis, preparation, formulation, delivery, and treatment of patients.

[0115] All headings and section titles are used for clarity and reference purposes only and should not be considered limiting. For example, those skilled in the art will understand the usefulness of combining various aspects of this disclosure from different headings and sections as appropriate, in accordance with the spirit and scope of the invention as described herein.

[0116] To facilitate understanding of the present invention, selected terms are defined below.

[0117] The terms "human CD38" and "human CD38 antigen" refer to the amino acid sequence of Sequence ID No. 1, or its functional fraction such as an epitope, as defined herein (Table 1). Generally, CD38 has a short cytoplasmic tail, a transmembrane domain, and an extracellular domain. The terms "cynomolgus monkey CD38" and "cynomolgus monkey CD38 antigen" refer to the amino acid sequence of Sequence ID No. 2, which is 92% identical to the amino acid sequence of human CD38 (Table 1). Synonyms for CD38 include cyclic ADP-ribose hydrolase, cyclic ADP-ribose hydrolase 1, ADP-ribosyl cyclase, ADP-ribosyl cyclase 1, cADPr hydrolase 1, CD38-rs1, I-19, NIM-R5 antigen, 2'-phospho-cyclic-ADP-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, 2'-phospho-cyclic-ADP-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, and T10. [Table 1]

[0118] The terms “therapeutic dose” and “therapeutic dosage” refer to the amount of a therapeutic agent that is sufficient to reduce or alleviate the severity and / or duration of a disorder or one or more symptoms; prevent the progression of the disorder; cause regression of the disorder; prevent the recurrence, onset, manifestation, or progression of one or more symptoms associated with the disorder; or to enhance or improve the preventive or therapeutic effect (or multiple) of another therapeutic agent (e.g., prophylactic or therapeutic agent) over such a period of time. The therapeutic dose may vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the ability of the drug to elicit the desired response in the individual. A therapeutic dose of an antibody is one in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the antibody or antibody portion. A therapeutic dose of an antibody for tumor treatment may be measured by its ability to stabilize disease progression. The ability of a compound to inhibit cancer may be evaluated in animal model systems that predict efficacy in human tumors.

[0119] The terms “patient” and “subject” include both humans and other animals, particularly mammals. Therefore, the compositions, dosages, and methods disclosed herein are applicable to both human and veterinary therapies. In one embodiment, the patient is a mammal, for example, a human.

[0120] The term "diseases for which binding to CD38 is indicated" means diseases in which the binding of a binding partner (e.g., the anti-CD38 antibody of the present invention) to CD38 provides a preventive or curative effect, including the alleviation of one or more symptoms of the disease. Such binding involves blocking other factors or binding partners of CD38, neutralizing CD38, ADCC, CDC, complement activation, and Alternatively, it may be possible to provide some other mechanism by which the disease is prevented or treated. The factors and binding partners of CD38 include autoantibodies against CD38, which are blocked by the anti-CD38 antibodies of the present invention. Such binding may be adaptive as a result of CD38 expression by cells or subsets of cells, e.g., MM cells, thereby providing a CD38 binding partner to a subject, resulting in the removal of such cells, e.g., lysis, via hemolysis or apoptosis. Such CD38 expression may be normal, overexpressed, inappropriately expressed, or as a result of CD38 activation, for example, compared to normal cells or other cell types during either a non-disease or diseased state.

[0121] The term "blood cancer" refers to malignant neoplasms of hematopoietic tissue, and includes leukemia, lymphoma, and multiple myeloma. Non-limiting examples of conditions associated with abnormal CD38 expression include multiple myeloma (Jackson et al. (1988) Clin. Exp. Immunol. 72:351-356), B-cell chronic lymphocytic leukemia (B-CLL) (Durig et al. (2002) Leukemia 16:30-35, Morabito et al. (2001) Leukemia Res. 25:927-932, Marinov et al. (1993) Neoplasma 40(6):355-358, and Jelinek et al. (2001) Br.J. Haematol. 115:854-861), and acute lymphoblastic leukemia (Keyhani et al. (1999) Leukemia Res. 24:153-159, and Marinov et al. (1993) Neoplasma Examples of leukemias include, but are not limited to, chronic myeloid leukemia (Marinov et al. (1993) Neoplasma 40(6):355-358), acute myeloid leukemia (Keyhani et al. (1999) Leukemia Res. 24:153-159), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia or chronic myeloid leukemia (CML), acute myeloid leukemia or acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), hairy cell leukemia (HCL), myelodysplastic syndrome (MDS), and all subtypes and stages of these leukemias (e.g., CML blast phase (BP), chronic phase (CP), or transitional phase (AP)), as well as other hematological disorders, which are defined by morphological, histochemical, and immunological techniques well known to those skilled in the art.

[0122] The terms "neoplasm" and "neoplastic condition" refer to conditions associated with the loss of normal control over cell proliferation, resulting in one or more symptoms including uncontrolled growth, lack of differentiation, dedifferentiation, local tissue invasion, and metastasis.

[0123] The term "isolated antibody" refers to an antibody that substantially contains no other antibodies with different antigen specificities. For example, an isolated antibody that specifically binds to CD38 substantially contains no antibodies that specifically bind to antigens other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform, or variant of human CD38 or cynomolgus monkey CD38 may have cross-reactivity to other relevant antigens from other species, such as homologs of CD38 species. Furthermore, an isolated antibody may substantially contain no other cellular material and / or chemical substances.

[0124] The terms "red blood cell," "RBC," and "erythrocyte" refer to hemoglobin-containing blood cells derived from the bone marrow that transport oxygen to cells and tissues and carbon dioxide back to the respiratory system. They are also called red blood cells, red blood corpuscles, hematides, and erythroid cells.

[0125] The terms "specific binding", "specifically binds to", and "specific for" when referring to the interaction between a particular antibody, protein, or peptide and an antigen, epitope or other chemical species mean binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is generally a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target. The anti-CD38 antibody of the present invention specifically binds to a CD38 ligand. The terms "specific binding", "specifically binds to", and "specific for" also mean that the interaction is dependent on the presence of a specific structure (e.g., an antigenic determinant or epitope) on the chemical species. For example, an antibody recognizes and binds to a specific protein structure rather than recognizing and binding to proteins as a whole. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free unlabeled A) in a reaction containing labeled "A" and the antibody will reduce the amount of labeled A bound to the antibody. Specific binding to a particular antigen or epitope is, for example, at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12Specific binding to a particular antigen or epitope can also be indicated by an antibody having a KD of M or greater, where KD refers to the dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen will have a KD that is 20, 50, 100, 500, 1,000, 5,000, or 10,000 times greater than that of the control molecule compared to the antigen or epitope in question. Furthermore, specific binding to a particular antigen or epitope can be indicated, for example, by an antibody having a KA or Ka to that epitope that is at least 20, 50, 100, 500, 1,000, 5,000, or 10,000 times greater than that of the control compared to the antigen or epitope, where KA or Ka refers to the association rate of a particular antibody-antigen interaction.

[0126] The term “over a period of time” refers to any period of time, such as a few minutes, a few hours, a few days, a few months, or a few years. For example, “over a period of time” could mean at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 1 year, or any time interval in between. In other words, antibodies from this composition can be absorbed by the individual to whom it is administered over a period of at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 1 year, or any time interval in between.

[0127] A composition that "substantially" contains a certain component means that the composition contains more than about 80% by weight of that component. Preferably, the composition may contain more than about 90% by weight of that component. Preferably, the composition may contain more than about 95% by weight of that component. Preferably, the composition The substance may contain more than approximately 97% by weight of the component. Preferably, the composition may contain more than approximately 98% by weight of the component. Preferably, the composition may contain more than approximately 99% by weight of the component.

[0128] The term "approximately" refers to a range of similar numbers, degrees, volumes, or time periods, where there are only slight fluctuations of up to 10%.

[0129] The term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering the compound of the present invention to a mammal. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulation materials involved in transporting or delivering the compound of interest from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for intravenous administration. In another embodiment, the pharmaceutically acceptable carrier is suitable for topical injection. In another embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration. In yet another embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous injection.

[0130] The term “pharmaceutical composition” refers to preparations suitable for administration to subjects and treatment of diseases. When the anti-CD38 antibodies of the present invention are administered as pharmaceuticals to mammals, such as humans, they may be administered “as is” or as pharmaceutical compositions containing the anti-CD38 antibodies in combination with pharmaceutically acceptable carriers and / or other excipients. Pharmaceutical compositions may be in the form of unit dosage forms for administering a specific dose of anti-CD38 antibody at a specific concentration, a specific amount, or a specific volume. Pharmaceutical compositions are provided that contain anti-CD38 antibodies either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers. Preferably, pharmaceutical compositions may contain unit dosage forms according to the present invention either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers. Preferably, pharmaceutical compositions may contain human anti-CD38 antibodies, such as those described herein, either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers.

[0131] The conventional structural unit of an antibody typically consists of a tetramer. Each tetramer typically comprises two identical polypeptide chain pairs, each pair having one "light" chain (typically with a molecular weight of about 25 kDa) and one "heavy" chain (typically with a molecular weight of about 50–70 kDa). Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, defining antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has several subclasses, including but not limited to IgM1 and IgM2. Thus, an "isotype" refers to any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions. The known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD, and IgE. Therapeutic antibodies can also contain hybrids of isotypes and / or subclasses.

[0132] Each variable weight (VH) and variable light (VL) region (approximately 100-110 amino acids long) is composed of three hypervariable regions called "complementarity-determining regions" (CDRs) and four framework regions (FRs) (approximately 15-30 amino acids long), which are arranged from the amino terminus to the carboxyl terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. "Variable" refers to the fact that the sequence of CDRs differs significantly between antibodies, thereby determining the unique antigen-binding site.

[0133] The hypervariable region generally consists of amino acid residues from approximately 24-34 (LCDR1, where "L" represents the light chain), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and from approximately 31-35B (HCDR1, where "H" represents the heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region (Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD), and / or those residues that form the hypervariable loop (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the light chain variable region, and residues 26-32 (HCDR1), 53-55 (HCDR2), and 96-101 (HCDR3) in the heavy chain variable region) (Chothia and Lesk (1987) J.Mol.Biol.196:901-917).

[0134] The Kabat numbering system is generally used when referring to residues in variable domains (approximately residues 1-107 in the light chain variable region and residues 1-113 in the heavy chain variable region) (e.g., Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD), while the EU numbering system is used for the Fc region.

[0135] The term "immunoglobulin (Ig) domain" refers to a region of immunoglobulin that has a specific tertiary structure. In addition to the variable domain, each heavy and light chain has a constant domain, namely a constant heavy (CH) domain, a constant light (CL) domain, and a hinge domain. In the association of IgG antibodies, each IgG isotype has three CH regions. The carboxyl terminus of each HC and LC defines a constant region that primarily performs effector functions. Therefore, the "CH" domains in the association of IgG are as follows: "CH1" refers to positions 118-220 on the EU index as in Kabat; "CH2" refers to positions 237-340 on the EU index as in Kabat; and "CH3" refers to positions 341-447 on the EU index as in Kabat.

[0136] Another type of Ig domain in the heavy chain is the hinge region. The term “hinge region” refers to a flexible polypeptide containing amino acids between the first and second constant domains of an antibody. Structurally, the CH1 domain of IgG terminates at position 220 by EU, and the CH2 domain of IgG begins at residue 237 by EU. Thus, with respect to IgG, the antibody hinge is defined herein as encompassing positions 221 (D221 in IgG1) to 236 (G236 in IgG1), where the numbering is by EU index as in Kabat. In some embodiments, a lower hinge is included, for example in relation to the Fc region, and this “lower hinge” generally refers to position 226 or 230.

[0137] The term "Fc region" refers to the polypeptide, including the constant region of an antibody excluding the first constant region immunoglobulin domain, and in some examples, part of the hinge. Therefore, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge at the N-terminus of these domains. In the case of IgA and IgM, Fc may also include the J chain. In the case of IgG, the Fc domain includes the immunoglobulin domains Cγ2 and Cγ3, as well as the lower hinge region between Cγ1 and Cγ2. The boundaries of the Fc region can vary, but the heavy chain Fc region of human IgG is typically defined to include residues C226 or P230 and its carboxyl terminus, where numbering is by EU index as in Kabat. In some embodiments, amino acid modifications are made to the Fc region, for example, to modify binding to one or more FcγR receptors or FcRn receptors, as fully described below.

[0138] CD38 antibody Therefore, the present invention provides isolated anti-CD38 antibodies that specifically bind to human and primate CD38 proteins for use in subcutaneous administration methods and unit dosage forms. Particularly useful in the present invention are antibodies that bind to both human and primate CD38 proteins, especially those of cynomolgus monkeys (Macaca Primates such as fascicularis (crab-eating macaque, also referred to herein as "cyno") are used in clinical trials.

[0139] In some embodiments, the anti-CD38 antibody of the present invention interacts with CD38 at several amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294, based on human sequence numbering. Preferably, the anti-CD38 antibody of the present invention may interact with CD38 at several amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of Sequence ID No. 1, based on human sequence numbering. Preferably, the anti-CD38 antibody of the present invention interacts with CD38 at several amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, F274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 2. It should be noted that these residues are identical in both humans and cynomolgus monkeys, except that S274 is actually F274 in cynomolgus monkeys. These residues may represent immunodominant epitopes and / or residues within the footprint of a particular antigen-binding peptide.

[0140] In some embodiments, the anti-CD38 antibody for use according to the present invention comprises a heavy chain containing the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the present invention comprises a light chain containing the following CDR amino acid sequences, namely SSNIGDNY (SEQ ID NO: 6, HCDR1 AB79), RDS (SEQ ID NO: 7, HCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, HCDR3 AB79) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the present invention comprises a heavy chain containing the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79) or variants of those sequences having up to three amino acid changes, and a light chain containing the following CDR amino acid sequences, namely SSNIGDNY (SEQ ID NO: 6, HCDR1 AB79), RDS (SEQ ID NO: 7, HCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, HCDR3 AB79) or variants of those sequences having up to three amino acid changes. In some embodiments, the anti-CD38 antibody comprises the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH ( The antibody contains a heavy chain containing the following CDR amino acid sequence (SEQ ID NO: 5, HCDR3 AB79). In some embodiments, the antibody contains a light chain containing the following CDR amino acid sequence, namely SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79). In some embodiments, the antibody contains the following CDR amino acid sequence, namely GFTFDDYG (SEQ ID NO: 3, HCDR1 The antibody comprises a heavy chain containing AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79), and a light chain containing the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79). In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Preferably, the VH chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the VH chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 85% sequence identity to SEQ ID NO: 9. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 90% sequence identity with SEQ ID NO: 9. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 95% sequence identity with SEQ ID NO: 9. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 97% sequence identity with SEQ ID NO: 9. Preferably, the VH chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 99% sequence identity with SEQ ID NO: 9.

[0141] In some embodiments, the antibody comprises a heavy chain containing the variable heavy (VH) chain amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (Sequence ID 9).

[0142] In some embodiments, the antibody includes a light chain containing an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 85% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 90% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 95% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 97% sequence identity with SEQ ID NO: 10. Preferably, the VL chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 99% sequence identity with SEQ ID NO: 10.

[0143] In some embodiments, the antibody comprises the variable light (VL) chain amino acid sequence of SEQ ID NO: 10. Includes light chain. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (Sequence ID 10).

[0144] In some embodiments, the antibody comprises a heavy chain containing the VH chain amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein, and a light chain containing the VL chain amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0145] As those skilled in the art will understand, variable heavy and light chains can bind to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4.

[0146] In some embodiments, the antibody comprises a heavy chain (HC) containing an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 85% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 90% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may contain a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 95% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, and the remainder of the heavy chain may have at least 97% sequence identity with SEQ ID NO: 11. Preferably, the heavy chain may include CDR sequences as defined by SEQ ID NOs: 3, 4, and 5, and the remainder of the heavy chain may have at least 99% sequence identity with SEQ ID NO: 11.

[0147] In some embodiments, the antibody contains the heavy chain (HC) amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 11).

[0148] In some embodiments, the antibody includes a light chain (LC) containing an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 85% sequence identity to SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. The light chain may contain a sequence, and the remainder of the light chain may have at least 90% sequence identity with SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 95% sequence identity with SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 97% sequence identity with SEQ ID NO: 12. Preferably, the light chain may contain a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 99% sequence identity with SEQ ID NO: 12.

[0149] In some embodiments, the antibody contains the light chain (LC) amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (Sequence ID 12). In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11 or a variant thereof as described herein, and the LC amino acid sequence of SEQ ID NO: 12 or a variant thereof as described herein.

[0150] The present invention comprises antibodies that bind to CD38 in both humans and cynomolgus monkeys and interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the following amino acid residues, namely, K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294, based on human numbering in SEQ ID NOs: 1 and 2. Preferably, the antibody may interact with at least 90% of these amino acid residues. Preferably, the antibody may interact with at least 95% of these amino acid residues. Preferably, the antibody may interact with at least 97% of these amino acid residues. Preferably, the antibody may interact with at least 98% of these amino acid residues. Preferably, the antibody may interact with at least 99% of these amino acid residues. Preferably, the antibody may interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids, namely, K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294, based on human numbering.

[0151] In some embodiments, the antibody is full-length. As used herein, “full-length antibody” means the structure that constitutes the native biological form of the antibody, including one or more modifications as outlined herein, including variable and constant regions.

[0152] Alternatively, the antibody may be in various structures, including, but not limited to, antibody fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimes”), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as “antibody conjugates”), and their respective fragments. Specific antibody fragments include (i) Fab fragments consisting of VL, VH, CL, and CH1 domains, (ii) Fd fragments consisting of VH and CH1 domains, (iii) Fv fragments consisting of VL and VH domains of a single antibody, (iv) dAb fragments consisting of a single variable region (Ward et al. (1989) Nature 341:544-546), (v) isolated CDR regions, and (vi) two linked Fab fragments. (vii) a single-stranded Fv molecule (scFv) in which the bivalent fragment, the F(ab')2 fragment, is linked by a peptide linker, thereby enabling the two domains to associate and form an antigen-binding site (Bird et al. (1988) Science 242:423-426, Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883), (viii) bispecific single-stranded Fv (WO03 / 11161), and (ix) a multivalent or multispecific fragment constructed by gene fusion, which includes, but is not limited to, "diabodies" or "triabodies" (Tomlinson et al. (2000) Methods Enzymol. 326:461-479, WO94 / 13804, Holliger et al. al.(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448).

[0153] Preferably, the antibody may be a Fab fragment. Preferably, the antibody may be an Fv fragment. Preferably, the antibody may be an Fd fragment. Preferably, the antibody structure may be an isolated CDR region. Preferably, the antibody may be an F(ab')2 fragment. Preferably, the antibody may be an scFv fragment.

[0154] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 1, 2, 4, 8, 10, 15, 20, 25, and / or 30 days after administration.

[0155] The term "significant level of cellular depletion" may refer to a level of cellular depletion that has adverse consequences for the subject.

[0156] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion one day after administration.

[0157] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion two days after administration.

[0158] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion four days after administration.

[0159] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 8 days after administration.

[0160] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 10 days after administration.

[0161] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 15 days after administration.

[0162] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 20 days after administration.

[0163] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 25 days after administration.

[0164] In some embodiments, the antibody does not cause significant levels of red blood cell and / or platelet depletion 30 days after administration.

[0165] Preferably, the antibodies used in this invention may result in the depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs after treatment. Preferably, the antibodies used in this invention may result in the depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets after treatment.

[0166] antibody modification The present invention further provides variant anti-CD38 antibodies. Specifically, there are several modifications that can be performed on the antibodies of the present invention, including, but not limited to, amino acid modifications (affinity maturation) in the CDR, amino acid modifications in the Fc region, glycosylated variants, and other types of covalent modifications.

[0167] The term "variant" means a polypeptide that is different from that of the parent polypeptide. Amino acid variants can include amino acid substitutions, insertions, and deletions. In general, a variant can contain any number of modifications as long as the protein's function is still present, as described herein. That is, for example, in the case of an amino acid variant created using the CDR of AB79, the antibody should still bind specifically to CD38 in both humans and cynomolgus monkeys. The term "variant Fc region" means an Fc sequence that is different from that of the wild-type or parent Fc sequence due to at least one amino acid modification. An Fc variant may refer to the Fc polypeptide itself, a composition containing the Fc variant polypeptide, or an amino acid sequence. For example, if an amino acid variant is created using an Fc region, the variant antibody should retain the function required for the antibody's specific use or indication. For example, one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions, e.g., 1-10, 1-5, 1-4, 1-3, and 1-2 substitutions can be utilized. For example, as generally outlined in U.S. Patent Applications No. 11 / 841,654, No. 12 / 341,769, U.S. Patent Publications No. 2004013210, No. 20050054832, No. 20060024298, No. 20060121032, No. 20060235208, No. 20070148170, and U.S. Patents No. 6,737,056, No. 7,670,600, and No. 6,086,875 (all of these patents are expressly invoked in whole by reference), suitable modifications can be made at one or more positions, particularly for specific amino acid substitutions that increase binding to the Fc receptor.

[0168] Preferably, the variant maintains the function of the parent sequence, i.e., the variant is a functional variant. Preferably, the antibody containing the variant sequence maintains the function of the parent antibody, i.e., the antibody containing the variant sequence is capable of binding to human CD38. Preferably, treatment with the variant may result in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs. Preferably, treatment with the variant may result in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets.

[0169] Variants can be considered in terms of similarity (i.e., amino acid residues having similar chemical properties / functions), and preferably, variants are represented in terms of sequence identity.

[0170] Sequence comparison can be performed visually or, more commonly, with the assistance of readily available sequence comparison programs. These publicly available and commercially available computer programs can calculate sequence identity between two or more sequences.

[0171] For example, it may be desirable to have 1 to 5 modifications in the Fc region and 1 to 5 modifications in the Fv region of the wild-type or manipulated protein. The variant polypeptide sequence will preferably have at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the parent sequence (e.g., the variable region, constant region, and / or heavy and light chain sequences of AB79). Preferably, the variant may have at least 80% sequence identity with the parent sequence. Preferably, the variant may have at least 85% sequence identity with the parent sequence. Preferably, the variant may have at least 90% sequence identity with the parent sequence. Preferably, the variant may have at least 92% sequence identity with the parent sequence. Preferably, the variant may have at least 95% sequence identity with the parent sequence. Preferably, the variant may have at least 97% sequence identity with respect to the parent sequence. Preferably, the variant may have at least 98% sequence identity with respect to the parent sequence. Preferably, the variant may have at least 99% sequence identity with respect to the parent sequence.

[0172] In one embodiment, sequence identity is determined over the entire sequence. In one embodiment, sequence identity is determined over the entire candidate sequence being compared with the sequences listed herein.

[0173] The term "amino acid substitution" refers to the replacement of an amino acid at a specific position in the parent polypeptide sequence with another amino acid. For example, substitution S100A refers to a variant polypeptide in which the serine at position 100 is replaced with alanine. Preferably, the amino acid substitution may be a conservative amino acid substitution. Preferably, the variant may contain one or more, for example, two or three, conservative amino acid substitutions. Amino acids having similar biochemical properties may be defined as amino acids that can be substituted via conservative substitution.

[0174] Unless otherwise expressly specified by reference to specific individual amino acids herein, amino acids may be substituted using conservative substitutions as listed below. Aliphatic polar uncharged amino acids may be cysteine, serine, threonine, methionine, asparagine, or glutamine residues. Aliphatic polar charged amino acids may be aspartic acid, glutamic acid, lysine, or arginine residues. Aromatic amino acids may be histidine, phenylalanine, tryptophan, or tyrosine residues. Conservative substitutions may be made, for example, according to Table 2 below. Amino acids in the same block in the second column, preferably in the same row in the third column, may be substituted for each other.

[0175] [Table 2]

[0176] The term "amino acid insertion" refers to the insertion of an amino acid at a specific position in the parent polypeptide sequence. It means the addition of something.

[0177] The term "amino acid deletion" refers to the removal of an amino acid at a specific position in the parent polypeptide sequence.

[0178] The terms “parent antibody” and “precursor antibody” refer to unmodified antibodies that are subsequently modified to create variants. In some embodiments, the parent antibody as used herein is AB79. In some embodiments, the parent antibody as used herein comprises a VH chain having the amino acid sequence of SEQ ID NO: 9 and a VL chain having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the parent antibody as used herein comprises a heavy chain amino acid sequence of SEQ ID NO: 11 and a light chain amino acid sequence of SEQ ID NO: 12. The parent antibody may refer to the polypeptide itself, a composition containing the parent antibody, or the amino acid sequence encoding it. Therefore, the term “parent Fc polypeptide” refers to an Fc polypeptide that is modified to create variants.

[0179] The terms "wild type," "WT," and "natural" refer to amino acid or nucleotide sequences found in nature, including allele variations. Wild-type proteins, polypeptides, antibodies, immunoglobulins, IgG, etc., have amino acid or nucleotide sequences that are not intentionally modified.

[0180] In some embodiments, one or more amino acid modifications are performed on one or more CDRs of the anti-CD38 antibody. Generally, only one, two, or three amino acids are substituted in any single CDR, and generally, four, five, six, seven, eight, nine, or ten or fewer changes are performed within a set of CDRs. However, it should be understood that any combination of no substitutions, one, two, or three substitutions in any CDR can be independently and selectively combined with any other substitutions.

[0181] In some cases, amino acid modifications in CDRs are referred to as "affinity maturation." An "affinity-matured" antibody is one that has one or more modifications in one or more CDRs that improve the affinity of the antibody to the antigen compared to a parent antibody that does not have such modifications. In some cases, it may be desirable to reduce the affinity of the antibody to its antigen.

[0182] Affinity maturation can be performed to increase the binding affinity of an antibody to an antigen by at least approximately 10%–50%, 100%, 150%, or more, or by 1–5 times, compared to the “parent” antibody. A preferred affinity-matured antibody will have an affinity for the target antigen at a nanomolar or even picomolar concentration. Affinity-matured antibodies are produced by known procedures (e.g., Marks et al. (1992) Biotechnol. 10:779-783, Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91:3809-3813, Shier et al. (1995) Gene 169:147-155, Yelton et al. (1995) J. Immunol. 155:1994-2004, Jackson et al. (1995) J. Immunol. 154(7):3310-9, and Hawkins et al. (1992) J. Mol. Biol. 226:889-896).

[0183] Alternatively, "silent" amino acid modifications, such as those that do not significantly alter the antibody's affinity for the antigen, can be performed on one or more of the CDRs of the antibody of the present invention. These can be done for several reasons, including optimization of expression (which can be done for the nucleic acids encoding the antibody of the present invention).

[0184] Therefore, variant CDRs and antibodies are included within the definitions of CDRs and antibodies of the present invention. Furthermore, the antibodies of the present invention may include amino acid modifications in one or more of the CDRs described in SEQ ID NOs: 3-8. Additionally, as outlined below, amino acid modifications may also be carried out independently and optionally in any region outside the CDR, including the framework and constant region.

[0185] In some embodiments, variant antibodies of AB79 that are specific to human CD38 (SEQ ID NO: 1) and cynomolgus monkey CD38 (SEQ ID NO: 2) are described. This antibody consists of six CDRs, each of which may differ from SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and / or SEQ ID NO: 8 by only 0, 1, or 2 amino acid substitutions.

[0186] In addition to the modifications outlined above, other modifications can be performed. For example, the molecule may be stabilized by incorporating disulfide crosslinks that link the VH and VL domains (Reiter et al. (1996) Nature Biotech. 14:1239-1245). Furthermore, there are various covalent modifications of antibodies that can be performed, as outlined below.

[0187] Covalent modifications of antibodies are within the scope of this invention and are generally, though not always, performed post-translation. For example, some types of covalent modifications of antibodies are introduced into the molecule by reacting specific amino acid residues of the antibody with an organic derivatizing agent that can react with a side chain or N-terminal or C-terminal residue of choice.

[0188] In some embodiments, the anti-CD38 antibody of the present invention specifically binds to one or more residues or regions of CD38, but does not cross-react with other proteins homologous to CD38, such as BST-1 (bone marrow stromal cell antigen 1) and / or Mo5 (also known as CD157).

[0189] Typically, the absence of cross-reactivity means less than approximately 5% competitive inhibition between molecules, as assessed by ELISA and / or FACS analysis using sufficient amounts of the molecule under suitable assay conditions.

[0190] Inhibition of CD38 activity and reduction of side effects The disclosed antibodies may be used in blocking ligand-receptor interactions or inhibiting receptor component interactions. The anti-CD38 antibodies of the present invention may be “blocking” or “neutralizing.” The term “neutralizing antibody” refers to an antibody that, upon binding to CD38, results in the inhibition of the biological activity of CD38, such as its ability to interact with ligands, enzymatic activity, signaling ability, and in particular, its ability to induce activated lymphocytes. Inhibition of the biological activity of CD38 can be assessed by one or more of several standard in vitro or in vivo assays known in the art.

[0191] The terms “inhibit binding” and “block binding” (for example, when referring to the inhibition / blockage of the binding of a CD38 antibody to CD38) encompass both partial and complete inhibition / blockage. Inhibition / blockage of the binding of a CD38 antibody to CD38 can reduce or alter the normal level or type of cellular signaling that occurs when the CD38 antibody binds to CD38 without inhibition or blockage. Inhibition and blockage are also intended to include any measurable reduction in the binding affinity of the CD38 antibody to CD38 when in contact with the anti-CD38 antibody compared to the ligand not in contact with the anti-CD38 antibody, e.g., blockage of the binding of the CD38 antibody to CD38 by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. Preferably, blockage of the binding of the CD38 antibody to CD38 may be at least about 70%. Preferably, the CD38 antibody to CD3 Blocking of binding to 8 may be at least about 80%. Preferably, blocking of the binding of the CD38 antibody to CD38 may be at least about 90%.

[0192] The disclosed anti-CD38 antibodies may also inhibit cell growth. The term “inhibits growth” means any measurable decrease in cell growth when in contact with the anti-CD38 antibody compared to the growth of the same cells not in contact with the anti-CD38 antibody, e.g., inhibition of growth of a cell culture by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. Preferably, the inhibition of growth may be at least about 70%. Preferably, the inhibition of growth may be at least about 80%. Preferably, the inhibition of growth may be at least about 90%.

[0193] In some embodiments, the disclosed anti-CD38 antibodies are capable of depleting activated lymphocytes and plasma cells. In this context, the term “depletion” means a measurable decrease in serum levels of activated lymphocytes and / or plasma cells in a subject compared to an untreated subject. Generally, depletion of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100% is observed. Preferably, depletion may be at least 50%. Preferably, depletion may be at least 60%. Preferably, depletion may be at least 70%. Preferably, depletion may be at least 80%. Preferably, depletion may be at least 90%. Preferably, depletion may be at least 100%. As shown in the examples below, one particular advantage of the antibodies of the present invention is the resilience of these cells after administration. In other words, as is known with regard to some treatments (e.g., with anti-CD20 antibodies), cell depletion can persist for a long time and cause undesirable side effects. As shown herein, the effects on activated lymphocytes and / or plasma cells are reversible.

[0194] The anti-CD38 antibody of the present invention enables reduced side effects compared to prior art anti-CD38 antibodies. In some embodiments, the antibody for use according to the present invention, e.g., AB79, does not induce TEAEs. In some embodiments, the antibody for use according to the present invention, e.g., AB79, enables a reduction in the incidence of TEAEs in the patient population compared to other anti-CD38 antibodies such as MOR202. TEAEs are typically referred to by grades 1, 2, 3, 4, and 5, with grade 1 being the least severe TEAE and grade 5 being the most severe TEAE. Based on FDA and other guidelines regarding the Common Terminology Criteria for Adverse Events of Antitumor Drugs (CTCAE) standards (see, for example, https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, and https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / ctc.htm, and Nilsson and Koke (2001) Drug Inform.J.35:1289-1299), such grades are generally determined as follows: Grade 1 is mild: no symptoms or mild symptoms; clinical or diagnostic findings only; no treatment required. Grade 2 is moderate: requires minimal, local, or non-invasive treatment; age-appropriate limitations in instrumental activities of daily living ("ADL"). Grade 3 is severe or medically significant but not immediately life-threatening: requires hospitalization or extended hospital stay; incapacitation; limitations in daily living activities (ADL). Grade 4 is life-threatening; requires emergency treatment. Grade 5 is death related to the adverse event (AE).

[0195] In some embodiments, the antibody used in the present invention, e.g., AB79, enables a reduction in the grade of TEAE in a patient population compared to other anti-CD38 antibodies such as MOR202. In some embodiments, the antibody used in the present invention, e.g., AB79, enables a reduction in the grade of TEAE from grade 5 to grade 4 compared to other anti-CD38 antibodies. This enables a reduction. In some embodiments, the antibody for use according to the present invention, e.g., AB79, enables a reduction in the grade of TEAE from grade 4 to grade 3 compared to other anti-CD38 antibodies. In some embodiments, the antibody for use according to the present invention, e.g., AB79, enables a reduction in the grade of TEAE from grade 3 to grade 2 compared to other anti-CD38 antibodies. In some embodiments, the antibody for use according to the present invention, e.g., AB79, enables a reduction in the grade of TEAE from grade 2 to grade 1 compared to other anti-CD38 antibodies.

[0196] In some embodiments, the antibody for use according to the present invention, for example AB79, enables a reduction in the grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, lymphopenia, and nausea.

[0197] In some embodiments, anti-CD38 antibodies result in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs. In some embodiments, AB79 antibodies result in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs. In some embodiments, AB79 antibodies result in depletion of less than 10% of RBCs.

[0198] In some embodiments, anti-CD38 antibodies result in depletion of less than 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% of platelets. In some embodiments, AB79 antibodies result in depletion of less than 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% of platelets. In some embodiments, AB79 antibodies result in depletion of less than 10% of platelets.

[0199] In some embodiments, diagnostic tests are used to determine the presence and / or grade of anemia, including hemolytic anemia. Diagnostic tests for anemia, including hemolytic anemia, include measurement of hemoglobin levels. Generally, hemoglobin levels are interpreted as follows: (i) very mild / absence of anemia: ≥12.0 g / dL, (ii) mild: 10-12 g / dL, (iii) moderate: 8-10 g / dL, (iv) severe: 6-8 g / dL, and (v) very severe: ≤6 g / dL. Other diagnostic tests for anemia, including hemolytic anemia, include measurement of haptoglobin levels. Generally, a haptoglobin level ≤25 mg / dL is an indicator of the presence of anemia, including hemolytic anemia. Other diagnostic tests include the direct antiglobulin test (DAT) (also known as the direct Coombs test), which is used to determine whether RBCs are coated in vivo with immunoglobulin, complement, or both.

[0200] In some embodiments, diagnostic tests are used to determine the presence and / or grade of thrombocytopenia. Generally, diagnostic tests for thrombocytopenia involve measuring the number of platelets per microliter (μL) of blood. Typically, 150 × 10¹⁶ platelets per μL of blood. 3 -450×10 3 There are 150 × 10 platelets per 1 μL of blood. Generally, <150 × 10 3 Thrombocytopenia is diagnosed when a certain number of platelets are present per μL of blood. 70-150 × 10¹⁴ 3 If individual cells are present, it is generally diagnosed as mild thrombocytopenia. 20-70 × 10⁴ cells per μL 3If these numbers are present, it is generally diagnosed as moderate thrombocytopenia. <20 × 10⁴ per μL of blood 3 If these symptoms are present, it is generally diagnosed as severe thrombocytopenia.

[0201] Signs of disease The antibodies, methods, and drug units of the present invention can be used in a variety of applications, including the treatment or mitigation of CD38-related diseases.

[0202] CD38 is expressed in immature hematopoietic cells, downregulated in mature cells, and reexpressed at high levels in activated lymphocytes and plasma cells. For example, high expression of CD38 is observed in activated B cells, plasma cells, activated CD4+ T cells, activated CD8+ T cells, NK cells, NKT cells, mature dendritic cells (DCs), and activated monocytes. Certain pathological conditions are associated with cells expressing CD38, and certain pathological conditions are associated with overexpression, high-density expression, or upregulated expression of CD38 on the cell surface. Whether a cell population expresses CD38 can be determined by methods known in the art, such as flow cytometry or immunohistochemical assays of the percentage of cells labeled with an antibody that specifically binds to CD38 in a given population, as is generally described below for diagnostic purposes. For example, a population of cells in which CD38 expression is detected in approximately 10–30% of cells may be considered weakly positive for CD38, and a population of cells in which CD38 expression is detected in more than approximately 30% of cells may be considered definitively positive for CD38 (as described in Jackson et al. (1988) Clin. Exp. Immunol. 72:351–356). However, other criteria can be used to determine whether a population of cells expresses CD38. The density of expression on the cell surface can be determined using methods known in the art, such as flow cytometry measurement of the mean fluorescence intensity of cells fluorescently labeled with an antibody that specifically binds to CD38.

[0203] The therapeutic anti-CD38 antibody of the present invention binds to CD38-positive cells and depletes these cells through multiple mechanisms of action, including both the CDC and ADCC pathways.

[0204] It is known in the art that certain pathological conditions are associated with cells expressing CD38, and that certain pathological conditions are associated with overexpression, high-density expression, or upregulated expression of CD38 on the surface of cells. Whether a cell population expresses CD38 can be determined by methods known in the art, such as flow cytometry or immunohistochemical assays of the percentage of cells in a given population labeled with an antibody that specifically binds to CD38, as is generally described below for diagnostic purposes. For example, a cell population in which CD38 expression is detected in about 10–30% of cells may be considered weakly positive for CD38, and a cell population in which CD38 expression is detected in more than about 30% of cells may be considered definitively positive for CD38 (as described in Jackson et al. (1988) Clin. Exp. Immunol. 72:351–356), but other criteria can be used to determine whether a cell population expresses CD38. The expression density on the cell surface can be determined using methods known in the art, such as flow cytometry measurement of the average fluorescence intensity of cells fluorescently labeled with an antibody that specifically binds to CD38.

[0205] In one embodiment, the present invention provides a method for treating a condition associated with the proliferation of CD38-expressing cells, comprising administering a pharmaceutically effective amount of a disclosed antibody to a patient. In some embodiments, the condition is cancer, and in certain embodiments, the cancer is hematological cancer. In some embodiments, the condition is multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, or Burkitt lymphoma. In some embodiments, the condition is multiple myeloma.

[0206] In some embodiments of the present invention, the hematological cancer is selected from the group consisting of chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and acute lymphocytic leukemia. In this case, blood cancer is chronic lymphocytic leukemia. In some embodiments of the present invention, blood cancer is chronic myeloid leukemia. In some embodiments of the present invention, blood cancer is acute myeloid leukemia. In some embodiments of the present invention, blood cancer is acute lymphocytic leukemia.

[0207] In some embodiments, the disease state is multiple myeloma.

[0208] CLL is the most common adult leukemia in the Western world. CLL is characterized by clonal proliferation of mature-looking lymphocytes that affect lymph nodes and other lymphoid tissues, and is progressive with bone marrow infiltration and presence in the peripheral blood. B-cell type (B-CLL) accounts for the majority of cases.

[0209] B-cell chronic lymphocytic leukemia (B-CLL) B-CLL is an incurable disease characterized by a progressive increase in anerergic monoclonal B-lineage cells that accumulate in the bone marrow and peripheral blood over many years. CD38 expression is considered an independent poor prognostic factor for B-CLL (Hamblin et al. (2002) Blood 99:1023-9).

[0210] B-CLL is characterized by two subtypes: mild and aggressive. These clinical phenotypes correlate with the presence or absence of somatic mutations in the immunoglobulin heavy chain variable region (IgVH) gene. As used herein, mild B-CLL refers to the disorder in subjects who have a mutated IgVH gene and / or exhibit one or more clinical phenotypes associated with mild B-CLL. As used herein, the term aggressive B-CLL refers to the disorder in subjects who have an unmutated IgVH gene and / or exhibit one or more clinical phenotypes associated with aggressive B-CLL.

[0211] Current standard treatment for B-CLL is palliative, primarily with the cell division inhibitors chlorambucil or fludarabine. If relapse occurs, combination therapy with fludarabine and cyclophosphamide, often combined with rituximab (a monoclonal antibody against CD20) or alemtuzumab (a monoclonal antibody against CD52), is frequently initiated. In one study, 35 patients with relapsed or refractory invasive B-cell NHL received high-dose chemotherapy (HCT), followed by rituximab 375 mg / m², starting on day 40. 2 The drug was administered weekly for four doses, with a further four doses repeated starting on day 180. Rituximab infusion was well-tolerated, with only one case of grade 3 / 4 fluid-related toxicity. The only unexpected adverse event observed in this study was delayed neutropenia in more than half of the patients (19 out of 35 patients, 46 episodes of grade 3 or 4 neutropenia, Kosmas et al. (2002) Leukemia 16:2004-2015 (available online at https: / / www.nature.com / articles / 2402639)). In another study, six patients received alemtuzumab intravenously three times a week, every other day, for 12 weeks. The dose was escalated daily until the patient could tolerate it (3, 10, then 30 mg). The main TEAEs were hematological adverse events: anemia, neutropenia (6 / 6 patients each), and thrombocytopenia (5 / 6 patients) (Ishizawa et al. (2017) Jpn.J.Clin.Oncol.47(1):54-60). Therefore, despite the reduction in hematological adverse events, there remains a significant unmet medical need for the treatment of B-CLL. In some embodiments, a method for treating B-CLL using the disclosed anti-CD38 antibody is provided, which may be carried out using combination therapy comprising any one of the above-mentioned drugs selectively and independently, as outlined below.

[0212] Multiple myeloma (MM) Multiple myeloma (MM) is a B-cell lineage disease characterized by the neoplastic proliferation of plasma cells in the bone marrow. It is a malignant disorder. Pharmacological findings in healthy volunteers supported further investigation of MM (Fedyk et al. (2018) Blood 132:3249 (the whole is incorporated herein by reference)). Myeloma cell proliferation causes a variety of effects, including osteolytic lesions (holes), decreased red blood cell count, abnormal protein production (with adjunctive damage to the kidneys, nerves, and other organs), reduced immune system function, and elevated blood calcium levels (hypercalcemia). Currently, treatment options include chemotherapy, preferably accompanied by autologous stem cell transplantation (ASCT) where possible. These treatment regimens show moderate response rates. However, only slight changes in overall survival are observed, with a median survival of approximately 3 years. Therefore, there is a significant and unmet medical need for the treatment of multiple myeloma. In some embodiments, methods for treating multiple myeloma using disclosed antibodies are provided.

[0213] Monoclonal gammaglobulinemia of unknown significance (MGUS) and smoldering multiple myeloma (SMM) Monoclonal gammaglobulinemia of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic pre-malignant disorders characterized by monoclonal plasma cell proliferation in the bone marrow and the absence of terminal organ damage.

[0214] Smoldering multiple myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells with a high risk of progression to symptomatic or active multiple myeloma (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590). An international consensus criteria defining SMM was adopted in 2003, requiring patients to have an M-protein level >30 g / L and / or >10% clonal plasma cells in the bone marrow (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757). Patients must not have associated organ or tissue impairment such as bone lesions or symptoms. Recent studies have identified two subsets of SMM: i) patients with progressing disease, and ii) patients with non-progressing disease (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757).

[0215] Due to the absence of end-organ damage, SMM is similar to monoclonal gammopathy of undetermined significance (MGUS) (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590). However, clinically, SMM has a much higher probability of progression to active multiple myeloma or amyloidosis within 20 years (78% probability for SMM versus 21% probability for MGUS) (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590).

[0216] The international consensus criteria defining MGUS require that the patient has an M-protein level <30 g / L, <10% plasma cells in the bone marrow, and the absence of associated organ or tissue impairment including organ damage, bone lesions or symptoms (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757).

[0217] Systemic light chain amyloidosis Amyloidosis refers to a family of protein misfolding diseases in which different types of proteins aggregate as extracellular insoluble fibrils. These are complex, multisystemic diseases. The most common type of systemic amyloidosis is systemic light chain (AL) amyloidosis (Gertz et al. (2004) Am.Soc.Hematol.2004:257-82). Like multiple myeloma, AL amyloidosis is a plasma cell tumor. AL amyloidosis produces an excess of monoclonal immunoglobulin-releasing light chains. Amyloid fibril deposits are the same free light chain proteins secreted by clonal plasma cells (Cohen and Comenzo (2010) Am.J.Hematol.2010:287-94, Merlini and Bellotti (2003) New England J.Med.349(6):583-96, Murray et al. (2010) Blood (ASH Annual Meeting Abstracts)116(21):abstr 1909). These amyloid fibril deposits result in peripheral organ damage and ultimately death. Therapies that suppress clonal plasma cells can alleviate AL amyloidosis disease by eliminating the factory that produces circulating toxic free light chains, which in turn may improve organ function and survival rates. There are no regulatory-approved treatments for systemic AL amyloidosis. The drugs used are those used to treat multiple myeloma. Therefore, there is a significant and unmet medical need for the treatment of patients with AL amyloidosis, and targeting CD38 on plasma cells is a meaningful therapeutic strategy.

[0218] Other CD38-related conditions The antibodies, methods, and dosage units of the present invention are used in various applications including treatment or alleviation of diseases and conditions associated with inflammation, immune diseases, and particularly CD38-related diseases such as diseases associated with activated lymphocytes. The anti-CD38 antibody of the present invention binds to CD38-positive cells and causes depletion of these cells such as activated lymphocytes via a plurality of mechanisms of action including both CDC and ADCC pathways.

[0219] Therefore, any autoimmune disease exhibiting either increased CD38 expression or an increased number of CD38-expressing cells as a component of the disease can be treated with the antibodies of the present invention. These include allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune urticaria, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman syndrome, celiac prussula dermatitis, chronic fatigue immunodeficiency syndrome, chronic inflammatory demyelinating polyneuropathy, and Churg Strauss syndrome, bullous pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, lupus discoid, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA neuropathy, IgM polyneuropathy, immune-mediated thrombocytopenia, juvenile arthritis, Kawasaki disease, lichen planus Plantus), lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis (polychrondritis), polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia (primary This includes, but is not limited to, agammaglobinulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, parenchymal organ graft rejection, Stiffman syndrome, systemic lupus erythematosus, systemic light chain amyloidosis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, vasculitis, such as herpetiform dermatitis vasculitis, vitiligo, and Wegner's granulomatosis.

[0220] In some embodiments, it is particularly useful for systemic lupus erythematosus (SLE), related The use of this antibody for use in the diagnosis and / or treatment of several diseases, including but not limited to autoimmune diseases, including but not limited to rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, systemic light chain amyloidosis, and graft-versus-host disease. In one embodiment, the disease is systemic lupus erythematosus (SLE). In one embodiment, the disease is rheumatoid arthritis (RA). In one embodiment, the disease is inflammatory bowel disease (IBD). In one embodiment, the disease is ulcerative colitis. In one embodiment, the disease is graft-versus-host disease. In one embodiment, the disease is systemic light chain amyloidosis.

[0221] Therefore, for example, patients with high plasma cell content, such as SLE patients showing high plasma cell levels, and RA patients who have shown unresponsiveness to CD20-based therapy can be treated.

[0222] Antibody composition for in vivo administration The antibody formulations used in the present invention are prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing antibodies of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed.).

[0223] The formulations described herein may also contain more than one active compound, preferably active compounds having complementary activity that does not adversely affect each other, as needed for the specific indication being treated. For example, it may be desirable to provide antibodies with other specificities. Alternatively or additionally, the composition may include cytotoxic agents, cytokines, growth inhibitors, and / or small molecule antagonists. Such molecules are preferably present in combination in amounts effective for the intended purpose.

[0224] Subcutaneous administration Anti-CD38 antibodies described herein, such as AB79, can be administered in therapeutically effective doses, thereby enabling subcutaneous administration. Subcutaneous administration is a minimally invasive mode of administration and is considered the most versatile and therefore preferred mode of administration for both short-term and long-term therapy. In some embodiments, subcutaneous administration can be performed by injection. In some embodiments, if multiple injections or multiple devices are required, the injection or device sites can be alternated.

[0225] Therefore, subcutaneous formulations are far easier for patients to self-administer, especially since patients may need to take the formulation regularly throughout their lives (for example, starting as early as the first year of a child's life). Furthermore, the ease and speed of subcutaneous delivery enable increased patient adherence to medication and faster access to the drug as needed. Thus, the subcutaneous formulation of anti-CD38 antibody provided herein offers substantial benefits superior to the prior art and solves a certain unmet need.

[0226] In some embodiments, the antibodies of the present invention are administered to subjects via a subcutaneous route according to known methods. In some embodiments, the antibodies of the present invention can be administered by subcutaneous injection. In specific embodiments, the subcutaneous formulation is administered by subcutaneous injection to the same site in the patient for repeated or sequential injections (e.g., in the upper arm, anterior thigh, lower abdomen, or upper back). In other embodiments, the subcutaneous formulation is administered by subcutaneous injection to different or alternating sites in the patient. Single or multiple doses of the formulation may be employed.

[0227] In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of cancer. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of hematological cancers. It can be used for the treatment of multiple myeloma. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of multiple myeloma.

[0228] In some embodiments, the antibodies of the present invention have increased bioavailability compared to prior art antibodies. In some embodiments, the bioavailability of the antibodies of the present invention is increased by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or more, compared to prior art antibodies that bind to human RBCs. In some embodiments, the bioavailability of the antibodies of the present invention is increased by 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, or 300%, or more, compared to prior art antibodies that bind to human RBCs. Preferably, the bioavailability may be increased by 50%. Preferably, the bioavailability may be increased by 60%. Preferably, the bioavailability may be increased by 70%. Preferably, the bioavailability may be increased by 80%. Preferably, the bioavailability may be increased by 90%.

[0229] In some embodiments, increased bioavailability enables subcutaneous administration.

[0230] In some embodiments, the antibody of the present invention leads to the depletion of NK cells, B cells, and / or T cells. In some embodiments, the antibody of the present invention enables increased depletion of NK cells compared to the depletion of B cells or T cells. In some embodiments, the antibody of the present invention enables increased depletion of NK cells compared to B cells, and increased depletion of NK cells compared to T cells. In some embodiments, the antibody of the present invention enables increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. In some embodiments, the antibody of the present invention enables increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. Preferably, the antibody of the present invention is CD38 - CD38 compared to cells + This could lead to increased cell depletion.

[0231] In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 50% to at least 80% compared to a normalized intravenous dose of the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 60% to at least 80% compared to a normalized intravenous dose of the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 50% to 70% compared to a normalized intravenous dose of the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 65% compared to a normalized intravenous dose of the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 70% compared to a normalized intravenous dose of the same dose.

[0232] In certain embodiments, the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 40%, at least 45%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, or at least 85% of the bioavailability of the anti-CD38 antibody described herein after subcutaneous administration is at least 40%, at least 45%, at least 50 may be at least 50% as compared to normalized intravenous administration. Preferably, the bioavailability may be at least 60% as compared to normalized intravenous administration for the same dose. Preferably, the bioavailability may be at least 70% as compared to normalized intravenous administration for the same dose. Preferably, the bioavailability may be at least 80% as compared to normalized intravenous administration for the same dose. Preferably, the bioavailability may be at least 90% as compared to normalized intravenous administration for the same dose.

[0233] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is 50% to 80% as compared to normalized intravenous administration for the same dose.

[0234] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is at least 50% as compared to normalized intravenous administration for the same dose.

[0235] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is at least 55% as compared to normalized intravenous administration for the same dose.

[0236] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is at least 60% as compared to normalized intravenous administration for the same dose.

[0237] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is at least 65% as compared to normalized intravenous administration for the same dose.

[0238] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibody of the present invention after subcutaneous administration is at least 70% as compared to normalized intravenous administration for the same dose.

[0239] In some embodiments, the present disclosure provides a method in which the bioavailability of the antibody of the present invention after subcutaneous administration is at least 75% compared to normalized intravenous administration for the same dose.

[0240] In some embodiments, the present disclosure provides a method in which the bioavailability of the antibody of the present invention after subcutaneous administration is at least 80% compared to normalized intravenous administration for the same dose.

[0241] In some embodiments, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody as described herein, which results in less than 10% depletion of RBCs.

[0242] In some embodiments, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody as described herein, which results in less than 10% depletion of platelets.

[0243] In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously by a single bolus injection. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously monthly. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously weekly. In certain embodiments, the anti-CD The CD38 antibody is administered subcutaneously twice a week. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously daily. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every 6 hours. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every 4 hours. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every 2 hours. In certain embodiments, the anti-CD38 antibody described herein is administered subcutaneously every hour.

[0244] In some embodiments, the subcutaneous unit dosage form is administered in doses of approximately 45 mg to approximately 1,800 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 1,800 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 600 mg to approximately 1,800 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 1,200 mg to approximately 1,800 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 1,200 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 1,200 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 600 mg to approximately 1,200 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 135 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 600 mg. In some embodiments, the subcutaneous unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 600 mg. In some embodiments, the dosage is expressed in milligrams per kilogram of body weight. In some embodiments, the dosage is expressed as a daily dose.

[0245] Unit dosage form In some embodiments, the therapeutic anti-CD38 antibody is formulated as part of a unit dosage form. In some embodiments, the anti-CD38 antibody comprises a heavy chain containing the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises a light chain containing the following CDR amino acid sequences, namely SSNIGDNY (SEQ ID NO: 6, HCDR1 AB79), RDS (SEQ ID NO: 7, HCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, HCDR3 AB79) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises a heavy chain containing the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79), or variants of these sequences having up to three amino acid changes, and a light chain containing the following CDR amino acid sequences, namely SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79), or variants of these sequences having up to three amino acid changes. In some embodiments, the antibody comprises a heavy chain containing the following CDR amino acid sequences: GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79). In some embodiments, the antibody comprises a light chain containing the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79). In some embodiments, the antibody comprises The antibody comprises a heavy chain containing the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79), and a light chain containing the following CDR amino acid sequences, namely SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79). In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 9. Preferably, the heavy chain may include the following CDR amino acid sequences, namely GFTDDDYG (SEQ ID NO: 3, HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4, HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 AB79), and the remainder of the heavy chain may have at least 80% sequence identity with SEQ ID NO: 9. In some embodiments, the antibody includes a heavy chain containing the variable heavy (VH) chain amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (Sequence ID 9).

[0246] In some embodiments, the antibody includes a light chain containing an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 10. Preferably, the light chain may contain the following CDR sequences, namely SSNIGDNY (SEQ ID NO: 6, LCDR1 AB79), RDS (SEQ ID NO: 7, LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 AB79), with the remainder of the light chain having at least 80% sequence identity with SEQ ID NO: 10. In some embodiments, the antibody includes a light chain containing a variable light (VL) chain amino acid sequence of SEQ ID NO: 10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (Sequence ID 10).

[0247] In some embodiments, the antibody comprises a heavy chain containing the VH chain amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein, and a light chain containing the VL chain amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0248] As will be understood by those skilled in the art, variable heavy and light chains can bind to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4. In some embodiments, the antibody includes a heavy chain (HC) having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain may include a CDR sequence as defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, with the remainder of the heavy chain having at least 80% sequence identity to SEQ ID NO: 11. In some embodiments, the antibody includes the heavy chain (HC) amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 11).

[0249] In some embodiments, the antibody includes a light chain (LC) having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain may include a CDR sequence as defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 80% sequence identity to SEQ ID NO: 12. In some embodiments, the antibody includes the light chain (LC) amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (Sequence ID 12).

[0250] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11 or a variant thereof as described herein, and the LC amino acid sequence of SEQ ID NO: 12 or a variant thereof as described herein.

[0251] In some embodiments, the formulation containing the anti-CD38 antibody is in unit dosage form. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 600 mg to approximately 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 1,200 mg to approximately 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 600 mg to approximately 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 135 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 45 mg to approximately 600 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of approximately 135 mg to approximately 600 mg. In some embodiments, the dosage is expressed in milligrams per kilogram of body weight. In some embodiments, the dosage is expressed as a daily dose.

[0252] In some embodiments, the unit dosage form of the anti-CD38 antibody provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents. In some embodiments, the anti-CD38 antibody is provided as a pharmaceutical composition comprising the unit dosage form according to the present invention. Preferably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents.

[0253] The dosage regimen is adjusted to provide the optimal desired response (e.g., therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the emergency of the treatment situation. The composition may be formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, a unit dosage form may, in some embodiments, refer to physically separate units suitable as unitary dosages for treating a subject, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier.

[0254] The details of the unit dosage form of the present invention are determined by and directly depend upon (a) the inherent properties of the active compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of formulating such active compound for the treatment of an individual.

[0255] The efficient dosage and dosage regimen of the anti-CD38 antibody used in this invention depend on the type and severity of the disease or condition being treated and can be determined by those skilled in the art.

[0256] In one embodiment, the anti-CD38 antibody is administered subcutaneously in a weekly dose of approximately 45 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 135 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 600 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 1,200 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 45 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 135 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 600 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 45 to approximately 135 mg. Preferably, the weekly dose may be approximately 45 to approximately 600 mg. Preferably, the weekly dose may be approximately 135 to approximately 600 mg.

[0257] Such administration may be repeated 1 to 14 times, for example, 3 to 5 times. A non-limiting range of examples for the therapeutically effective dose of the anti-CD38 antibody used in the present invention is about 45 to about 1,800 mg. Preferably, the dose may be about 135 to about 1,800 mg. Preferably, the dose may be about 600 to about 1,800 mg. Preferably, the dose may be about 1,200 to about 1,800 mg. Preferably, the dose may be about 45 to about 1,200 mg. Preferably, the dose may be about 135 to about 1,200 mg. Preferably, the dose may be about 600 to about 1,200 mg. Preferably, the dose may be about 45 to about 135 mg. Preferably, the dose may be about 45 to about 600 mg. Preferably, the dosage may be approximately 135 to 600 mg.

[0258] As a non-limiting example, the treatment according to the present invention may be administered using single or divided doses at intervals of 24, 18, 12, 8, 6, 4, 2, or every hour, or in any combination thereof, from the start of treatment at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 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, 3 For at least one day on days 8, 39, or 40, or alternatively, for at least one week on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or any combination thereof, approximately 45 to approximately 1,800 mg per day, for example, 45, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260 ,280,300,320,340,360,380,400,420,440,460,480,500,520,540,560,580,600,620,640,660,680,700,720,740,760,780,800,820,840,860,880,900,920,940,960,980,1000,1020,1040,1060,1080,1100,1120,1140,116 The daily dose of antibody may be provided in amounts of 0, 1180, 1200, 1220, 1240, 1260, 1280, 1300, 1320, 1340, 1360, 1380, 1400, 1420, 1440, 1460, 1480, 1500, 1520, 1540, 1560, 1580, 1600, 1620, 1640, 1660, 1680, 1700, 1720, 1740, 1760, 1780, or 1800 mg. Preferably, the daily dose may be about 45 mg. Preferably, the daily dose may be about 100 mg. Preferably, the daily dose may be about 135 mg. Preferably, the daily dose may be about 150 mg. Preferably, the daily dose may be about 200 mg. Preferably, the daily dose may be about 300 mg. Preferably, the daily dose may be about 400 mg. Preferably, the daily dose may be about 500 mg. Preferably, the daily dose may be about 600 mg. Preferably, the daily dose may be about 700 mg. Preferably, the daily dose may be about 800 mg. Preferably, the daily dose may be about 900 mg. Preferably, the daily dose may be about 1000 mg. Preferably, the daily dose may be about 1100 mg. Preferably, the daily dose may be about 1200 mg. Preferably, the daily dose may be about 1300 mg. Preferably, the daily dose may be about 1400 mg. Preferably, the daily dose may be about 1500 mg. Preferably, the daily dose may be about 1600 mg. Preferably, the daily dose may be about 1700 mg. Preferably, the daily dose may be approximately 1800 mg.

[0259] In one embodiment, the anti-CD38 antibody is administered in a weekly dose of approximately 45 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 135 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 600 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 1,200 to approximately 1,800 mg. Preferably, the weekly dose may be approximately 45 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 135 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 600 to approximately 1,200 mg. Preferably, the weekly dose may be approximately 45 to approximately 135 mg. Preferably, the weekly dose may be approximately 45 to approximately 600 mg. Preferably, the weekly dose may be approximately 135 to approximately 600 mg. Such administration may be repeated 1 to 14 times, for example, 3 to 5 times. The administration may be performed by continuous infusion over a period of 1 to 24 hours, for example, over a period of 1 to 12 hours. Such a regimen may be repeated once or multiple times as needed, for example, after 6 or 12 months. The dosage may be determined or adjusted by measuring the amount of the compound of the present invention in the blood immediately after administration, for example, by taking a biological sample and using an anti-idiotype antibody that targets the antigen-binding region of an anti-CD38 antibody.

[0260] In one embodiment, the therapeutic antibody is formulated at a concentration of 100 mg / ml. In some embodiments, volumes of 1.75 mL, 2.0 mL, 2.25 mL, or 2.5 mL are injected into the thigh, abdomen, or arm. In some embodiments, volumes of 1.75 mL, 2.0 mL, 2.25 mL, or 2.5 mL are injected into the thigh or abdomen. In some embodiments, a volume of 2.25 mL is injected into the thigh or abdomen. In some embodiments, the dose is administered over a period of 4 hours, 6 hours, 8 hours, or 10 hours. In some embodiments, the dose is administered over a period of 8 hours. In some embodiments, 2, 4, 6, or 8 doses are administered. In some embodiments, the dose is administered every 2 hours.

[0261] In further embodiments, the anti-CD38 antibody is administered once a week for 2 to 12 weeks. Preferably, the antibody may be administered once a week for, for example, 3 to 10 weeks. Preferably, the antibody may be administered once a week for, for example, 4 to 8 weeks. Preferably, the antibody may be administered once a week for, for example, 5 to 7 weeks.

[0262] In one embodiment, the anti-CD38 antibody is administered subcutaneously at a frequency that varies over time. Preferably, the antibody may be administered once a week for 8 weeks, then once every two weeks for 16 weeks, and thereafter, in 28-day treatment cycles every four weeks until unacceptable toxicity is observed or the subject discontinues treatment for other reasons.

[0263] In one embodiment, the anti-CD38 antibody is administered as maintenance therapy, for example, once a week for a period of six months or more.

[0264] In one embodiment, the anti-CD38 antibody is administered by a regimen that includes a single injection of the anti-CD38 antibody followed by an injection of the anti-CD38 antibody conjugated with a radioisotope. The regimen may be repeated, for example, after 7 to 9 days.

[0265] In one embodiment, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody as described herein, which results in less than 10% depletion of RBCs.

[0266] In one embodiment, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody as described herein, which results in less than 10% depletion of platelets.

[0267] In some embodiments, the anti-CD38 antibody for use according to the present invention is used in combination with one or more additional therapeutic agents, such as chemotherapeutic agents. Non-limiting examples of DNA-damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and their analogs or metabolites, as well as doxorubicin), topoisomerase II inhibitors (e.g., etoposide, teniposide, and daunorubicin), alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine) Examples include bazine, methotrexate, mitomycin C, and cyclophosphamide, DNA insertion agents (e.g., cisplatin, oxaliplatin, and carboplatin), DNA insertion agents and free radical generators such as bleomycin, and nucleoside mimetic compounds (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

[0268] Chemotherapy agents that interfere with cell replication include paclitaxel, docetaxel, and related analogues; vincristine, vinblastine, and related analogues; thalidomide, lenalidomide, and related analogues (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; antibodies that bind to proteins that are overexpressed, inappropriately expressed, or activated in cancer, thereby downregulating cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, overexpressed, inappropriately expressed, or activated in cancer, whose inhibition downregulates cell replication.

[0269] In some embodiments, the antibody of the present invention can be used before, concurrently with, or after treatment with Velcade® (bortezomib).

[0270] treatment means The method of the present invention uses a therapy to provide a positive therapeutic response with respect to a disease or condition. The term “positive therapeutic response” means improvement of the disease or condition and / or improvement of symptoms associated with the disease or condition. For example, a positive therapeutic response would refer to one or more of the following improvements of a disease: (1) a reduction in the number of neoplastic cells, (2) an increase in neoplastic cell death, (3) an inhibition of neoplastic cell survival, (5) an inhibition of tumor growth (i.e., some degree of slowing, preferably cessation), (6) an increased patient survival rate, and (7) some relief of one or more symptoms associated with the disease or condition.

[0271] A positive therapeutic response in any given disease or condition can be determined by standardized response criteria specific to that disease or condition. Tumor response can be assessed in terms of changes in tumor morphology (i.e., overall tumor load, tumor size, etc.) using screening techniques such as magnetic resonance imaging (MRI) scans, X-ray imaging, computed tomography (CT) scans, bone scanning imaging, endoscopy, and tumor biopsy samples including bone marrow aspiration (BMA) and counting of circulating tumor cells.

[0272] In addition to these positive therapeutic responses, subjects receiving therapy may experience beneficial effects such as improvement in disease-related symptoms. In the case of B-cell tumors, subjects may experience a reduction in so-called B symptoms, such as night sweats, fever, weight loss, and / or urticaria. In the case of premalignant conditions, therapy with anti-CD38 therapeutic antibodies may block the development of associated malignancies, such as multiple myeloma, and / or extend the time before such development in subjects with monoclonal gammaglobulinemia of unspecified significance (MGUS).

[0273] The improvement of the disease can be characterized as a complete response. The term "complete response" refers to the absence of clinically detectable disease, accompanied by the normalization of previously abnormal radiographic analyses, bone marrow, and cerebrospinal fluid (CSF), or, in the case of myeloma, abnormal monoclonal proteins.

[0274] Such a response may last for at least 4 to 8 weeks, or at least 6 to 8 weeks, after treatment by the method of the present invention. Alternatively, improvement in the disease may be classified as a partial response. The term “partial response” may refer to a reduction of at least about 50% of all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured size of the tumor volume or the amount of abnormal monoclonal protein) in the absence of new lesions, which may last for at least 4 to 8 weeks, or at least 6 to 8 weeks.

[0275] The treatment according to the present invention includes a "therapeutically effective amount" of the pharmaceutical product used.

[0276] The terms “therapeutic dose” and “therapeutic dosage” refer to the amount of a therapeutic agent that is sufficient to reduce or alleviate the severity and / or duration of a disorder or one or more symptoms; prevent the progression of the disorder; cause regression of the disorder; prevent the recurrence, onset, manifestation, or progression of one or more symptoms associated with the disorder; or to enhance or improve the preventive or therapeutic effect (may be one or more) of another therapeutic agent (e.g., a prophylactic or therapeutic agent) over such a period of time. The therapeutic dose may vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the drug’s ability to elicit the desired response in the individual. The therapeutic dose is also the amount at which the therapeutically beneficial effect outweighs any toxic or adverse effects of the antibody or antibody portion. The “therapeutic dose” of an antibody for tumor treatment may be measured by its ability to stabilize disease progression. The ability of a compound to inhibit cancer may be evaluated in animal model systems that predict efficacy in human tumors.

[0277] Alternatively, this property of a composition may be evaluated by in vitro assays known to those skilled in the art, which test the compound's ability to inhibit cell growth or induce apoptosis. A therapeutically effective amount of the therapeutic compound may reduce tumor size or otherwise alleviate symptoms in a subject. Those skilled in the art will be able to determine such an amount based on factors such as the subject's size, the severity of the subject's symptoms, and the specific composition or route of administration selected.

[0278] Anti-CD38 antibody kit In another aspect of the present invention, a kit for the treatment of a disease or condition associated with hematological cancer is provided. In one embodiment, the kit contains a certain dose of an anti-CD38 antibody described herein, such as AB79. In some embodiments, the kit provided herein may contain one or more doses of a liquid or lyophilized formulation as provided herein. If the kit contains a lyophilized formulation of an anti-CD38 antibody described herein, such as AB79, the kit will generally also contain a liquid suitable for reconstituting the liquid formulation, such as sterile water or a pharmaceutically acceptable buffer. In some embodiments, the kit is administered subcutaneously by a healthcare professional. This may include anti-CD38 antibody preparations described herein, pre-filled in syringes for use in the field or at home.

[0279] In certain embodiments, the kit may be for a single dose or administration of an anti-CD38 antibody described herein, such as AB79. In other embodiments, the kit may contain multiple doses of an anti-CD38 antibody described herein, such as AB79, for subcutaneous administration. In one embodiment, the kit may contain an anti-CD38 antibody preparation described herein, pre-filled in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0280] product In other embodiments, a product is provided containing a material useful for treating the aforementioned disorders. The product includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be formed from a variety of materials such as glass or plastic. The container holds a composition that is effective in treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a subcutaneous needle). The active agent in the composition is an antibody. A label on or associated with the container indicates that the composition is used to treat a selected condition. The product may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. It may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and accompanying documentation including instructions for use. [Examples]

[0281] Example 1: Model-based characterization of anti-CD38 antibodies in cynomolgus monkeys The anti-CD38 antibody AB79 is distinguished from daratumumab (Darzalex®), a recently approved cytolytic CD38 monoclonal antibody for the treatment of multiple myeloma, by its binding to cynomolgus monkey (cyno) CD38. This unique function supported the use of cynomolgus monkeys in preclinical studies to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and safety of AB79. For this purpose, assays were developed to measure drug concentration, immunogenicity, and quantify T, B, and NK lymphocytes in the blood of cynomolgus monkeys. These parameters were assessed in eight pharmacological and toxicological preclinical studies. Of the cell populations tested, CD38 is most highly expressed on NK cells. Therefore, it is assumed that the drug effect on NK cells will be closest to the effect on the target cells considered: plasmablasts, plasma cells, and other activated lymphocytes.

[0282] Data were pooled from eight studies in healthy monkeys using dose ranges of 0.03–100 mg / kg, and mathematical models were developed to describe the pharmacokinetics and exposure-response relationships for each cell type. NK cell depletion was identified as the most sensitive pharmacodynamic effect of AB79. This depletion was described using a turnover model (EC50 = 34.8 μg / mL (relative to depletion rate)), with complete depletion achieved with an IV dose of 0.3 mg / kg. A moderate effect on T cell count was observed using a direct response model (EC50 = 9.43 μg / mL), and a moderate effect on B cell count was observed using a four-pass compartment model (EC50 = 19.3 μg / mL (relative to depletion rate)). These analyses demonstrated the observation that each measured lymphocyte subset was removed by AB79 at different rates and required different timeframes to deplete blood compartments.

[0283] Mathematical models describing PK and PD data are useful tools for obtaining mechanistic and quantitative insights into the relationship between drug exposure and effects (Friberg et al. (2002) J. Clin. Oncol. 20:4713-4721, Mager e (t al. (2003) Drug Metab. Dispos. 31:510-518, Han and Zhou (2011) Ther. Deliv. 2:359-368). The pharmacology of AB79 can be explained by utilizing the typical PK characteristics of IgG antibodies, including distribution and disappearance, and physiological and genetic similarities between monkeys and humans (Glassman). (and Balthasar (2014) Cancer Biol. Med. 11:20-33, Kamath (2016) Drug Discov. Today Technol. 21-22:75-83). In addition, these models have been successfully applied to predict PK concentrations and PD effects in healthy human subjects (Han and Zhou (2011) Ther. Deliv. 2:359-368).

[0284] Materials and methods A summary of the monkey studies is shown in chronological order in Table 3. Single-dose studies 2, 7, and 8 were conducted primarily to evaluate the PK and PD of AB79 administered intravenously (IV) and subcutaneously (SC). Repeated-dose studies were conducted to evaluate safety, PK, and PD, including two 4-week studies (Studies 1 and 3) and three 13-week studies (Studies 4, 5, and 6) under GLP conditions. A dosing error occurred in the 13-week study 5. Animals in the lowest-dose group received 0.01 mg / kg instead of the intended 0.1 mg / kg at a point in time (second dosing), and then continued at 0.1 mg / kg. These data were added to the dataset along with the correct information on the actual dose administered. Study 6 replicated the low-dose, once-weekly group of Study 5 at 0.1 mg / kg. All animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, adopted and published by the National Institutes of Health. [Table 3]

[0285] bioanalysis PK was analyzed using a validated method developed and implemented by Charles River Laboratories (Reno, NV). Briefly, the concentration of AB79 was measured in monkey serum using indirect enzyme-linked immunosorbent assay (ELISA). A 96-well microtiter format was coated with an anti-idiotype antibody against AB79. Blanks, standards, and quality control (QC) samples containing AB79 at various concentrations were added to the plates and incubated at room temperature (RT) for 55–65 minutes. After washing the microtiter plates, peroxidase-labeled AffiniPure mouse anti-human IgG (peroxidase AffiniPure mouse anti-human IgG, Fcγ fragment specific, Jackson ImmunoResearch) was added and incubated on the plates for a further 55–65 minutes. The plates were washed again, tetramethylbenzidine (TMB) was added to the wells to generate a chromophore, and color development was stopped by adding a stop solution (2N sulfuric acid). Absorbance at 450 nm was measured using a SPECTRAmax® 190 microplate reader (Molecular Devices), and the AB79 concentration was determined using 4-parameter logistic weighting (1 / y). 2 The values ​​were calculated using a standard calibration curve. In Study 1 (Table 3), the limit of quantification (LLOQ) of AB79 in serum was 0.061 μg / mL, while in all other studies it was 0.05 μg / mL.

[0286] Determination of anti-AB79 antibody (immunogenicity) Screening of anti-drug antibodies (ADAs) in monkey serum was performed using a qualitative electrochemiluminescence (ECL) method validated and implemented by Charles River Laboratories (Reno, NV). Briefly, undiluted serum samples were incubated with 300 mM acetic acid. The acid-dissociated samples were incubated in a mixture of biotinylated AB79, SULFO-TAG-labeled AB79 (labeled by Charles River Laboratories, Meso Scale Diagnostics), and 1.5 M Trizma base to neutralize the acid and form an immunocomplex. This complex was then added to a streptavidin-coated MSD plate (Meso Scale Diagnostics) and bound. After washing, MSD reading buffer T (Meso Scale Diagnostics) was added to the plate, and then SULFO-TAG™ was excited via the electrochemical reaction of Ru(bpy)3 to generate luminescence (light), which was then read using MSD Sector 6000 (Meso Scale Diagnostics). The complex was detected by reading it using Diagnostics. The amount of luminescence correlated with the level of monkey anti-AB79 antibody present in the serum of each sample.

[0287] Characterization of blood cells To evaluate and compare the levels of AB79 binding between humans and monkeys, blood samples from each were collected in sodium heparin tubes. Aliquots (100 μL) of blood were mixed with an appropriate volume of antibody (Figure 1) and incubated in the dark at room temperature for 15–20 minutes. After incubation, 1 mL of BD FACS lysis solution (1x, BD Biosciences, San Jose, CA) was added to lyse the red blood cells, and the cells were incubated in the dark at room temperature for 10 minutes, then centrifuged, decanted, and resuspended in 1 mL of staining buffer containing bovine serum albumin (BD Biosciences). The cells were again centrifuged, decanted, and fluoresceined in 250 μL of Flow Fix (1% paraformaldehyde in Dulbecco's PBS (Life Technologies, Carlsbad, CA) without calcium and magnesium), and fluorescence was measured by flow cytometry analysis using a FACSCanto® II flow cytometer (BD Biosciences). Monkey NK cells (CD3-, CD159a+), B cells (CD3-, CD20+), We measured T cells (CD3+), as well as human NK cells (CD3-, CD16 / CD56+), B cells (CD3-, CD19+), and T cells (CD3+). The average fluorescence intensity of AB79 staining for each cell population was converted to the number of soluble fluorescent molecules (MOEF) that produce the same amount of fluorescence intensity using a standard curve created with Rainbow Beads (Spherotech, Lake Forest, IL).

[0288] In the studies summarized in Table 3, cells were stained and analyzed using validated methods developed and implemented by Charles River Laboratories (Reno, NV). Monkey blood samples were collected in sodium-heparinized tubes at multiple time points before and after AB79 treatment, and specific lymphocyte populations were measured by flow cytometry using a FACSCanto® II flow cytometer (BD Biosciences). Commercial antibodies and CD38 antibody (Ab19, U.S. Patent No. 8,362,211) were titrated to optimal concentrations for staining. Monkey CD38+ / -, T cell (CD3+), B cell (CD3- / CD20+), and natural killer (NK) cell (CD3- / CD20- / CD16+) populations were identified, and lymphocytes were quantified using CD45TruCount® tubes (BD Biosciences). Approximately 100 μL aliquots of each blood sample were placed in the appropriate wells of a 96-well plate, the antibody was added in the indicated volume, mixed, and incubated in the dark at room temperature for at least 30 minutes. After incubation, the erythrocytes were lysed, the sample was mixed, and incubated in the dark at room temperature for a further 10 minutes. The plate was centrifuged, and the supernatant was decanted. The cell pellet was then resuspended in 1,800 μL of staining buffer, the sample was mixed, centrifuged, and the supernatant was decanted. The cell pellet was resuspended in 500 μL of staining buffer containing fetal bovine serum, and approximately 300 μL of cell suspension was transferred to a 96-well V-bottom plate for analysis. The NK cell percentage, as well as the total T cell and B cell percentages, were applied to the cell count obtained using a TruCount® tube (BD Biosciences, San Jose, CA), and this was used to determine the absolute cell number for each cell population. In studies 1–4, subsets of CD38+ NK cells, B cells, and T cells were assessed at baseline using labeled anti-CD38 antibodies AB79 or Ab19 (Figure 1). Although TSF-19 binds to different epitopes, the results were very similar and are therefore not presented separately. Treated samples were analyzed immediately.

[0289] PK model development During the development of the PK model, one-, two-, and three-compartment model structures were investigated. The two-compartment model was clearly superior to the one-compartment model, as judged by the reduction in goodness-of-fit (GOF) plots and objective function value (OFV). Based on visual inspection of the diagnostic plots, the introduction of a third compartment was not necessary to adequately describe the data. Bioavailability (F) was modeled using a logit transformation, F = exp(PAR) / (1 + exp(PAR)) (where PAR represents the model parameter), to ensure that the estimate was reliably bounded between 0 and 1. Nonlinear PK at low concentrations was modeled using a quasi-steady-state (QSS) approximation model of the target-mediated pharmacokinetic (TMDD) process (Gibiansky and Gibiansky (2009) Expert Opin. Drug Metab. Toxicol. 5:803-812).

[0290] A schematic diagram of the model is provided in Figure 3C. For the QSS approximation, it is assumed that the steady-state concentrations of the free drug C, target R, and drug-target complex RC are established very rapidly compared to all other processes. This implies that the binding process is in equilibrium with the dissociation and internal migration processes, and that the following equality applies in appropriate units: K ON *C*R=(K OFF +K INT )*RC(where K ON K is the coupling rate constant. OFF K is the dissociation rate constant. INT (This represents the internal migration rate constant.)

[0291] Inter-subject variability (BSV) was investigated for all parameters and modeled using the following type of exponential function model: PAR i =TVPAR*e ETAPAR i (In the formula, PAR i is an individual, TVPAR is a typical parameter estimate, and ETAPAR i (This is an estimate of the deviation of individual i). ETAPAR iThe values ​​were assumed to follow a normal distribution with a mean of zero. The residuals were described using an additive and proportional composite error model (Beal and Sheiner (1992) NONMEM User Guides, in University of California, CA).

[0292] To identify potential covariate effects of AB79 on PK, the following parameters were investigated: body weight, sex, dose, route of administration, and study.

[0293] PK-PD Model Development PK-PD models were developed separately for each of the three cell types. Note that measurements taken close to drug administration (<8 hours post-administration) were not used in model development because they were likely affected by nonspecific, drug-independent effects due to multiple blood samples being collected over a short period (Figure 4). The PK model and parameter estimates were fixed. Various forms of turnover, transit compartment, and direct response models were tested (Friberg et al. (2002) J. Clin. Oncol. 20:4713-4721, Mager et al. (2003) Drug Metab. Dispos. 31:510-518). In the turnover models, the drug effect was introduced into the cell elimination rate in the form of an Emax-type model, with or without the Hill coefficient. Here, the Emax model is a function f of the drug concentration c in the following form: f(c) = EMAX*c H / (c H +C50 H (EMAX represents the maximum effect, C50 is the concentration at which half of the maximum effect is achieved, and H represents the Hill coefficient). In the transit compartment model (TCM), drug effects were introduced and tested at different locations, namely proliferation rate, circulating cells, and a third transit compartment. Combinations of these effects and whether the data supported the existence of a feedback mechanism from circulation to proliferation rate were also tested. In addition, Emax-type direct response models with and without the Hill coefficient were tested to describe the drug concentration-effect curve.

[0294] Random effects parameters were introduced to estimate intersubject variability for baseline cell number, cell generation rate (KIN), transit time (MTT) in the transit compartment model, C50, and EMAX. Individual mean baseline cell levels were provided in the dataset (column BL), which were used as typical values ​​in this model. Random effects parameters were added to allow for adjustment of individual baseline estimates based on all individual measurements. PD residuals were described using a proportional error model.

[0295] To validate the models during the modeling process (PK and PK-PD), we evaluated the models using OFV, standard errors, GOF plots, and individual prediction vs. data plots, and compared them with alternative models.

[0296] The following software packages were used: NONMEM (version 7.2), KIWI (version 1.6), Berkeley Madonna (version 8.3.14), PSN (version 4), and R (version 3.3.0).

[0297] Dataset preparation Datasets from eight monkey studies were collected, reorganized into a single format, and merged into three separate PK-PD datasets readable by non-membrane organisms (NONMEM). Each of the three datasets contained individual monkey characteristics (study, ID, group, weight, sex), medication information, PK, and data on either NK, B, or T cells. For the control group of animals... Assuming the absence of serum levels of AB79, only cell counts were added to the dataset, and PK data was not included. Time-resolved information on anti-drug immunogenicity status (ADA), i.e., TITER and a 0 / 1 flag variable ADAF (ADAF=1 if ADA affects AB79 concentration, ADAF=0 otherwise), including quantitative measurement results, was added to each observation in a separate column. Since ADA titers were measured using different methodological details in different studies, direct quantitative comparisons between studies are not possible. To ensure consistent use of ADA information across all studies, the following procedure was applied separately for each animal: ADA titers that increased from the initially measured level at a point after 7 days were considered ADA positive and flagged in the dataset (ADAF=1). If a sample was flagged as ADA positive at a point in time, all samples collected from that animal after that point in time, regardless of the measured titer, were also flagged as ADA positive. ADA positive observations were not used for parameter estimation during model development. Note that PD measurements from the sampling point for PK concentrations affected by ADA were also flagged with ADAF=1.

[0298] For cell count data, individual baseline values ​​for each cell type (NK cells, B cells, and T cells) were calculated as the average of all available pre-medication measurements for a given animal. In most studies, this was a single measurement. The baseline value for each animal was then added to each observation for that animal as an observed value at the time of the first medication event (time=0) and as a constant value in column BL. Based on these baseline values, the percentage of each observed cell count relative to the baseline was calculated and added to the dataset.

[0299] Scaling of monkey PK parameters The final PK and PK-PD models were used as a starting point for simulating PK and PK-PD profiles for human first-dose clinical trials. Comparative analysis of data from therapeutic monoclonal antibodies has shown that PK parameters derived from monkey studies can be scaled to predict human PK profiles with acceptable accuracy (Han and Zhou (2011) Ther. Deliv. 2:359-368). The publication showed that human clearance of monoclonal antibodies can be reliably predicted using a fixed index of 0.85. Therefore, this relationship was applied to scaling human clearance parameters (CL, Q), while volume parameters (VC, VP) were scaled using the direct relationship between body weight (BW).

number

[0300] result Pharmacokinetics of AB79 The PK dataset was pooled from all eight studies in healthy monkeys, excluding the placebo group (Table 3). In total, the set included data from 140 animals, 58 male and 82 female. The body weight of the studied animals ranged from 2.1 to 4.7 kg, and the doses ranged from 0.03 to 100 mg per kg of body weight (mg / kg). One group in Study 7 and three groups in Study 8 received SC doses of 0.03, 0.1, 0.3, and 1 mg / kg (15 animals in total). The study included 2,199 measurable PK observations exceeding LLOQ (Figure 3A, B). ADA was assessed in parallel with AB79 concentrations. 229 PK observations were found to be influenced by ADA (Figure 5). PK was most densely sampled after the initial dose, and even in long-term toxicological studies, most animals were completed before day 98. Only Study 4 included a recovery group, and PK data was only collected from four animals: two from the 80 mg / kg group and one each from the 30 mg / kg and 3 mg / kg groups (Figure 3B).

[0301] First, PK analysis was performed for each of the monkey studies using the standard non-compartmental technique (NCA). Based on single-dose studies (IV bolus injection or 30-minute IV infusion), the volume of distribution in the terminal phase (Vz) was calculated to be between 64 and 116 mL / kg, clearance between 6.04 and 14.7 mL / kg / day, and terminal elimination half-life (T1 / 2) between 4.75 and 11.2 days. The area under the concentration-time curve (AUC) and maximum concentration (Cmax) values ​​were found to increase proportionally with the dose over a wide range. Only the PK profile of the lowest dose group (<1 mg / kg, D-F in Figure 3) provides evidence of non-linearly increasing clearance at concentrations below 0.5 μg / mL, likely induced by a target-mediated dynamic disorder (TMDD) (Kamath (2016) Drug Discov. Today Technol. 21-22:75-83). A linear two-compartment model was constructed based on data from all monkey studies except for the two lowest-dose groups (dose > 0.3 mg / kg). When the PK of the lowest-dose groups was simulated and superimposed on the measured concentrations, it became clear that the linear model overestimated the concentrations (Figure 3, D-F).

[0302] Available PK data after single-dose SC administration revealed that Cmax was 70–80% lower in the SC group compared to the IV group at the same dose, and that AUC was comparable. No differences in PK parameters were observed between male and female monkeys. These initial analysis results were used as a starting point for model development.

[0303] PK model development Model development began with single-dose IV drug data, and the initial model was gradually expanded using more complex data. Similar to other therapeutic antibodies, PK generally follows a linear two-compartment model (Kamath (2016) Drug Discovery. Today). (Technol.21-22:75-83). The nonlinear disappearance component (TMDD) describing accelerated clearance at low concentrations was modeled using a quasi-steady state (QSS) approximation (Gibiansky and Gibiansky (2009) Expert Opin. Drug Metab. Toxicol.5:803-812). The assumption that the drug-target association process is much faster than the processes of drug dissociation, distribution, and disappearance, as well as the disappearance of the target and drug-target complex, leads to a simplified TMDD model (Figure 3, Table 4). The amount of data at low concentrations was relatively small, and as a result, not all parameters were estimated in a single estimation run of the software program. Therefore, the parameters of the TMDD model were initially estimated by focusing on data from low-dose single-dose studies 7 and 8. The resulting TMDD parameter estimates were then kept fixed throughout the final estimation for the entire dataset (Table 4).

[0304] [Table 4]

[0305] Absorption parameter K A The estimates for F were obtained when data from the SC group were added. All SC data are from four lower single-dose groups from studies 7 and 8. These lower doses (≤1 mg / kg) covered a clinically significant range, but may limit the generalizability of the parameter estimates for higher doses.

[0306] The inter-subject variability (BSV) of PK parameters was described using an exponential function model. Absorption rate (K A ), clearance (CL), and peripheral distribution volume (V) P ) has an estimated BSV of approximately 40%, and the median distributed volume (V C ) had an estimated BSV of approximately 20% (Table 4). Covariate analysis revealed that V C The effects of the administration route on V were identified. CTypical values ​​were 0.141 L when administered intravenously and 0.043 L when administered via seroconcentrate (approximately 70% smaller). No other significant covariate effects were identified. Due to the limited amount of data at low concentrations, intersubjective variability and individual prediction of TMDD parameters are limited by the internal transfer rate K. INT Estimation was performed only for (BSV: 49%). Model evaluation based on residual errors, OFV, standard errors, GOF plots, and individual curve fittings confirmed that the final model adequately describes the PK of AB79 in healthy monkeys (Table 4, Figure 6).

[0307] Pharmacodynamics The levels of AB79 binding on human and monkey circulating NK cells, T cells, and B cells were compared by flow cytometry analysis. As shown in Figure 7, monkey lymphocytes had slightly lower CD38 expression levels compared to their human counterparts, based on the number of fluorescent molecules (MOEF) showing the same fluorescence intensity as AB79, although the relationships between cell types were similar, for example, CD38 expression was NK cells > B cells > T cells. These data support the use of this non-human primate species as a meaningful model to help predict the potential of AB79 for PD activity in humans.

[0308] For a detailed quantitative analysis of the relationship between drug exposure (PK) and the degree and duration of cellular depletion (PD), datasets from PK concentrations, NK cells, B cells, and T cell counts from all eight monkey studies, including placebo-treated animals where available, were compiled (Table 3). Initial characterization of the datasets showed that at baseline, T cells were the most abundant lymphocyte subtype, with a median of 3,732 cells per μL (interquartile range (IQR): 2,881–5,176), compared to B cells (IQR: 860.8–1,890) at 1,279 cells per μL and NK cells (IQR: 482.8–970.1) at 685 cells per μL. Baseline CD38 expression in these cell populations was assessed in studies 1–4 (Table 3, n=67). 86.7% (SD 11.3) of NK cells expressed CD38, with less variability. In contrast, 58.7% (SD27.0) of B cells and 34.5% (SD24.5) of T cells expressed CD38, showing greater variability.

[0309] Data from placebo-treated animals showed that the average number of each cell type varied over time between individual animals beyond what would be expected from intra-individual variability (Figure 8). For example, the mean coefficient of variation for B cell counts in individual placebo curves was 27%, while individual mean B cell levels ranged from 436.6 to 4,389. Additionally, differences existed between male and female animals, as well as between animals from different studies, further increasing variability (Figure 9). Based on these results, the post-treatment cell count for each cell type was calculated at each time point as a percentage of its individual baseline value, rather than as an absolute cell count. For example, a value of 33% means that the cell count in the sample was one-third of the baseline cell count. This provided a standardized value comparable across the entire dataset.

[0310] The rapid onset of AB79-binding cell depletion suggests that initial blood concentrations lead to lymphocyte count reduction (Figure 10). With IV administration of 0.3 mg / kg of AB79, the median maximum effect on NK cells was 93.9% depletion (i.e., 6.1% of baseline cell count remained). At 0.1 mg / kg, the peak depletion was 71% (29% of baseline remained). At doses >0.3 mg / kg, NK cells were almost completely depleted in the blood compartment (lowest point (range), 1.06% of baseline (0.17, 6.23), Figure 10A). After a single dose of 0.3 mg / kg, although the rate of recovery varied considerably among individuals, it took approximately 7 days for NK cells to recover to a mean of 50% of baseline (Figure 10B, C). Consistent with these results, NK function was also tested in a subset of animals in Study 7 (n=3 / group, Table 3). This experiment showed a dose-dependent reduction, with minimal change in serum NK activity at 48 hours post-treatment in animals treated with 0.1 mg / kg AB79 (lysate % in 100:1 effector: target ratio ±SD; 44.5% ± 23.6% vs. 41.4% ± 25.8%), and almost complete loss of NK activity in animals treated with 1.0 mg / kg (lysate % in 100:1 effector: target ratio ±SD; 37.4% ± 10.3% vs. 6.8% ± 12.5%). NK cell function showed recovery at the next time point measured, 57 days (lysate % in 100:1 effector: target ratio ±SD; 16.0% ± 11.9%).

[0311] B cells and T cells were depleted to a lower degree compared to NK cells, but this is because This is consistent with lower CD38 expression levels (Figure 7). For example, at AB79 IV at 0.3 mg / kg, B cells had a median maximum depletion level of 45% of baseline, and T cells were depleted to 43% of baseline (Figure 10 D, G). At this dose level, a 50% reduction in B cell number from baseline was not achieved in any animal. Only at the highest dose of ≥30 mg / kg were B cells almost completely depleted (Figure 10 D). T cells were depleted to a similar extent as B cells, but recovered more quickly (Figure 10 G-I).

[0312] Two studies,7 and8, compared IV and SC administration (C, F, and I in Figure 10). There were no clear differences in cell depletion between the administration routes. At lower doses (Study 8), sustained (>24-hour) cell depletion below baseline levels (50%) was observed only in the NK cell population, not in T and B cells, although all cells showed specific cell depletion at an early stage. The timing of NK cell depletion appeared similar across dose groups regardless of the administration route, and the duration of depletion was dose-dependent. Cell recovery was observed by day 57 in all study groups.

[0313] PK-PD model To describe the effects of AB79 exposure on NK cells, B cells, and T cells, separate PK-PD models were developed. During PK-PD modeling, PK parameters were kept fixed to the estimates of the final PK model, and various PD models were tested (see Materials and Methods for details). The peripheral blood NK cell population was well described by a turnover model, and the depleting drug effect was associated with the depletion rate via PK concentration using an Emax-type model. In this model, EMAX represents the maximum rate of additional NK cell depletion, and C50 represents the concentration at which the rate of additional NK cell depletion is halved. The structural PK-PD model of NK cells is as follows:

number

[0314] In the formula, NK represents the actual number of NK cells, K IN is the generation rate, K OUT This represents the elimination rate when the drug is not present. Given a baseline measurement, BL K OUT is, equation K OUT =K INNote that this is defined by / BL, where c represents the AB79 concentration in the central compartment. When all parameters were estimated at once, the software program did not produce stable results. The individual estimates of KIN, EMAX, and C50 were highly correlated. Furthermore, due to the limited distinction between the maximum effects of different doses (see previous section) and the large inter-subject variability, accurate estimates of all parameters could not be expected. In a series of estimations, one or two of the three parameters KIN, EMAX, and C50 were fixed to different values, while the others were estimated. Fixing KIN to 10,000 and EMAX to 322 achieved stable performance and reasonable goodness of fit. A typical C50 estimate was 29.0 μg / mL (Table 5). In addition, the sensitivity of the selected KIN and EMAX values ​​was tested by selecting different combinations of higher and lower values. Inter-subject variability was observed in the NK production rate K IN The values ​​for 113% and C50 were high at 149%, which is consistent with the large individual differences at baseline and among treated animals. This model was evaluated based on residual error, OFV, standard error, GOF plot, and individual curve fitting (Table 5, Figure 4).

[0315] [Table 5]

[0316] The passage compartment model was superior to direct response or turnover models for describing AB79-induced B cell depletion. Four passage compartments proved sufficient, and the drug effect was described by an Emax-type model for depletion rate. Similar to the NK cell depletion model, EMAX represents the maximum rate, and C50 represents the concentration at which the rate reaches its maximum half. Therefore, the structural PK-PD model of B cells can be derived from the following five equations:

number

number

number

[0317] TR i (i=1~4) represents 4 passage compartments. TR , K PROL , and K CIRC This is given by the following equation K TR =K PROL =K CIRC Defined by =4 / MTT, where MTT represents transit time (Friberg et al. (2002) J. Clin. Oncol. 20:4713-4721). B represents the number of B cells in the blood, and c represents the AB79 concentration in the central compartment.

[0318] With EMAX fixed at 2.37, a typical C50 was 19.5 μg / mL, and a typical mean transit time (MTT) was 8.48 days (Table 5). The delay of the maximum effect relative to the maximum AB79 concentration was well captured. This model indicates that AB79 primarily affects circulating B cells. Additional effects on progenitor cells and feedback loops were not necessary to describe the available monkey B cell data. Inter-subject variability of 135% for MTT and 24.1% for baseline B cell levels (BASE) indicates significant individual variability among animals.

[0319] Drug-induced T-cell depletion accompanied by rapid recovery was well described by the following direct response model: T(c)=BL T *(1-EMAX*c / (c+C50))(where T represents the actual number of T cells, BL) T(where c represents the baseline T cell count, and c represents the AB79 concentration in the central compartment). A typical C50 was estimated to be 11.86 μg / mL, and a typical EMAX was 0.47, indicating that in this example, only about half of the T cells could be depleted by AB79 (Table 5). However, it should be noted that the inter-subject variability for EMAX was close to 70%. In this model, unlike the NK and B cell depletion models, C50 represents the concentration at which T cell depletion occurred at its maximum of half.

[0320] For NK cells, model evaluation of the final PK-PD model for B and T cells based on residual error, OFV, standard error, GOF plot, and individual curve fitting confirmed that they adequately describe the available monkey data (Table 5, Figure 4).

[0321] Human PK and cell depletion simulation Monkey PK and PK-PD models were used as a starting point for model-based simulations of human PK and cell count data to support the design of a first-in-hit (FIH) clinical trial in healthy volunteers and to justify the selected dose. For this purpose, the model structure, including TMDD derived from monkey data, was also assumed to describe the main features of human PK and the resulting lymphocyte depletion. To obtain predictions for human PK parameters, the following estimates of monkey PK parameters were scaled: central and peripheral distribution volume (V) using a simple and straightforward approach for monoclonal antibodies. C , V P ), as well as clearance (CL) and intercompartmental clearance (Q) (Han and Zhou (2011) Ther. Deliv. 2:359-368). Since AB79 is a fully human monoclonal antibody, its immunogenicity in humans is expected to be lower than that observed in monkeys. Therefore, ADA-positive samples were excluded from the dataset for modeling and simulation purposes.

[0322] Using a scaled model, we simulated NK cell, B cell, and T cell depletion profiles for exposures and single doses of 0.0003–1.0 mg / kg via 2-hour infusion (IV) or subcutaneous injection (SC) as planned in FIH studies (Figure 11). The simulations showed that after an IV dose of 0.0003 mg / kg, No observable drug-inducible effect on NK cell count, nor even measurable PK concentrations above LLOQ, were expected. Due to variability and the limited size of the dose groups, the minimum detectable drug effect on NK cell count was assumed to be a reduction of at least 10%. At doses of 0.01 mg / kg IV and 0.03 mg / kg SC, NK cells were predicted to be depleted to less than 90% of baseline levels.

[0323] With 0.3 mg / kg IV administration, the model predicted that NK cells would be depleted to 17% of baseline within 3 hours of the end of infusion and recover to over 50% after 11 days (Figure 11). At the same dose, the model predicted that B cells would be maximally depleted to 67% of baseline after 2.5 days, and T cells would be immediately depleted to 86% of baseline. For subcutaneous administration of the same 0.3 mg / kg dose, the model predicted that it would result in less and later maximal depletion (lowest point compared to baseline: NK cells 37%, B cells 74%, T cells 94%).

[0324] These in vitro and in vivo preclinical studies demonstrate that monkeys are a suitable animal model for studying the pharmacology of AB79. Densely sampled PK and cell count data of NK, B, and T lymphocytes from eight monkey studies using diverse dose and drug regimens provide a rich data source for a comprehensive and quantitative understanding of the relationship between AB79 dose, exposure, and cell depletion. The resulting population PK and PK-PD models adequately describe the observed data and provide powerful tools for predicting exposure and lymphocyte depletion not only in future studies in monkeys but also in clinical trials in human subjects.

[0325] A single-dose escalation trial of first-in-human (FIH) administration in healthy volunteers was conducted (www.clinicaltrials.gov:NCT02219256) (Figure 12). The intended pharmacological effect of AB79 is the depletion of activated lymphocytes. However, significant and sustained depletion of lymphocytes (enhanced pharmacology) can lead to immune system impairment, which may be unacceptable to patients or healthy research participants. Therefore, a safe IV starting dose of 0.0003 mg / kg was selected for the FIH trial.

[0326] The monkey data suggested that NK cell depletion was determined to be the most sensitive biological effect. PK-NK simulation results helped determine the minimum dose level of 0.01 mg / kg IV at which the most sensitive pharmacological effect (NK cell depletion) is expected to be detectable in humans. New data emerging from the FIH trial revealed that the overall pattern of dose-dependent and cell-type-specific depletion effects of AB79 is consistent with model-based predictions (manuscript in preparation). AB79 appears to be even more efficient than predicted. For example, with a 0.03 mg / kg IV dose, NK cells in human subjects were depleted to less than 10% of baseline. The median lowest depletion point in monkeys at this dose was 20.0% (Figure 10).

[0327] Three cytolytic anti-CD38 monoclonal antibodies (daratumumab, isatuximab, and MOR202) are in clinical development for multiple myeloma (van de Donk et al. (2016) Immunol. Rev. 270:95-112). Daratumumab (Darzalex®, administered intravenously) was recently approved in the United States for multiple myeloma and in Europe for non-Hodgkin lymphoma. Unlike AB79, daratumumab does not cross-react with monkey CD38. Therefore, a comparison between the results with AB79 and daratumumab in cynomolgus monkeys was not possible. Furthermore, patients with multiple myeloma have high levels of CD38-positive malignant cells, which may necessitate higher effective antibody concentrations for the indication of this cancer. (de Weers et al. (2011) J. Immunol. 186:1840-18 48).

[0328] However, it is noteworthy that daratumumab is approved for multiple myeloma at a weekly IV dose of 16 mg / kg, even though AB79 achieved complete depletion of peripheral NK cells at approximately 1 mg / kg and complete depletion of B cells at approximately 3 mg / kg (Figure 10).

[0329] Despite the rich database from eight monkey studies, several limitations were identified. AB79 effectively depletes NK cells even at the lowest dose studied, 0.03 mg / kg. At such low doses, PK rapidly decreased below the quantification limit of bioanalytical assays, hindering the elucidation of exposure-effect relationships at lower doses. Furthermore, while it was observed during preclinical development that maximal cell depletion occurred immediately after maximal drug concentration, elucidating the initial stages of depletion is technically limited by the overall sample size and, potentially, nonspecific cell depletion due to repeated blood collection (blood collection effect). The blood collection effect was observed as transient pancytopenia characterized by depletion of cell types not binding to AB79 and was not dose-dependent, suggesting it was due to blood volume loss as a result of multiple blood collections rather than any specific effect of AB79 (Figure 13). Consequently, the ability to accurately estimate model parameters, particularly with respect to NK cell depletion, was limited, and typical values ​​for KIN and EMAX required fixing to achieve stable and sufficient estimates.

[0330] The effect of AB79 on tissue plasma cells or plasmablasts could not be measured. However, like plasma cells and plasmablasts, NK cells have high levels of CD38 on their surface, and the cytolytic efficiency of certain lymphocyte subsets is at least partially dependent on the expression level of CD38. Therefore, the cytolytic effect of AB79 on plasmablasts and plasma cells may be equivalent to that on NK cells. Currently, information on the long-term effects of AB79 treatment in monkeys is limited. Only a small subset of animals in a 13-week toxicological study were investigated over a longer period in the recovery group, and most animals in all dose groups developed ADA. Moreover, baseline values ​​and depletion profiles of different lymphocyte subsets varied considerably between individuals. Therefore, the long-term effects of AB79 could not be investigated in monkeys and would need to be studied in humans.

[0331] With the emergence of new human data, a detailed comparison of human and monkey PK and PD data would be of interest. Constructing PK models based on human data and comparing them with monkey models would allow for the refinement of AB79's TMDD model. Data generated from patient studies would provide insights into how AB79-mediated depletion of B-lineage cells compares between RA and SLE patients, as well as between multiple myeloma patients and healthy subjects. In addition to CD38 expression levels, investigating subject- or disease-related factors that may influence cell depletion efficiency is also important and could lead to individualized treatment. Furthermore, thorough direct in vitro and in vivo comparisons of AB79 with daratumumab and / or other CD38 antibodies would reveal valuable information about the pharmacology of anti-CD38 antibodies and their optimal applications.

[0332] Extensive pharmacological data and PK and PK-PD models enabled the characterization of exposure-response relationships in cynomolgus monkeys. Model-based analyses of NK cells, B cells, and T cells supported and quantified the finding that each of the blood lymphocyte subsets is depleted by antibodies at different rates and requires different periods to fill blood compartments. These models proved to be excellent tools for simulating PK and PD data under different drug delivery scenarios in preparation for clinical trials.

[0333] Example 2: CD38+ cell depletion by AB79 CD38 is a cADPR hydrolase expressed on human plasmablasts, plasma cells, NK cells, and activated T and B cells based on AB79 binding, but is not present on mature platelets or red blood cells. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), plasma cells, as well as activated B and T cells, may be important causative agents of the disease. CD20 is targeted, and CD20 低 / 陰性Unlike other B-cell selective therapies that do not directly deplete plasmablasts, CD38 is highly expressed on plasmablasts and plasma cells, making these cells direct targets for AB79. In vitro studies using human blood cells and cell lines have shown that AB79 binding to CD38 does not result in cytokine activation in PBMCs, demonstrating that AB79 is not an agonist, as discussed below. Rather, AB79 mediates cell depletion of human B-lineage cell lines by ADCC and CDC, and in most instances, cell lines with increased CD38 expression were more susceptible to cell lysis (Figure 14). This is consistent with findings in healthy cynomolgus monkeys, where the efficiency of depletion correlated with CD38 expression levels and AB79 dose levels. NK cells expressing high levels of CD38 were depleted to a greater extent than CD20+ B cells and CD3+ T cells with lower CD38 expression (Figure 15). In vivo, AB79 strongly suppressed the human B-cell recall response to antigens in a mouse adoptive transfer model (Figure 16). In summary, these data support further investigation of AB79 in autoimmune diseases.

[0334] Human PBMCs were treated with AB79 under several conditions, and inflammatory cytokine release was measured. Since AB79 cross-reacts with monkey CD38, which shares 91% protein identity with human proteins, the relationship between cell type-specific depletion and AB79 dose was demonstrated using cynomolgus monkeys. Using a second animal model, mouse adoptive human PBMCs, we determined whether AB79 could target human antibody-producing cells.

[0335] AB79 binds to CD38 and mediates ADCC and CDC. The number of receptors was determined using a mouse anti-human CD38 antibody (clone HIT2) with an FI kit (DAKO, catalog number K0078). The mean fluorescence intensity (MFI) of the stained sample was converted into a calibration curve created from the MFI of five bead populations, each bound to a specified number of antibody molecules. The absolute number of receptors was calculated by subtracting the MFI of the isotype control (mouse IgG1) from the MFI of the anti-CD38 antibody.

[0336] CDC was evaluated by plated cell lines at 10,000 cells / well and adding AB79, control IgG, or culture medium. A typical 5-point dose-response curve (0.001–10 mg / ml) was performed. Rabbit complement (2–15 ul, no. CL 3441 CedarLane Laboratories) was added to each well except the control well. Cytotoxicity was detected by luminescence using CytoTox-Glo reagent (Promega, G7571 / G7573). Groups tested: cells alone, cells + complement, cells + IgG control + complement, cells + AB79 + complement. CDC% equation: CDC% = 100 - ((RLU (test) / RLU (complement alone)) × 100).

[0337] ADCC was tested by plated 5000 target cells / well (T, cell line) with 50 ml of AB79, control IgG, Triton X-100 (1%, Sigma Chemical), or medium alone, and 50 ml of human effector (E) PBMCs, in a T:E cell ratio of 1:25 to 1:50. A typical 9-point antibody dose-response curve (0.000001 to 100 nM) was performed. Experimental lysis = PBMC + cell line + antibody. Spontaneous lysis = PBMC + cell line without antibody. Maximum lysis = cell line + Triton X-100. Cytotoxicity was assessed using the CytoTox-Glo® cytotoxic luminescence assay (Promega).

[0338] AB79 does not have agonist activity. The ability of AB79 treatment to induce cytokine production in human PBMCs was compared with negative IgG1 isotype controls and positive controls: PHA, anti-CD3 (clonal OKT3), or anti-CD52 (Campath) antibodies.

[0339] Soluble AB79 did not increase IL-6 levels (mean ± SD) in PBMCs collected from four different subjects after 24-hour incubation compared to IgG1 isotype controls. PHA increased cytokine levels in all subjects, demonstrating that these cells have the ability to produce IL-6. Similar results were observed in PBMCs stimulated for 48 hours, as well as when IL-2, IL-4, IL-10, GM-CSF, IFNγ, and TNFα were tested (data not shown) (Figure 18).

[0340] The method by which antibodies are presented to cells can contribute to the performance of the antibody, i.e., ligand binding and cellular response (Stebbings et al. (2007) J.Immunol. 179:3325-3331). Stebbings et al. showed that when antibodies were highly concentrated and attached to the well surface, for example, when the antibody was added to the well in solution and the liquid evaporated (dry binding), when it was bound to the well in solution (wet binding), or when it was added directly to PBMCs (soluble), the maximal cellular response (cytokine release) to the agonist antibody occurred (Figure 18A). AB79 did not stimulate cytokine production using any of these approaches (Figure 18B).

[0341] AB79 (100 mg / ml) did not stimulate IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFNγ, or TNFα after 24 hours under any of the conditions tested. AB79 did not induce IL-10 or GM-CSF, but both were induced by anti-CD3 (not shown; all values ​​except anti-CD3 were below LLOQ). IL-8 was constitutively produced by PBMCs and was not altered by any treatment (data not shown) (Table 6).

[0342] [Table 6]

[0343] AB79 depletes CD38+ cells. AB79 binds to CD38 with high affinity and mediates CDC and ADCC. AB79 is not an agonist and did not induce cytokine release from human PBMCs. AB79 bound to CD38 from both human and cynomolgus monkeys. Lymphocytes from both species had similar cell-specific CD38 expression patterns, based on median fluorescence intensity of AB79 staining: NK cells > B cells > T cells. Treatment with AB79 depleted monkey lymphocytes in a reversible, cell-specific, and dose-dependent manner. AB79 effectively blocked the human antibody recall response in a mouse adoptive transfer model.

[0344] In a cohort treated with AB79 via SC injection, dose-dependent reduction in NK cells (Figure 24) and plasmablasts (Figure 25) was observed when the dose was ≥ 0.1 mg / kg. -1 Observed at 0.6 mg kg -1 In all subjects who received the injection, plasmablasts were reduced by ≥90%. NK cells were reduced by 75% at 0.6 mg / kg. -1 This occurs (data is not shown), and of these, C max 23.0 ng mL -1 (Table 7) Plasmablast and NK cell levels decreased from baseline within 8 hours post-injection, and 48 hours later. max The time required for recovery to baseline levels varied, ranging from 0.1, 0.3, and 0.6 mg / kg. -1 Recovery to baseline in terms of dose (i.e., within -20% of baseline level) required an average of 4, 78, and 50 days, respectively (data not shown). Minimal reduction or no reduction was observed for total lymphocytes, B cells and T cells, cytotoxic T cells, helper T cells, monocytes (Figure 25), as well as granulocytes, erythrocytes and platelets (data not shown).

[0345] [Table 7]

[0346] Summary of AB79 and daratumumab erythrocyte binding The RBC binding profiles of AB79 and daratumumab were compared. As shown in Figure 26, there appeared to be differences in the magnitude of RBC binding (i.e., MFI) between the drugs in 3 out of 4 donors tested. However, this difference may be due to differences in biotin levels on each antibody, with daratumumab having 1.6 to 2.0 times higher biotin than AB79. An alternative analysis to control for potential differences in antibody fluorescence labeling is to compare the concentration-versus-binding profiles of each antibody, with a useful metric being the concentration at which maximum binding occurs (i.e., maximum specific binding to the antigen (Bmax)). Yes. Bmax was identical for both antibodies in 3 out of 4 donors (e.g., 1 μg / mL in donor 1). Collectively, these data indicate that both antibodies bind with similar affinity within the current resolution limit of the assay (which is 10x). In conclusion, both AB79 and daratumumab bound to RBCs with affinities within 10x of each other in this assay. No differences of more than 10x in the binding affinity of these antibodies to RBCs were observed within this assay system.

[0347] Example 3: Phase 1 / 2a study to investigate the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of AB79 administered subcutaneously as monotherapy in human patients with relapsed / refractory (r / r) multiple myeloma (MM). The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) in participants with relapsed and / or refractory multiple myeloma (RRMM) in the Phase 1 of the study, and to provide a preliminary assessment of the clinical activity of AB79 monotherapy. This study includes patients with RRMM who have been previously treated with at least a proteasome inhibitor (PI), immunomodulatory agent (IMid), alkylating agent, and steroid. Patients must have refractory disease or be intolerant to at least one PI and at least one IMiD, and have received at least three prior therapies, or at least two prior therapies if one of those therapies included a combination of a PI and an IMiD. Prior exposure to anti-CD38 agents is acceptable but not required in the Phase 1b dose-escalation portion. In the expanded phase 2a portion of the study, patients must also have at least one disease refractory to anti-CD38 monoclonal therapy at some point during treatment. The study is a multicenter trial conducted in the United States, involving approximately 42 participants.

[0348] Phase 1 The Phase 1 study population consisted of approximately 24 adult participants aged 18 or older. Patient characteristics are shown in Table 8. [Table 8]

[0349] Phase 1 participants will be randomly assigned to one of the following six dose-escalation AB79 treatment groups: Cohort 1: 45 mg, Cohort 2: 135 mg, Cohort 3: 300 mg, Cohort 4: 600 mg, Cohort 5: 1200 mg, and Cohort 6: 1800 mg (Table 9). AB79 will be delivered by subcutaneous injection once weekly for 8 weeks, then every 2 weeks for 16 weeks, and thereafter every 4 weeks in 28-day treatment cycles until treatment is discontinued due to disease progression (PD), unacceptable toxicity, or other reasons. Participants may receive premedication 1 to 3 hours before administration of AB79 on each dosing day, such as: for example, dexamethasone (20 mg), acetaminophen (650 to 1000 mg), diphenhydramine (25 to 50 mg), and montelukast (10 mg).

[0350] [Table 9]

[0351] The total duration of participation in this study is 36 months (3 years). In Phase 1, participants who discontinue treatment for any reason other than disease progression (PD) will continue to receive progression-free survival (PFS) follow-up at the site every 4 weeks for up to 12 months from the last dose of the investigational drug, or until PD, death, loss of follow-up, withdrawal of consent, or termination of the study. Participants will be followed for follow-up evaluation until 30 days from the last dose of the investigational drug, or until the initiation of subsequent alternative anticancer therapy, whichever comes first.

[0352] Phase 1 Primary Endpoint Criteria The primary outcome measures for a maximum of one year include: • Number of participants who reported one or more treatment-induced adverse events (TEAEs) • Number of participants with dose-limiting toxicity (DLT): DLT is defined as any of the following events: Grade 4 abnormal clinical laboratory values, excluding events clearly attributable to external causes; Grade 3 nausea / vomiting, fatigue lasting less than 72 hours, elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels resolving to baseline or Grade 1 (≦) within 7 days, or non-hematological TEAEs of Grade 3 (≧), excluding injectable reactions (IR) in response to symptomatic treatment; Grade 3 (≧) hemolysis, grade 3 (≧) decreased or increased platelet count with clinically significant bleeding, or hematological TEAEs of NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 4; and incomplete recovery from treatment-related toxicity causing a delay of more than 2 weeks (>) of the next scheduled injection prior to the start of Cycle 2 is considered a DLT. • Number of participants with Grade 3 or higher TEAEs: AE grades are assessed according to NCI CTCAE, version 4.03. Grade 1 scales as mild; Grade 2 scales as moderate; Grade 3 scales as severe or medically significant but not immediately life-threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to the AE. • Number of participants with severe TEAEs • Number of participants with TEAEs leading to treatment discontinuation • Number of participants with TEAEs that could lead to a dose change

[0353] Secondary endpoint measurement criteria: Secondary endpoint criteria include: • Cmax: Maximum observed serum concentration of AB79 [Time frame: Cycles 1 and 2: Multiple time points before and after drug administration on day 1 (maximum 168 hours)]. • Tmax: Time to reach the maximum observed serum concentration (Cmax) of AB79 [Time frame: Cycles 1 and 2: Multiple time points before and after drug administration on day 1 (maximum 168 hours)]. • AUC: Area under the serum concentration-time curve from time 0 to the time of the last quantifiable concentration [Time frame: Cycles 1 and 2: Multiple time points before and after drug administration on day 1 (maximum 168 hours)]. • Phase 1: ORR [Timeframe: up to 1 year]: ORR is defined as the percentage of participants who achieved a partial response (PR) of 50% or greater tumor reduction during the study. PR is defined as a reduction of ≥50% in serum M protein and a reduction of ≥90% or <200 mg / 24 hours in 24-hour urinary M protein. • Percentage of participants with minimal response (MR) [Time frame: up to 1 year]: MR is defined as a reduction of ≥25% but ≤49% in serum M protein and a reduction of 50% to 89% in 24-hour urinary M protein. • Percentage of participants who tested positive for anti-drug antibodies (ADA) [Time frame: up to 1 year].

[0354] result: As of March 5, 2019, 19 patients were enrolled across four medication cohorts (45 mg, 135 mg, 300 mg, and 600 mg) and had received at least one cycle of AB79. As of March 5, 2019, nine patients were still under monitoring for treatment, nine patients had discontinued AB79 due to disease progression, and one patient had withdrawn their consent.

[0355] As of March 5, 2019, no dose-limiting toxicity (DLT) has been reported in DLT-evaluable patients across all four cohorts (45 mg, 135 mg, 300 mg, and 600 mg). No adverse events were reported. There were no injection site reactions or systemic infusion reactions. No drug-related SAEs, study-related deaths, or AEs leading to study discontinuation were reported (see Table 10). Furthermore, there were no notable laboratory findings except for one Grade 3 transient treatment-related neutropenia event and one transient anemia. Disease progression in one patient was associated with Grade 3 thrombocytopenia, anemia, and increased creatinine. This study is ongoing, and the patient is still being followed.

[0356] [Table 10]

[0357] As of March 5, 2019, the most common (>2 patients) TEAEs across all four cohorts, based on basic terms and without regard to causality, were anemia (n=7 patients), insomnia (n=5 patients each), upper respiratory tract infection, dizziness, headache, and hypertension (n=4 patients each), as well as diarrhea, fatigue, loss of appetite, and muscle spasms (n=3 patients each). All AEs were grade 1 or 2, with the exception of anemia (n=2 patients), diarrhea, decreased platelet count, neutropenia, increased creatinine, headache, hypertension, and musculoskeletal pain (n=1 patient each), which were grade 3. Only one neutropenia event and one anemia event were reported as being related to the investigational drug. No cases of IRR, cytokine release syndrome, or injection site reactions were observed. Therefore, the present invention is safer for clinical use compared to previous anti-CD38 antibodies such as daratumumab, isatuximab, or MOR202. We provide an anti-CD38 antibody.

[0358] Figure 20 shows that exposure to subcutaneously administered Ab79 increased with increasing dose over time, which is consistent with targeted drug clearance.

[0359] Subcutaneously administered Ab79 reduced the levels of plasmablasts in the blood (Figure 21), plasmablasts in bone marrow aspirate (Figure 22), and plasma cells in bone marrow aspirate (Figure 23) in a dose-dependent manner. CD38 saturated target cells in peripheral blood at doses of ≥45 mg per week and in bone marrow at doses of ≥300 mg per week. The levels of target cells in bone marrow and peripheral blood were reduced in a dose-dependent manner at doses of ≤300 mg.

[0360] In patients with advanced RRMM, AB79 showed initial signs of antitumor activity, as evidenced by at least a 50% reduction in disease burden in some patients and long-term disease stabilization in others. While additional data are needed to characterize the clinical benefits of this drug, the emerging data supports the continued development of AB79.

[0361] Two CD38 mAbs are currently in clinical development; of these, intravenous daratumumab is approved for patients with MM (relapsed and newly diagnosed), and intravenous isatuximab is under investigation. The most frequent adverse events (≥20%) with daratumumab monotherapy or in combination with a standard antimyeloma regimen are infusion-related reactions (IRRs), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, fever, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infections (Darzalex USPI). Daratumumab can cause severe and / or serious infusion reactions, including anaphylactic reactions, which have been reported in approximately half of all patients (Darzalex USPI). Importantly, attention must be paid to the interference of daratumumab with certain clinical laboratory assays, which can complicate blood compatibility testing (Darzalex USPI). Isatuximab, a humanized anti-CD38 monoclonal antibody, has also been investigated in multiple myeloma. Reported adverse events (AEs) with isatuximab (≧24%) included infusion reactions, nausea, fatigue, dyspnea, and cough, which were typically grade ≤2 (Richter et al. (2016) JCO 34(15):8005, Dimopolos et al. (2018) Blood 132(suppl.1):ASH abstract 155 / oral presentation)). Therefore, based on the available evidence, there remains a need for new drugs, including a new generation of CD-38 targeted therapies with higher selectivity, and therefore higher efficacy, resulting in lower toxicity and improved patient convenience, to continue improving clinical outcomes.

[0362] Phase 2 The Phase 2a study population consists of approximately 18 participants. Phase 2a dosages and premedications are based on a review of available safety, efficacy, pharmacokinetic, and pharmacodynamic data from the preceding Phase 1 cohort.

[0363] [Table 11]

[0364] Primary endpoint measurement criteria for Phase 2a The primary outcome measures for a maximum of one year include: • Overall Response Rate (ORR): ORR is defined as the percentage of participants who achieved a partial response (PR) of 50 percent (%) or greater tumor reduction during the study. PR is defined as a reduction of ≥50% in serum M protein and a reduction of ≥90% or <200 milligrams (mg / ) per 24 hours in 24-hour urine M protein.

[0365] Secondary endpoint measurement criteria for Phase 2a The secondary endpoint metrics for a maximum of one year include: • Phase 2a: Number of participants with DLT • Phase 2a: Number of participants in whom one or more TEAEs are reported. • Phase 2a: Number of participants with TEAEs leading to dose change • Phase 2a: Number of participants with TEAEs leading to treatment discontinuation • Phase 2a: Number of participants with clinically significant laboratory values • Phase 2a: Number of participants with clinically significant vital sign measurements • Phase 2a: Duration of Response (DOR): DOR is the time from the date of the first response report to the date of the first reported PD. PD is an increase of ≥25% from the lowest response value in any of the following: serum M protein (the increase must be ≥0.5 g / dL; if the baseline M component is ≥5 g / dL, an increase of ≥1 g / dL in serum M component is sufficient to define relapse), and / or urinary M protein (the increase must be ≥200 mg / 24 hours), and / or abnormal (involved) / uninvolved (uninvolved) only in participants who do not have measurable serum and / or urinary M protein levels. ved) Differences between free light chain (FLC) levels (the increase must be >10 mg / dL), and, only in participants who do not have measurable serum and / or urinary M protein levels and do not have diseases measurable by FLC levels, bone marrow plasma cell percentage (the percentage must be ≥10%), or definitive development of new bone lesions or soft tissue plasmacytomas or an increase in the size of bone lesions or soft tissue plasmacytomas, and development of hypercalcemia that may be attributable solely to impaired plasma cell proliferation. • Phase 2a: Progression-free survival (PFS): PFS is the time from the date of the first dose to the earliest date of PD. PD is a ≥25% increase from the lowest response value in any of the following: serum M protein (the increase must be ≥0.5 g / dL; if the baseline M component is ≥5 g / dL, an increase of ≥1 g / dL in serum M component is sufficient to define relapse), and / or urinary M protein (the increase must be ≥200 mg / 24 hours), and / or measurable serum and / or urinary M protein. In participants without a level, the difference between abnormal and normal FLC levels (the increase must be >10 mg / dL), and in participants without measurable serum and / or urinary M-protein levels and without diseases measurable by FLC levels, the bone marrow plasma cell percentage (the percentage must be ≥10%), or the definitive development of new bone lesions or soft tissue plasmacytomas or an increase in the size of bone lesions or soft tissue plasmacytomas, and the development of hypercalcemia that may be solely attributable to impaired plasma cell proliferation. • Phase 2a: Overall Survival (OS): OS is defined as the time from the date of the first dose of medication to the date of death due to any cause. • Phase 2a: Time to response (TTR): TTR is defined as the time from the date of the first dose to the date of the first response report (partial response (PR) or better). PR is defined as a reduction of ≥50% in serum M protein and / or a reduction of ≥90% or <200 mg / 24 hours in 24-hour urinary M protein.

[0366] Inclusion criteria for Phase 1 and Phase 2a studies: Subjects received one of the following final treatments / procedures within the minimum interval specified prior to the first dose of AB79: myeloma-specific therapy (30-day washout period), antibody therapy (including anti-CD38) (120-day washout period), corticosteroid therapy (30-day washout period), autologous transplantation (90-day washout period), radiotherapy (30-day washout period), or major surgery (30-day washout period).

[0367] For participants with multimyalgia (MM), a measurable disease is defined as one of the following: (a) serum M protein ≥ 500 mg / dL (≥ 5 g / L), (b) urinary M protein ≥ 200 mg / 24 hours, or (c) for participants who do not have measurable M protein in serum protein electrophoresis (SPEP) or urinary protein electrophoresis (UPEP), serum FLC assay results with an abnormal (involved) FLC level ≥ 10 mg / dL (≥ 100 mg / L), assuming an abnormal serum FLC ratio.

[0368] Prior treatment must meet all of the following criteria: (a) Participants have been previously treated with at least one proteasome inhibitor (PI), immunomodulator (IMid), alkylating agent, and steroid; (b) Participants are refractory or intolerant to at least one PI and at least one IMid; patients have either received ≥3 prior treatment lines, or at least two prior treatment lines if one of those lines included a combination of PI and IMid; (c) Participants may, but are not required, have been previously exposed to anti-CD38 agents, either as monotherapy or in combination.

[0369] In the Phase 2a portion of the study, participants with MM must also be refractory to at least one anti-CD38 monoclonal antibody therapy at any point during treatment. "Refractory" is defined as an increase of at least 25% in M ​​protein, or PD during treatment or within 60 days after discontinuation of treatment. A "treatment line" is defined as a planned treatment program of one or more cycles. This may consist of a planned one or more cycles of monotherapy or combination therapy, as well as a series of treatments administered in a planned manner. A new treatment line is initiated if the planned course of treatment is modified to include other therapeutic agents (alone or in combination) as a result of PD, relapse, or toxicity. A new treatment line is also initiated if a planned off-therapy observation period is interrupted due to the need for additional treatment for the disease.

[0370] Exclusion criteria for the study: 1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 3. 2. I have previously undergone allogeneic stem cell transplantation. 3. The patient has previously received anti-CD38 antibody therapy and has not completed the 120-day washout period prior to receiving AB79. 4. The patient has not recovered to baseline or received an NCI CTCAE grade ≤1 from adverse events to previous myeloma treatment or procedure (chemotherapy, immunotherapy, or radiotherapy). 5. Clinical signs of central nervous system (CNS) lesions in MM. 6. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active HIV, or cytomegalovirus (CMV) infection. 7. POEMS (Polyneuropathy, Organomegaly, Endocrine Disorders, Monoclonal Gammaglobulinemia, and Skin Changes) syndrome, Monoclonal Gammaglobulinemia of Unspecified Significance, Smoldering Myeloma, Solitary Plasmacytoma, Amyloidosis, Waldenström Macroglobulinemia, or IgM Myeloma. 8. The patient has a positive Coombs test result during screening.

[0371] Reference The content of all cited references (references, patents, patent applications, and websites) that can be cited throughout this application is expressed herein by reference in whole for any purpose to the same extent as each individual reference is specifically and individually indicated so that the whole may be invoked by reference for any purpose, and the same applies to the references cited therein.

[0372] Equal portions This disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments described above should be considered illustrative rather than limiting in any way to this disclosure. Accordingly, the scope of this disclosure is indicated not by the above description but by the appended claims, and therefore, all variations falling within the meaning of the claims and their equivalents are intended to be encompassed within this disclosure. Modifications for carrying out the invention that are obvious to those skilled in the art are intended to fall within the scope of the appended claims.

Claims

1. A method for treating a disease in a subject, the method comprising subcutaneously administering a sufficient amount of isolated human anti-CD38 antibody to the subject, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region including CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light (VL) chain region including CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, the disease is one for which binding to CD38 is indicated, and the antibody is administered in a dosage of 45 to 1,800 milligrams.

2. The method according to claim 1, wherein the administration of the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia.

3. The method according to any one of the prior claims, wherein administration of the anti-CD38 antibody results in an incidence of less than 30% of one or more grade 3 or 4 treatment-related adverse events (TRAEs) or treatment-induced adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia.

4. The method according to any one of the prior claims, wherein the anti-CD38 antibody causes depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the RBCs.

5. The method according to any one of the prior claims, wherein the anti-CD38 antibody causes depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets.

6. The method according to any one of the prior claims, wherein the disease is an autoimmune disease or cancer.

7. The method according to any one of the prior claims, wherein the disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, systemic light chain amyloidosis, and graft-versus-host disease.

8. The method according to any one of the prior claims, wherein the disease is selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

9. The method according to any one of the prior claims, wherein the disease is multiple myeloma.

10. The method according to any one of the prior claims, wherein the VH chain region has the amino acid sequence of SEQ ID NO: 9 and the VL chain region has the amino acid sequence of SEQ ID NO:

10.

11. The method according to any one of the prior claims, wherein the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO:

12.

12. Any of the prior claims, wherein the antibody is administered in doses of 135 to 1,800 milligrams, 600 to 1,800 milligrams, 1,200 to 1,800 milligrams, 45 to 1,200 milligrams, 45 to 600 milligrams, 45 to 135 milligrams, 135 to 1,200 milligrams, 135 to 600 milligrams, or 1,200 to 1,800 milligrams. The method described in paragraph 1.

13. The method according to any one of the prior claims, wherein the human anti-CD38 antibody is administered in the form of a pharmaceutically acceptable composition.

14. The method according to any one of the prior claims, wherein the amount of medication prescribed is a weekly dose.

15. A method for treating blood cancer in a subject, the method comprising subcutaneously administering an isolated human anti-CD38 antibody to the subject, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region having CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light (VL) chain region having CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, and the antibody is administered in a dosage of 45 to 1,800 milligrams.

16. The method according to claim 15, wherein the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia.

17. The method according to claim 15 or 16, wherein administration of the anti-CD38 antibody results in an incidence of less than 30% of one or more grade 3 or 4 treatment-related adverse events (TRAEs) or treatment-induced adverse events (TEAEs) selected from the group consisting of anemia including hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia.

18. The method according to any one of claims 15 to 17, wherein the anti-CD38 antibody causes depletion of less than 10% of the RBCs.

19. The method according to any one of claims 15 to 18, wherein the anti-CD38 antibody causes depletion of less than 10% of platelets.

20. The method according to any one of claims 15 to 19, wherein the hematological cancer is selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

21. The method according to claim 20, wherein the blood cancer is multiple myeloma.

22. The method according to any one of claims 15 to 21, wherein the VH chain region has the amino acid sequence of SEQ ID NO: 9 and the VL chain region has the amino acid sequence of SEQ ID NO:

10.

23. The method according to any one of claims 15 to 22, wherein the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO:

12.

24. The method according to any one of claims 15 to 23, wherein the antibody is administered in a dosage of 135 to 1,800 milligrams, 600 to 1,800 milligrams, 1,200 to 1,800 milligrams, 45 to 1,200 milligrams, 45 to 600 milligrams, 45 to 135 milligrams, 135 to 1,200 milligrams, 135 to 600 milligrams, or 1,200 to 1,800 milligrams.

25. The method according to any one of claims 15 to 24, wherein the human anti-CD38 antibody is administered in the form of a pharmaceutically acceptable composition.

26. The method according to any one of claims 15 to 25, wherein the amount of medication prescribed is a weekly dose.

27. A unit dosage form comprising an isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10, wherein the isolated antibody binds to CD38 and does not bind to human erythrocytes, and the unit dosage form is formulated for subcutaneous administration at a dose of 45 to 1,800 milligrams of the antibody.

28. The unit dosage form according to claim 27, wherein the unit dosage form is formulated for subcutaneous administration in doses of 135 to 1,800 milligrams, 600 to 1,800 milligrams, 1,200 to 1,800 milligrams, 45 to 1,200 milligrams, 45 to 600 milligrams, 45 to 135 milligrams, 135 to 1,200 milligrams, 135 to 600 milligrams, or 1,200 to 1,800 milligrams of the antibody.

29. The unit dosage form according to claim 27 or claim 28, wherein the isolated antibody comprises a heavy chain containing SEQ ID NO: 11 and a light chain containing SEQ ID NO:

12.

30. The unit dosage form according to any one of claims 27 to 29, wherein the unit dosage form is formulated for subcutaneous administration of the antibody in the treatment of a hematological cancer selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

31. The unit dosage form according to claim 30, wherein the blood cancer is multiple myeloma.

32. The unit dosage form according to any one of claims 27 to 31, wherein the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia.

33. The unit dosage form according to any one of claims 27 to 32, wherein the anti-CD38 antibody causes depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the RBCs.

34. The unit dosage form according to any one of claims 27 to 33, wherein the anti-CD38 antibody causes depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets.

35. The unit dosage form according to any one of claims 27 to 34, wherein the aforementioned dosage is a weekly dosage.

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