Subcutaneous administration of anti-CD38 antibodies for treating patients with moderate to severe systemic lupus erythematosus

Abstract

Methods of treating a patient suffering from moderate to severe systemic lupus erythematosus (SLE) by subcutaneous administration of an isolated anti-CD38 antibody are disclosed. Also disclosed are unit dosage forms of an anti-CD38 antibody for use in the treatment of patients suffering from moderate to severe SLE.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 USC §119(e) to U.S. Provisional Application Serial No. 63 / 375,197 filed on September 9, 2022, U.S. Provisional Application Serial No. 63 / 381,128 filed on October 26, 2022, U.S. Provisional Application Serial No. 63 / 382,275 filed on November 3, 2022, and U.S. Provisional Application Serial No. 63 / 519,535 filed on August 14, 2023, the entire disclosures of which are incorporated herein by reference.

[0003] Incorporation by reference of materials submitted in electronic form

[0004] This application contains a sequence listing, which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The XML file was created on August 31, 2023, is named 101588-5016-WO SequenceListing.xml, and is 16,384 bytes in size. Technical Field

[0005] Disclosed are methods for treating patients with moderate to severe systemic lupus erythematosus (SLE) by subcutaneous administration of an isolated anti-CD38 antibody. Also disclosed are unit dosage forms of the anti-CD38 antibody for treating patients with moderate to severe SLE. Background Art

[0006] Systemic lupus erythematosus (SLE) is a severe autoimmune rheumatic disease for which effective therapies have remained elusive, leaving patients with moderate to severe disease with significant unmet medical needs.

[0007] SLE is a heterogeneous autoimmune disease characterized by dysregulation of T and B lineage cells and other components of the innate immune system (Li et al. (2022) J. Autoimmun. 132: p. 102870 and Ma et al. (2019) Int. J. Mol. Sci. 20 (23); which are incorporated herein by reference in their entirety). A hallmark of the disease is the production of pathogenic autoantibodies against double-stranded DNA (dsDNA), phospholipids, blood cells, and other targets (Dema, B. and N. Charles. (2016) Antibodies (Basel). 5 (1); which are incorporated herein by reference in their entirety). Tissue damage in SLE is primarily caused by these pathogenic autoantibodies through immune complex deposition and Fc and complement-mediated inflammation, as well as through direct antibody-target interactions. Almost any organ or system in the body may be affected by SLE.

[0008] The clinical course of SLE is episodic, with flare-ups of disease activity over time that lead to increasing disability and organ damage. For moderate to severe cases, the current standard of care includes off-label therapies, including immunosuppressants (such as azathioprine, cyclophosphamide, and mycophenolate mofetil), antimalarials (such as hydroxychloroquine and chloroquine phosphate), corticosteroids (such as prednisone), and high-dose intravenous immunoglobulin (IVIg).

[0009] The therapeutic agent for treating SLE has shown limited success in targeting autoantibody production. Short-lived plasmablasts (PB), plasma cells (i.e., terminally differentiated B cells) and long-lived plasma cells produce characteristic pathogenic autoantibodies, and are therefore crucial in the pathogenesis of SLE. Studies have shown that the number of PBs in the blood of patients with active SLE increases (Dorner et al. (2011) Arthritis. Res. Ther. 13 (5): p. 243; It is incorporated herein by reference in its entirety).

[0010] In order to avoid the toxicity associated with general immunosuppression, trials using biological agents for selective B cell depletion have been conducted. However, most trials have given disappointing results (Cinquina et al. (2022) Curr. Rheumatol. Res. 3(1): 1-3); it is incorporated herein by reference in its entirety). These failures may be partly due to the heterogeneity of SLE pathophysiology, which suggests that more effective targeted therapies need to be developed.

[0011] CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PB and plasma cells, making it a potential target for the treatment of SLE (Parodis et al. (2022) Front. Med. (Lausanne). 9: p. 952304; which is incorporated herein by reference in its entirety). In an ex vivo study of CD38 expression on various immune cells in peripheral blood mononuclear cells from patients with SLE, the highest CD38 expression was observed on plasma cells and PB, followed by natural killer (NK) cells, plasmacytoid dendritic cells, regulatory T cell subsets, and naive T cells (Burns et al. (2021) Int. J. Mol. Sci. 22 (5); which is incorporated herein by reference in its entirety).

[0012] Other studies have demonstrated that the levels of PB expressing CD38 are increased in patients with SLE (Clemens et al. (2017) Clin. Pharmacokinet. 56(8):915-24; Sanada et al. (2016) Blood 128(7):923-33; Wang et al. (2016) Arthrit. Rheumatol. 68(suppl 10):1085; which are incorporated herein by reference in their entirety). Daratumumab is a commercially available CD38 antibody approved for the treatment of multiple myeloma that effectively depletes plasma cells and PB in peripheral blood mononuclear cells from patients with SLE in vitro in a dose-dependent manner (Ramaschi et al. (1996) Blood 87(6):2308-13; which are incorporated herein by reference in their entirety).

[0013] AB79 (the drug substance component of mezagitamab, also known as TAK-079) is a fully human IgG1 monoclonal antibody (mAb) that specifically binds to CD38 with high affinity (Kd=3.5nM) (U.S. Patent No. US 8,362,211, the contents of which are hereby incorporated by reference in their entirety). Available nonclinical and first-in-human data show an acceptable safety profile and encouraging pharmacodynamic (PD) effects in reducing target cells expressing CD38 (Korver et al. (2019) J. Pharmacol. Exp. Ther. 370(2): p. 182-196; Fedyk et al. (2020) Br. J. Clin. Pharmacol. 86(7): p. 1314-1325; which are incorporated herein by reference in their entirety). AB79 reduces the levels of plasma cells and plasmablasts in the blood isolated from healthy subjects and systemic lupus erythematosus (SLE) patients. In SLE cases, 80% of plasma cell populations (including short-lived and long-lived plasma cells) were reduced. In addition, the number of cells producing pathogenic autoantibodies was also reduced, including VH4-34 9G4+ antibodies (reduced by 70%), anti-Ro antibodies (reduced by 70%), and anti-dsDNA antibodies (reduced by 80%).

[0014] The level of unmet need in treating patients with moderate to severe SLE remains high, and therapies with new mechanisms of action are needed to improve efficacy in reducing disease activity, to help reduce corticosteroid use and to improve the quality of life of patients with SLE.

[0015] It is an object of the present invention to provide a method of treating patients with moderate to severe SLE by subcutaneous administration of AB79 (as the drug substance component of Mazettuzumab), a fully human IgG1 mAb that binds to CD38 with high affinity. Summary of the invention

[0016] Provided herein are methods and unit dosage forms comprising an anti-CD38 antibody or antigen-binding fragment thereof for treating a patient with moderate to severe SLE.

[0017] In one aspect, the present invention provides a method of treating moderate or severe SLE in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antibody-binding fragment thereof comprises: a variable heavy chain (VH) region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the subject is diagnosed with severe SLE.

[0018] In another aspect, the present invention provides a method of reducing the level of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the subject is diagnosed with severe SLE.

[0019] In one aspect, the present invention provides a method of reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the subject is diagnosed with severe SLE.

[0020] In another aspect, the present invention provides a method of reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE as disclosed herein, wherein the immunoglobulins are IgA, IgG and / or IgM.

[0021] In one aspect, the present invention provides a method of reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antibody-binding fragment thereof comprises: (a) a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and (b) a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the subject is diagnosed with severe SLE.

[0022] In another aspect, the present invention provides a method of reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE as disclosed herein, wherein the one or more autoantibodies are selected from the group consisting of anti-dsDNA, anti-SmDp, beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A and Sjögren's syndrome SS-B.

[0023] In one aspect, the invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

[0024] In another aspect, the present invention provides a method as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 10; optionally wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 10; optionally wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 10; optionally wherein the heavy chain (HC) of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 11; and / or the light chain (LC) of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 12. NO:12 has an amino acid sequence with at least 95% identity; optionally wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO:1 and SEQ ID NO:2 based on human sequence numbering ... -8 M or greater affinity to human CD38 (SEQ ID NO: 1), and wherein the affinity is measured by a standard Biacore assay; optionally wherein the VH region comprises SEQ ID NO: 9 and the VL region comprises SEQ ID NO: 10; and optionally wherein the isolated antibody or antigen-binding fragment thereof comprises a HC as shown in SEQ ID NO: 11 and a LC as shown in SEQ ID NO: 12.

[0025] In one aspect, the present invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain; optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and optionally wherein the isolated antibody or antigen-binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgG1 antibody.

[0026] In another aspect, the present invention provides a method as disclosed herein, wherein the subject receives one or more background SLE drugs, optionally wherein the one or more background SLE drugs are selected from the group consisting of immunosuppressants, steroids and immunoglobulins; and optionally wherein the one or more background SLE drugs are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil and / or mycophenolic acid.

[0027] In one aspect, the present invention provides a method as disclosed herein, wherein the one or more background SLE drugs are administered in combination with the antibody or antigen-binding fragment thereof.

[0028] In another aspect, the present invention provides a method as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in a Grade 3 or 4 incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of less than 10%; optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infections, fever, herpes zoster, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphocytopenia, cardiac disorders, palpitations and dyspnea; and optionally wherein administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs with a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

[0029] In one aspect, the present invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg and about 140 mg; and optionally wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg, about 90 mg or about 135 mg.

[0030] In another aspect, the invention provides a method as disclosed herein, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0031] In one aspect, the present invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition, and optionally wherein the pharmaceutically acceptable composition comprises the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient or stabilizer.

[0032] In another aspect, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises the HC as shown in SEQ ID NO: 11 and the LC as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks.

[0033] In one aspect, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mazetuzumab.

[0034] In another aspect, the present invention provides a unit dosage form comprising an isolated antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising a VH region, the VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO:3, a CDR2 having an amino acid sequence of SEQ ID NO:4, and a CDR3 having an amino acid sequence of SEQ ID NO:5; and a VL region, the VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO:6, a CDR2 having an amino acid sequence of SEQ ID NO:7, and a CDR3 having an amino acid sequence of SEQ ID NO:8; wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO:1), and the unit dosage form is formulated for subcutaneous administration of the antibody or antibody-binding fragment thereof at a dose of 40 mg to 140 mg to treat moderate or severe systemic lupus erythematosus (SLE).

[0035] In one aspect, the present invention provides a unit dosage form as disclosed herein, wherein the unit dosage form is formulated for subcutaneous administration of the antibody or its antigen-binding fragment to treat severe SLE. In another aspect, the present invention provides a unit dosage form as disclosed herein, wherein the antibody or its antigen-binding fragment further comprises one or more engineered sugar forms, wherein the engineered sugar forms comprise glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

[0036] In one aspect, the present invention provides a unit dosage form as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 10; optionally wherein the VH region comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 9, and / or the VL region comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 10; optionally wherein the VH region comprises an amino acid sequence having at least 99% identity with SEQ ID NO: 9, and / or the VL region comprises an amino acid sequence having at least 99% identity with SEQ ID NO: 10; optionally wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 11, and / or the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 12; optionally wherein the isolated antibody or antigen-binding fragment thereof is identical to SEQ ID NO: 11 based on human sequence numbering. NO:1 and at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO:2 interact; optionally wherein the isolated antibody or antigen-binding fragment thereof is 10 -8 M or greater affinity to human CD38 (SEQ ID NO: 1), and wherein the affinity is measured by a standard Biacore assay; optionally wherein the VH region comprises SEQ ID NO: 9 and the VL region comprises SEQ ID NO: 10; and optionally wherein the isolated antibody or antigen-binding fragment thereof comprises a HC as shown in SEQ ID NO: 11 and a LC as shown in SEQ ID NO: 12.

[0037] In another aspect, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain; optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and optionally wherein the isolated antibody or antigen-binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgG1 antibody.

[0038] In one aspect, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is used in combination with one or more background SLE drugs, optionally wherein the one or more background SLE drugs are selected from the group consisting of immunosuppressants, steroids and immunoglobulins; optionally wherein the one or more background SLE drugs are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil and / or mycophenolic acid; and optionally wherein the unit dosage form also comprises the one or more background SLE drugs.

[0039] In another aspect, the present invention provides a unit dosage form as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in a Grade 3 or 4 incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of less than 10%; optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, fever, herpes zoster, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations and dyspnea; and optionally wherein administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs with a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

[0040] In one aspect, the invention provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg and about 140 mg; and optionally wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg, about 90 mg or about 135 mg.

[0041] In another aspect, the invention provides a unit dosage form as disclosed herein, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks or once every four weeks.

[0042] In one aspect, the invention provides a unit dosage form as disclosed herein, further comprising at least one pharmaceutically acceptable carrier, excipient or stabilizer.

[0043] In another aspect, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises HC as shown in SEQ ID NO: 11 and LC as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks.

[0044] In yet another aspect, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mazetuzumab.

[0045] In one aspect, the present invention provides a human anti-CD38 antibody or an antigen-binding fragment thereof for treating moderate or severe systemic lupus erythematosus (SLE), reducing the level of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE, or reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

[0046] In one aspect, the present invention provides a human anti-CD38 antibody or an antigen-binding fragment thereof for treating moderate or severe systemic lupus erythematosus (SLE), wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

[0047] In one aspect, the present invention provides a human anti-CD38 antibody or an antigen-binding fragment thereof for reducing the level of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

[0048] In one aspect, the present invention provides a human anti-CD38 antibody or an antigen-binding fragment thereof for reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the immunoglobulin is IgA, IgG, and / or IgM.

[0049] In one aspect, the present invention provides a human anti-CD38 antibody or an antigen-binding fragment thereof for reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the one or more autoantibodies are selected from the group consisting of anti-dsDNA, anti-SmDp, beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A, and Sjögren's syndrome SS-B.

[0050] In one aspect, the present invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for treating moderate or severe systemic lupus erythematosus (SLE) in a subject, wherein (i) the level of plasmablasts and / or plasma cells in the subject is reduced; (ii) the level of one or more immunoglobulins in the subject is reduced; and / or (iii) the level of one or more autoantibodies in the subject is reduced; wherein the antibody or antibody-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the immunoglobulin is IgA, IgG, and / or IgM. In some embodiments, the one or more autoantibodies are selected from the group consisting of anti-dsDNA, anti-SmDp, Beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A, and Sjögren's syndrome SS-B. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The objects and features of the present invention may be better understood by referring to the drawings described below.

[0052] Figure 1is a schematic diagram of the TAK-079-2001 trial design. This Phase 1b study compared active mazezumab in combination with background SLE standard therapy with matching placebo in combination with background SLE standard therapy across 3 sequentially enrolled cohorts in a double-blind study design that included a 28-day screening period; a 12-week treatment period with a single SC dose injection every 3 weeks (4 doses total); a 12-week safety follow-up (FU) period; and a 12-week long-term safety follow-up period.

[0053] Figure 2 TAK-079-2001 study cohort review is shown. This phase 1b study compared active mazetzumab in combination with background SLE standard therapy and matching placebo in combination with background SLE standard therapy across 3 sequentially enrolled cohorts in a double-blind study design with a safety review at the end of each cohort and 3:1 randomization to mazetzumab:placebo.

[0054] Figure 3A-3B The pharmacokinetics (PK) of mazezumab in SLE patients showed a nonlinear increase in exposure over the dose range tested. Figure 3A Shown are mean (± SD) serum TAK-079 concentration-time curves (pharmacokinetic analysis set) for treatments side by side at dosing intervals 1-4. The vertical lines at each nominal time point represent ± SD. When mean-SD on the original scale is ≤ 0, the lower SD bar is not presented on the semi-log scale. Figure 3B The mean (± SD) serum TAK-079 concentration-time curves (pharmacokinetic analysis set) for treatment side by side with dosing intervals 1 and 2 are shown. The vertical lines at each nominal time point represent ± SD. When the mean-SD on the original scale is ≤ 0, the lower SD bar is not presented on the semi-log scale. Unplanned visits are not included.

[0055] Figures 4A-4D The pharmacodynamics of mazetuzumab in SLE patients are shown. Figure 4A Receptor occupancy and population changes in NK cells are shown. Figure 4B Receptor occupancy in plasmablasts (PB) is shown. Figure 4C Shown are dose-dependent longitudinal changes in serum IgG levels expressed as mean percent change from pre-treatment baseline ± SD (pharmacodynamic analysis set). Figure 4D Dose-dependent longitudinal changes in serum IgG levels expressed as mean percent change from pre-treatment baseline ± SEM are shown. Baseline was considered to be study day 1. *Day 85 was the end-of-dosing visit.

[0056] Figure 5Percent change in serum immunoglobulin A (pharmacodynamic analysis set) is shown. The vertical line at each nominal time point represents the SD. Baseline is considered to be study day 1. *Day 85 is the end-of-dose visit.

[0057] Figure 6A-6B Temporal curves of IgG, autoantibodies, and clinical scores are shown. The reductions in serum IgG and autoantibodies were modest and did not appear to be related to each other or to clinical responses. Fig. 6A Data are shown for subjects at the highest dose tested, 135 mg. Figure 6B Data from CLASI responders in the group treated with mazetzumab are shown.

[0058] Figures 7A-7C A population is shown to be depleted by mazezumab in a largely CD38-dependent manner. Fig. 7A Depletion of selected CD38-positive cell populations (marked) plotted against baseline CD38 expression is shown. Figure 7B TSNE cluster mapping of 20 clusters identified after CyTOF analysis is shown, revealing discrete populations that were maintained during the study (in Fig. 8A and Figure 8B ). Figure 7C Heat map expression of CD38 throughout the study is shown.

[0059] Fig. 8A Twenty cluster analyses and phenotype heatmaps of PBMCs from patients treated with mazetzumab are shown. Figure 8B A labeled TSNE plot is shown.

[0060] Figures 9A-9C Fifty cluster analyses of PBMCs from patients treated with mazetuzumab are shown. Fig. 9A Phenotypic heatmaps and cluster sizes (percentage of selected events) are shown. Evaluation of treatment efficacy identified two clusters with similarities to effector-like CD8 T cells (cluster 32, Fig. 9B ) and CD4 T cells (cluster 34, Fig. 9C ) Clusters with consistent phenotypes. p values ​​for the 135 mg dose compared to placebo were < 0.05 (*), 0.01 (**), or 0.001 (***).

[0061] Fig.10 The pharmacokinetics of mazezumab in SLE patients showed a nonlinear increase in exposure over the dose range tested.

[0062] Fig.11LS mean change from baseline in CLASI total activity score by treatment group-MMRM (safety analysis set) is shown. CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; MMRM: mixed effects model for repeated measures. MMRM analysis of all post-baseline visits was performed with change from baseline as outcome, treatment, visit, and (treatment × visit) interaction as factors, and baseline value and (baseline × visit) interaction as covariates. Degrees of freedom were calculated using the Kenward-Rogers method, and the covariance matrix was based on an autoregressive (1) covariance structure. The vertical lines at each study day represent ±SEM. *Day 85 was the end-of-dose visit.

[0063] Fig.12 Individual CLASI observations by baseline total activity score category are shown (safety analysis set). CLASI responders showed substantial, clinically meaningful improvements in skin manifestations by the end of treatment. Subgroup analysis of total activity scores revealed that all subjects with baseline CLASI scores >10 met responder criteria at the end of treatment. CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index. Baseline was considered to be Study Day 1.

[0064] Fig.13 The LS mean change from baseline in the total score of SLEDAI-2K by treatment group-MMRM is shown (safety analysis set). MMRM: mixed effects model for repeated measures; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index-2000. According to the MMRM analysis of all post-baseline visits, the analysis used the change from baseline as the outcome, treatment, visit and (treatment × visit) interaction terms as factors, and baseline value and (baseline × visit) interaction as covariates. The degrees of freedom were calculated using the Kenward-Rogers method, and the covariance matrix was based on the autoregressive (1) covariance structure. The vertical lines at each study day represent ±SEM. *Day 85 was the end of dosing visit.

[0065] Fig.14 Individual SLEDAI-2K observations by baseline total score category (safety analysis set) are shown. SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index-2000. Baseline was considered to be Study Day 1. DETAILED DESCRIPTION

[0066] The present invention relates to methods and unit dosage forms for subcutaneously administering a therapeutically effective amount of an isolated anti-CD38 antibody to treat patients with moderate or severe systemic lupus erythematosus (SLE).

[0067] SLE is a serious disease characterized by abnormal immune system activity, resulting in variable clinical symptoms. Due to the genetic and phenotypic heterogeneity of SLE, it is challenging to treat and identify new therapies for SLE, which makes it a significant unmet medical need, especially for patients with moderate to severe SLE (Kiriakidou and Ching (2020) Ann. Intern. Med. 172(11): ITC81-ITC96; which is incorporated herein by reference).

[0068] SLE is characterized by dysregulation of other components of T and B lineage cells and the innate immune system. The hallmark of the disease is the production of pathogenic autoantibodies against double-stranded DNA (dsDNA), phospholipids, blood cells, and other targets. Tissue damage in SLE is mainly caused by these pathogenic autoantibodies through immune complex deposition and Fc and complement-mediated inflammation and by direct antibody-target interactions (Rahman and Isenberg (2008) N. Engl. J. Med. 358 (9): 929-39; It is incorporated herein by reference in its entirety). Almost any organ or system of the body may be affected by SLE (D'Cruz (2006) Blood (ASH Annual Meeting Abstracts) 129: 2359-67; Lateef and Petri (2012) Arthritis Res. Ther. 14 (Suppl 4): S4; It is incorporated herein by reference in its entirety).

[0069] The clinical course of SLE is sporadic, and over time, disease activity can flare up suddenly, leading to an increase in disability and organ damage. For moderate to severe cases, current standard care includes off-label therapy, including immunosuppressants (azathioprine, cyclophosphamide and mycophenolate mofetil), high-dose steroids and intravenous (IV) immunoglobulin for cytopenia. The therapeutic agent for the treatment of SLE has shown limited success. Short-lived plasmablasts (PB), plasma cells (i.e., terminally differentiated B cells) and long-lived plasma cells produce characteristic pathogenic autoantibodies, and are therefore crucial in the pathogenesis of SLE.

[0070] Studies have shown that the number of plasmablasts (PB) in the blood of patients with active SLE is increased (D'Cruz (2006) Blood (ASH Annual Meeting Abstracts) 129: 2359-67; Clemens et al. (2017) Clin. Pharmacokinet. 56 (8): 915-24; Sanada et al. (2016) Blood 128 (7): 923-33; Wang et al. (2016) Arthrit. Rheumatol. 68 (suppl 10): 1085; which are incorporated by reference in their entirety). CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PB and plasma cells (Sullivan et al. (2017) Blood 129 (22): 3033-7; which are incorporated by reference in their entirety), making it a potential target for the treatment of SLE. In an ex vivo study of CD38 expression on various immune cells in peripheral blood mononuclear cells from patients with SLE, the highest CD38 expression was observed on plasma cells and PB, followed by natural killer (NK) cells, plasmacytoid dendritic cells, regulatory T cell subsets, and naive T cells (Ramaschi et al., (1996) Blood 87(6):2308-13; which is incorporated herein by reference in its entirety).

[0071] CD38 expression is significantly higher on plasma cells and PBs compared to other immune cells, suggesting that it is possible to selectively deplete these cells with anti-CD38 antibodies. Daratumumab is a commercially available anti-CD38 antibody that effectively depletes plasma cells and PBs from peripheral blood mononuclear cells of patients with SLE in vitro in a dose-dependent manner (Ramaschi et al. (1996) Blood 87(6):2308-13; which is incorporated herein by reference in its entirety). Intravenous daratumumab has been approved for patients with multiple myeloma (relapsed and newly diagnosed). However, the most common adverse reactions (≥20%) of daratumumab monotherapy or in combination with standard anti-myeloma regimens are infusion-related reactions (IRR), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle cramps, arthralgia, back pain, fever, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection (Darzalex USPI). Daratumumab can cause severe and / or serious infusion reactions, including anaphylaxis, and is reported in approximately 30% of all patients (Darzalex USPI). It is also important to note that daratumumab interferes with certain laboratory assays, which importantly may complicate blood compatibility testing. (Darzalex USPI).

[0072] Other Morphosys antibodies targeting CD38 are known (see, e.g., WO 2006 / 125640, which is incorporated herein by reference in its entirety, disclosing four human antibodies: MOR03077, MOR03079, MOR03080 and MOR03100, and two murine antibodies: OKT10 and IB4). These prior art antibodies are inferior to another anti-CD38 antibody, TAK-079, for a number of reasons. MOR03080 binds to human CD38 and cynomolgus monkey CD38, but has a low affinity for human CD38 (Biacore KD = 27.5 nm). OKT10 binds to human CD38 and cynomolgus monkey CD38, but has a low / moderate affinity for human CD38 (Biacore KD = 8.28 nm). MOR03079 binds to human CD38 with high affinity (Biacore KD = 2.4 nm), but not to cynomolgus CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD = 10 nm and 56 nm, respectively). In contrast, TAK-079 binds to human and cynomolgus CD38 with high affinity (Biacore KD = 5.4 nm for human CD38). In addition, prior art antibodies have poor ADCC and CDC activity.

[0073] The advantage of more effective ADCC is the ability to deliver anti-CD38 therapeutics in the form of small volume injections. Safety profiles and PD target effects were observed after subcutaneous administration of TAK-079 up to 0.6 mg / kg to healthy subjects. A single subcutaneous dose of 0.6 mg / kg TAK-079 reduced PB levels in peripheral blood by >90% and NK cell levels by >80%, while there was no comparable reduction in monocytes and B and T cells. 21 days after administration, PB and NK cell levels returned to an average of 50% of baseline levels. At this dose, there were no serious adverse events (SAEs), deaths in the study, or adverse events (AEs) leading to study discontinuation (WO 2019 / 140410, which is incorporated herein by reference in its entirety). Further studies have shown that after subcutaneous administration of 45mg, 135mg, 300mg or 600mg doses of TAK-079 to patients with relapsed and / or refractory multiple myeloma (RRMM), no drug-related SAEs, deaths in the study, or AEs that led to the suspension of the study were reported. The administration of TAK-079 reduces the plasmablast levels in blood and bone marrow aspirates and the plasma cell levels in bone marrow aspirates in a dose-dependent manner. In patients with advanced RRMM, TAK-079 also shows early signs of anti-tumor activity, as evidenced by a reduction of at least 50% in the disease burden of some patients and prolonged disease stability in other patients (WO 2019 / 186273, which is incorporated herein by reference in its entirety). However, the feasibility and efficacy of administering TAK-079 to treat patients with SLE, especially those with moderate or severe SLE, are unclear.

[0074] The methods and unit doses of the present disclosure provide for the first time subcutaneous administration of a therapeutically effective dose of an anti-CD38 antibody for treating patients with moderate or severe SLE.

[0075] The present invention provides methods and unit dosage forms for subcutaneously administering a therapeutically effective amount of an isolated anti-CD38 antibody or antigen-binding fragment to a patient with moderate or severe SLE. In some embodiments, the antibody or antigen-binding fragment for subcutaneous administration comprises a variable heavy chain region (VH) comprising SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereof) or consisting of SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereof); and a variable light chain region (VL) comprising SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereof) or consisting of SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereof). In some embodiments, the patient is diagnosed with moderate SLE. In some embodiments, the patient is diagnosed with severe SLE. In some embodiments, the antibody or its antigen-binding fragment is administered subcutaneously at a dosage of 40 mg to 140 mg.

[0076] Unless otherwise defined herein, the scientific and technical terms used in conjunction with the present invention should have the meanings commonly understood by those skilled in the art. The meaning and scope of the terms should be clear. However, if there is any implicit ambiguity, the definition provided herein takes precedence over any dictionary or external definition. In addition, unless the context requires otherwise, singular terms should include plural terms and plural terms should include singular terms. Unless otherwise specified, the term "or" includes "and / or". In addition, the use of the terms "including", "includes" or "included" is not restrictive. Unless otherwise specifically stated, terms such as "element" and "component" cover the elements and components constituting a unit and the elements and components constituting more than one subunit.

[0077] Unless otherwise indicated, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, delivery, and treatment of patients. Commercial enzymatic reactions and purification techniques are performed according to the manufacturer's specifications, as commonly accomplished in the art or as described herein.

[0078] All headings and section names are used for clarity and reference purposes only and should not be considered limiting in any way. For example, one skilled in the art will recognize the usefulness of combining various aspects of the present disclosure from different headings and sections as appropriate in accordance with the spirit and scope of the invention described herein.

[0079] In order to more readily understand the present invention, selected terms are defined below.

[0080] The terms "human CD38" and "human CD38 antigen" refer to the amino acid sequence of SEQ ID NO: 1 as defined herein, or a functional portion thereof, such as an epitope (Table 1). Typically, CD38 has a short intracytoplasmic tail, a transmembrane domain, and an extracellular domain. The terms "cynomolgus CD38" and "cynomolgus CD38 antigen" refer to the amino acid sequence of SEQ 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-ribosyltransferase; 2'-phospho-ADP-ribosyl cyclase; 2'-phospho-cyclic-ADP-ribosyltransferase; 2'-phospho-ADP-ribosyl cyclase; and T10.

[0081] Table 1. Amino acid sequences of human and cynomolgus monkey CD38

[0082]

[0083] The terms "therapeutically effective amount" and "therapeutically effective dose" refer to an amount of therapy sufficient to reduce or ameliorate the severity and / or duration of a condition or one or more symptoms thereof; prevent the progression of a condition; cause regression of a condition; prevent the recurrence, development, onset or progression of one or more symptoms associated with a condition; or enhance or improve the prophylactic or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent) at a dose and for a period of time required to achieve the desired therapeutic result. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual. A therapeutically effective amount of an antibody or antigen-binding fragment thereof is an amount in which any toxic or deleterious effects of the antibody or antigen-binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0084] The terms "patient" and "subject" include both humans and other animals. Therefore, the compositions, doses and methods disclosed herein are applicable to both human and veterinary therapy. In one embodiment, the patient is a mammal, such as a human.

[0085] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities. For example, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind to an antigen other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform or variant of human CD38 or cynomolgus CD38 may have cross-reactivity to other related antigens, such as related antigens from other species (such as CD38 species homologs). In addition, the isolated antibody may be substantially free of other cellular materials and / or chemicals.

[0086] The term "about" refers to a close degree in quantity, degree, volume, time, etc., with only minimal variations of up to 10% in size.

[0087] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle suitable for administering the compound of the invention to a mammal. The carrier includes a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration.

[0088] The term "pharmaceutical composition" refers to a preparation suitable for administration to a subject and treating a disease. When the anti-CD38 antibodies of the present invention are administered to a mammal (e.g., a human) as a medicament, they may be administered "as is" or as a pharmaceutical composition containing an anti-CD38 antibody in combination with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The pharmaceutical composition may be in the form of a unit dosage form for administering a specific dose of an anti-CD38 antibody at a specific concentration, a specific amount, or a specific volume. A pharmaceutical composition comprising an anti-CD38 antibody is provided, alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. Suitably, the pharmaceutical composition may comprise a unit dosage form according to the present invention, alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. Suitably, the pharmaceutical composition may comprise a human anti-CD38 antibody as described herein, alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier.

[0089] Traditional antibody structural units usually include tetramers. Each tetramer is usually composed of two pairs of identical polypeptide chains, each pair having a "light" chain (usually having a molecular weight of about 25kDa) and a "heavy" chain (usually having a molecular weight of about 50-70kDa). Human light chains (LC) are classified as kappa light chains and lambda light chains. Heavy chains (HC) are classified as μ, δ, γ, α or ε, and the isotypes of the antibodies are defined as IgM, IgD, IgG, IgA and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3 and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. Therefore, "isotype" refers to any subclass of immunoglobulin defined by the chemical and antigenic properties of its constant region. Known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD and IgE. Therapeutic antibodies may also comprise hybrids of isotypes and / or subclasses.

[0090] Each VH and VL region (about 100 to 110 amino acids in length) is composed of three hypervariable regions called "complementarity determining regions" (CDRs) and four framework regions (FRs) (about 15-30 amino acids in length) arranged from amino-terminus to carboxyl-terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. "Variable" means that the sequence of CDRs differs greatly among antibodies and thus determines a unique antigen binding site.

[0091] The hypervariable regions generally encompass amino acid residues 24-34 (LCDR1; "L" for light chain), 50-56 (LCDR2), and 89-97 (LCDR3) from the VL region and approximately 31-35B (HCDR1; "H" for heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) from the VL region (Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health). of Health, Bethesda, MD; which is incorporated herein by reference in its entirety) and / or those residues that form the hypervariable loop in the VL region (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3)) and those residues that form the hypervariable loop in the VH region 26-32 (HCDR1), 53-55 (HCDR2), and 96-101 (HCDR3) (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917; which is incorporated herein by reference in its entirety).

[0092] The Kabat numbering system is generally used when referring to residues in the variable domains (approximately residues 1-107 in the VL region and residues 1-113 in the VH region) (e.g., Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD; which is incorporated herein by reference in its entirety), with the EU numbering system used for the Fc region.

[0093] The term "immunoglobulin (Ig) domain" refers to an immunoglobulin region with a distinct tertiary structure. An Ig domain includes a VH and VL region, a CDR, a framework region, a constant region domain, and a hinge region. Each HC and LC has a constant region domain called a constant heavy chain (CH) domain and a constant light chain (CL) domain. In the case of an IgG antibody, each IgG isotype has a constant region comprising three CH domains. The carboxyl-terminal portion of each HC and LC defines a constant region that is primarily responsible for effector function. Therefore, the "CH" domain in the case of IgG is as follows: "CH1" refers to position 118-220 according to the EU index as in Kabat. "CH2" refers to position 237-340 according to the EU index as in Kabat, and "CH3" refers to position 341-447 according to the EU index as in Kabat.

[0094] Another type of Ig domain of HC is the hinge region. The term "hinge region" refers to a flexible polypeptide of amino acids contained between the first constant domain and the second constant domain of an antibody. Structurally, the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain begins at residue EU position 237. Thus, for IgG, the antibody hinge is defined herein to include positions 221 (D221 in IgG1) to 236 (G236 in IgG1), where numbering is according to the EU index as in Kabat. In some embodiments, for example, in the case of an Fc region, a lower hinge is included, the "lower hinge" typically referring to positions 226 or 230.

[0095] The term "Fc region" refers to a polypeptide comprising the constant region of an antibody, excluding the CH1 domain and, in some cases, excluding portions of the hinge. Thus, Fc refers to the last two constant region Ig domains (CH2 and CH3) of IgA, IgD, and IgG, the last three constant region Ig domains of IgE and IgM, and the flexible hinge at the N-terminus of these domains. For IgA and IgM, Fc may include a J chain. For IgG, the Fc domain includes the Ig domains Cγ2 and Cγ3 (Cγ2 and Cγ3) and the lower hinge region between Cγ1 (Cγ1) and Cγ2 (Cγ2). Although the boundaries of the Fc region may vary, the human IgG HC Fc region is generally defined as including residues C226 or P230 at its carboxyl terminus, wherein numbering is based on the EU index as in Kabat. In some embodiments, as described more fully below, the Fc region is amino acid modified, for example, to alter binding to one or more FcγR receptors or FcRn receptors.

[0096] CD38 Antibody

[0097] Therefore, the present invention provides an isolated anti-CD38 antibody that specifically binds to human and primate CD38 proteins, which can be used in a subcutaneous administration method and unit dosage form for treating patients with moderate or severe SLE. The antibodies or antigen-binding fragments thereof used in the present invention bind to both human and primate CD38 proteins, particularly primates used in clinical trials, such as cynomolgus monkeys (Macaca fascicularis, Crab eating macaque, also referred to herein as "cyno").

[0098] "TAK-079" or "mazetuzumab" is a therapeutic protein comprising a fully human immunoglobulin IgG1 monoclonal antibody that specifically binds to CD38 with high affinity (Kd = 3.5 nM), which is referred to herein as AB79 (U.S. Pat. No. US 8,362,211, the contents of which are incorporated herein by reference in their entirety). The amino acid sequence of mazetuzumab is shown in Table 2.

[0099] Table 2: Amino acid sequence of Mazetuzumab

[0100]

[0101]

[0102] TAK-079 suppresses the growth of tumor cells expressing CD38 via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) by cell depletion.TAK-079 also reduces the level of plasma cells and plasmablasts in the blood separated from healthy subjects and systemic lupus erythematosus (SLE) patients.In SLE cases, 80% of plasma cell colonies (including short-lived and long-lived plasma cells) are reduced.In addition, the cell number producing pathogenic autoantibodies is also reduced, including VH4-34 9G4+ antibodies (reducing 70%), anti-Ro antibodies (reducing 70%) and anti-dsDNA antibodies (reducing 80%).Anti-human CD38 mAb daratumumab also depletes plasmablasts and plasma cells expressing CD38 in samples from patients with SLE and RA in a dose-dependent manner in vitro. Unlike daratumumab, TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys, providing a unique opportunity to determine whether reducing the levels of cells expressing CD38 affects inflammation and tissue damage in non-human primate autoimmune disease models. In healthy cynomolgus monkeys, the efficiency of lymphocyte, as well as B, T, and NK cell depletion positively correlated with CD38 expression levels and AB79 dose levels (PCT Application No. PCT / US2017 / 042128; U.S. Patent No. US 8,362,211; which are incorporated herein by reference in their entirety).

[0103] In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof of the invention interact with CD38 at a number of 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. Suitably, the anti-CD38 antibodies or antigen-binding fragments thereof of the invention may interact with CD38 at a number of amino acid residues including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 based on human sequence numbering. Suitably, the anti-CD38 antibodies or antigen-binding fragments thereof of the invention interact with CD38 at a number of 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 humans and cynomolgus monkeys, except that S274 is actually F274 in cynomolgus monkeys. These residues may represent immunodominant epitopes and / or residues within the region occupied by the specific antigen binding peptide.

[0104] In some embodiments, the anti-CD38 antibody used in accordance with the present invention comprises a heavy chain (HC) comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079) and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 TAK-079), or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody used in accordance with the present invention comprises a light chain (LC) comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079) and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079), or variants of those sequences having up to three amino acid changes. In some embodiments, an antibody for use according to the present invention comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO:4; HCDR2 TAK-079), and ARG SLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 TAK-079), or variants of those sequences having up to three amino acid changes; and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 TAK-079), RDS (SEQ ID NO:7; LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 TAK-079), or variants of those sequences having up to three amino acid changes. In some embodiments, the anti-CD38 antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079), and ARGSLF HDSSGFYFGH (SEQ ID NO: 5; HCDR3 TAK-079). In some embodiments, the antibody comprises a LC comprising the following CDR amino acid sequences: SSN IGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079).In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079) and ARGSLFHDSSGF YFGH (SEQ ID NO: 5; HCDR3 TAK-079); and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079) and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079). In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the VH region sequence may have at least 80% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the VH region sequence may have at least 85% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the VH region sequence may have at least 90% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the VH region sequence may have at least 95% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise CDR sequences as defined in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, and the remainder of the VH region sequence may have at least 97% sequence identity with SEQ ID NO: 9. Suitably, the VH region may comprise CDR sequences as defined in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, and the remainder of the VH region sequence may have at least 99% sequence identity with SEQ ID NO: 9.

[0105] In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO:9.

[0106] In some embodiments, the antibody comprises a LC comprising a VL region amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 85% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 90% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 95% sequence identity with SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 97% sequence identity with SEQ ID NO: 10. Suitably, the VL region may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the VL region sequence may have at least 99% sequence identity with SEQ ID NO: 10.

[0107] In some embodiments, the antibody comprises a LC comprising the VL region amino acid sequence of SEQ ID NO:10.

[0108] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9 as described herein, or a variant thereof; and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10 as described herein, or a variant thereof.

[0109] As will be appreciated by those skilled in the art, the VH and VL regions may be linked to human IgG constant domain sequences (typically IgGl, IgG2 or IgG4).

[0110] In some embodiments, the antibody comprises a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, and the remainder of the HC may have at least 85% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the HC may have at least 90% sequence identity with SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the HC may have at least 95% sequence identity with SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the HC may have at least 97% sequence identity with SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the HC may have at least 99% sequence identity with SEQ ID NO: 11.

[0111] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises a light chain (LC) comprising or consisting of an amino acid sequence having at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the LC may have at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the LC may have at least 85% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 90% sequence identity with SEQ ID NO:12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 95% sequence identity with SEQ ID NO:12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 97% sequence identity with SEQ ID NO:12. Suitably, the LC may comprise CDR sequences as defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 99% sequence identity with SEQ ID NO:12.

[0112] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO:12.

[0113] 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, or consists of 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.

[0114] The invention encompasses antibodies that bind to both human and cynomolgus CD38 and interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the following amino acid residues: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human numbering. Suitably, the antibody can interact with at least 90% of these amino acid residues. Suitably, the antibody can interact with at least 95% of these amino acid residues. Suitably, the antibody can interact with at least 97% of these amino acid residues. Suitably, the antibody can interact with at least 98% of these amino acid residues. Suitably, the antibody can interact with at least 99% of these amino acid residues. Suitably, the antibody can interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human numbering.

[0115] In some embodiments, the antibody is a full-length antibody.A "full-length antibody" herein refers to the structure that constitutes the natural biological form of an antibody, including variable and constant regions, including one or more modifications as outlined herein.

[0116] Alternatively, the antibody may be of various structures including, but not limited to, antibody fragments, antigen-binding fragments, monoclonal antibodies, bispecific antibodies, miniantibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), and fragments of each. Specific antibody fragments include, but are not limited to, (i) a Fab fragment consisting of the VL, VH, CL and CH1 domains, (ii) a Fd fragment consisting of the VH and CH1 domains, (iii) a Fv fragment consisting of the VL and VH domains of a single antibody, (iv) a dAb fragment consisting of a single variable region (Ward et al. (1989) Nature 341:544-546), (v) isolated CDR regions, (vi) a F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, (vii) a single-chain Fv molecule (scFv) in which the VH domain and the VL domain are connected by a peptide linker that allows the two domains to associate to 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-chain Fv (WO 03 / 11161) and (ix) "diabodies" or "tribodies", which are multivalent or multispecific fragments constructed by gene fusion (Tomlinson et al. (2000) Methods Enzymol. 326:461-479; WO 94 / 13804; Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448).

[0117] Suitably, the antibody may be a Fab fragment. Suitably, the antibody may be a Fv fragment. Suitably, the antibody may be a Fd fragment. Suitably, the antibody structure may be an isolated CDR region. Suitably, the antibody may be a F(ab')2 fragment. Suitably, the antibody may be a scFv fragment.

[0118] In some embodiments, the antibodies or antigen-binding fragments thereof of the invention further comprise one or more engineered sugar forms. In some embodiments, the engineered sugar forms comprise glycosylation of one or more polypeptides. In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. In some embodiments, the glycosylation is O-linked glycosylation.

[0119] In some embodiments, the isolated antibody of the invention is mazezumab.

[0120] Antibody modification

[0121] The present invention further provides variant anti-CD38 antibodies. That is, many modifications can be made to the antibodies of the present invention, including but not limited to amino acid modifications in CDR (affinity maturation), amino acid modifications in VH region and / or VL region, amino acid modifications in HC and / or LC, amino acid modifications in Fc region, glycosylation variants, other types of covalent modifications, etc.

[0122] The term "variant" means a polypeptide that is different from a parent polypeptide. Amino acid variants may include substitutions, insertions and deletions of amino acids. In general, variants may include many modifications, as long as the function of the protein still exists, as described herein. That is, in the case of amino acid variants, for example, produced using the CDRs of TAK-079, the antibody should still specifically bind to human and cynomolgus CD38. The term "variant Fc region" refers to an Fc sequence that is different from a wild-type or parent Fc sequence due to at least one amino acid modification. Fc variants may refer to the Fc polypeptide itself, a composition comprising an Fc variant polypeptide, or an amino acid sequence. If, for example, an amino acid variant is produced using the Fc region, the variant antibody should maintain the function required for a specific application or indication of the antibody. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, such as 1-10, 1-5, 1-4, 1-3 and 1-2 substitutions, may be used. Suitable modifications may be made at one or more positions as generally described, for example, in U.S. Patent Application Serial Nos. 11 / 841,654; 12 / 341,769; U.S. Patent Publication Nos. 2004013210; 20050054832; 20060024298; 20060121032; 20060235208; 20070148170; and U.S. Patent Nos. 6,737,056; 7,670,600; and 6,086,875, all of which are expressly incorporated by reference in their entireties, particularly with respect to specific amino acid substitutions that increase binding to Fc receptors.

[0123] Variants may be considered in terms of similarity (ie, amino acid residues having similar chemical properties / functions), preferably variants are described in terms of sequence identity.

[0124] Sequence comparisons can be performed visually, or more usually, with the aid of readily available sequence comparison programs. These publicly available and commercially available computer programs can calculate the sequence identity between two or more sequences.

[0125] For example, it may be desirable to have 1 to 5 modifications in the Fc region of a wild-type or engineered protein, and 1 to 5 modifications in the Fv region. 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., VH or VL region, constant region, and / or HC and LC sequences of TAK-079). Suitably, the variant may have at least 80% sequence identity with the parent sequence. Suitably, the variant may have at least 85% sequence identity with the parent sequence. Suitably, the variant may have at least 90% sequence identity with the parent sequence. Suitably, the variant may have at least 92% sequence identity with the parent sequence. Suitably, the variant may have at least 95% sequence identity with the parent sequence. Suitably, the variant may have at least 97% sequence identity with the parent sequence. Suitably, the variant may have at least 98% sequence identity with the parent sequence. Suitably, the variant may have at least 99% sequence identity with the parent sequence.

[0126] In one embodiment, sequence identity is determined across the entire sequence.In one embodiment, sequence identity is determined across the entire candidate sequence compared to a sequence described herein.

[0127] The term "amino acid substitution" refers to the replacement of an amino acid at a specific position in a parent polypeptide sequence by another amino acid. For example, the replacement S100A refers to a variant polypeptide in which the serine at position 100 is replaced by alanine. Suitably, the amino acid substitution may be a conservative amino acid substitution. Suitably, the variant may comprise one or more, such as two or three conservative amino acid substitutions. Amino acids with similar biochemical properties may be defined as amino acids that may be substituted via conservative substitutions.

[0128] Unless otherwise expressly indicated herein by reference to a specific single amino acid, conservative substitutions as described below may be used to replace amino acids. The aliphatic polar uncharged amino acid may be a cysteine, serine, threonine, methionine, asparagine or glutamine residue. The aliphatic polar charged amino acid may be an aspartic acid, glutamic acid, lysine or arginine residue. The aromatic amino acid may be a histidine, phenylalanine, tryptophan or tyrosine residue. Conservative substitutions may be made, for example, according to Table 3 below. Amino acids in the same block in the second column and preferably in the same row in the third column may be substituted with each other:

[0129] Table 3. Conservative substitutions

[0130] Aliphatic Non-polar GAP ILV Polarity - No charge CSTM NQ Polarity – Electric charge DE KR Aromatic HFW

[0131] The term "amino acid insertion" refers to the addition of an amino acid at a specific position in a parent polypeptide sequence.

[0132] The term "amino acid deletion" refers to the removal of an amino acid at a specific position in a parent polypeptide sequence.

[0133] The terms "parent antibody" and "precursor antibody" refer to an unmodified antibody that is subsequently modified to produce a variant. In one embodiment, the parent antibody herein is TAK-079. In one embodiment, the parent antibody herein comprises a VH region having an amino acid sequence of SEQ ID NO: 9 and a VL region having an amino acid sequence of SEQ ID NO: 10. In one embodiment, the parent antibody herein comprises an HC amino acid sequence of SEQ ID NO: 11 and an LC amino acid sequence of SEQ ID NO: 12. The parent antibody may refer to the polypeptide itself, a composition comprising the parent antibody, or an amino acid sequence encoding the polypeptide. Therefore, the term "parent Fc polypeptide" refers to an Fc polypeptide that has been modified to produce a variant.

[0134] The terms "wild type", "WT" and "native" refer to an amino acid sequence or nucleotide sequence found in nature, including allelic variations. A WT protein, polypeptide, antibody, immunoglobulin, IgG, etc. has an amino acid sequence or nucleotide sequence that has not been intentionally modified.

[0135] In some embodiments, one or more amino acid modifications are made in one or more CDRs of an anti-CD38 antibody. Generally, only 1, 2, or 3 amino acids are substituted in any single CDR, and generally no more than 4, 5, 6, 7, 8, 9, or 10 changes are made within a group of CDRs. However, it should be understood that any combination of no substitution, 1, 2, or 3 substitutions in any CDR can be independently and optionally combined with any other substitution.

[0136] 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 changes in one or more CDRs that result in improved affinity of the antibody for an antigen compared to a parent antibody that does not have those changes. In some cases, it may be desirable to reduce the affinity of an antibody for its antigen.

[0137] Affinity maturation can be performed to increase the binding affinity of an antibody for an antigen by at least about 10% to 50%, 100%, 150% or more, or 1-5 fold compared to a "parent" antibody. Preferred affinity mature antibodies have nanomolar or even picomolar affinities for the target antigen. 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; which are incorporated herein by reference in their entireties).

[0138] Alternatively, "silent" amino acid modifications, such as those that do not significantly change the affinity of the antibody for the antigen, may be made, for example, in one or more CDRs of an antibody of the invention. These modifications may be made for a number of reasons, including optimizing expression (such as modifications that may be made to nucleic acids encoding an antibody of the invention).

[0139] Thus, variant CDRs and antibodies are included within the definition of CDRs and antibodies of the invention; that is, the antibodies of the invention may comprise amino acid modifications in one or more CDRs set forth in SEQ ID NOs: 3 to 8. In addition, as outlined below, amino acid modifications may also be independently and optionally made in any region outside of the CDRs, including framework regions and constant regions.

[0140] In some embodiments, variant antibodies of TAK-079 specific for human CD38 (SEQ ID NO: 1) and cynomolgus CD38 (SEQ ID NO: 2) are described. The antibody consists of six CDRs, wherein each CDR of this antibody 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 0, 1 or 2 amino acid substitutions.

[0141] Glycosylation

[0142] Another type of modification is a change in glycosylation. In one embodiment, the antibodies disclosed herein may be modified to include one or more engineered sugar forms. As used herein, "engineered sugar form" means a carbohydrate component covalently attached to an antibody, wherein the carbohydrate component is chemically different from the carbohydrate component of the parent antibody. Engineered sugar forms can be used for a variety of purposes, including but not limited to enhancing or reducing effector function. A preferred form of engineered sugar form is afucosylation, which has been shown to be associated with an increase in ADCC function, presumably through tighter binding to the FcγRIIIa receptor. In this context, "afucosylation" means that most antibodies produced in host cells are substantially free of fucose, for example, 90-95-98% of the antibodies produced do not have significant fucose as a component of the carbohydrate portion of the antibody (usually attached at N297 of the Fc region). Functionally defined, afucosylated antibodies typically exhibit at least 50% or higher affinity for the FcγRIIIa receptor.

[0143] Engineered glycoforms can be generated by a variety of methods known in the art (U.S. Pat. No. US 8,362,211; which is incorporated herein by reference in its entirety). Engineered glycoforms generally refer to different carbohydrates or oligosaccharides; therefore, antibodies can include engineered glycoforms.

[0144] Alternatively, engineered sugar forms can refer to IgG variants comprising different carbohydrates or oligosaccharides. As known in the art, the glycosylation pattern can depend on the sequence of the protein (e.g., the presence or absence of specific glycosylated amino acid residues, as discussed below), or the host cell or organism that produces the protein. Specific expression systems are discussed below.

[0145] Glycosylation of polypeptides is usually either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are identification sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used.

[0146] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence so that it contains one or more of the above tripeptide sequences (for N-linked glycosylation sites). The alteration may also be accomplished by adding one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites) or replacing the starting sequence with the one or more serine or threonine residues. For convenience, the amino acid sequence of the antibody is preferably altered by changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases so that codons that will be translated into the desired amino acids are produced.

[0147] Another means of increasing the number of carbohydrate moieties on an antibody is by chemical or enzymatic coupling of glycosides to proteins. The advantage of these procedures is that they do not require the production of proteins in host cells with glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling method used, one or more sugars may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups, such as those of cysteine, (d) free hydroxyl groups, such as those of serine, threonine or hydroxyproline, (e) aromatic residues, such as those of phenylalanine, tyrosine or tryptophan, or (f) the amide group of glutamine. These methods are described in WO87 / 05330 and Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp. 259-306, both of which are incorporated by reference.

[0148] The removal of carbohydrate moieties present on the starting antibody (e.g., post-translation) can be accomplished chemically or enzymatically. Chemical deglycosylation requires exposing the protein to the compound trifluoromethanesulfonic acid or an equivalent compound. This treatment results in the cleavage of most or all sugars other than the linked sugar (N-acetylglucosamine or N-acetylgalactosamine) while maintaining the integrity of the polypeptide. Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch.Biochem.Biophys.259:52 and Edge et al., 1981, Anal.Biochem.118:131, both of which are incorporated by reference in their entirety. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by using a variety of endoglycosidases and exoglycosidases, such as by Thotakura et al., 1987, Meth.Enzymol.138:350, which are incorporated by reference in their entirety. Glycosylation at potential glycosylation sites can be prevented by using the compound tunicamycin as described by Duskin et al., 1982, J. Biol. Chem. 257: 3105, incorporated by reference in its entirety. Tunicamycin blocks the formation of protein-N-glycosidic bonds.

[0149] Another type of covalent modification of antibodies includes connecting the antibody to various non-protein polymers, including but not limited to various polyols, such as polyethylene glycol, polypropylene glycol or polyoxyalkylenes, in a manner described in, for example, Nektar Therapeutics' 2005-2006 PEG Catalog (available on the Nektar website), U.S. Patents 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 or 4,179,337, all of which are incorporated by reference in their entirety. In addition, as is known in the art, amino acid substitutions can be made at various positions within the antibody to facilitate the addition of polymers such as PEG. See, for example, U.S. Publication No. 2005 / 0114037A1, which is incorporated by reference in its entirety.

[0150] In addition to the modifications outlined above, other modifications may be made. For example, the molecule may be stabilized by incorporating disulfide bridges connecting the VH and VL domains (Reiter et al. (1996) Nature Biotech. 14: 1239-1245; which is incorporated herein by reference in its entirety). In addition, there are various covalent modifications of antibodies that may be made as outlined below.

[0151] Covalent modifications of antibodies are included within the scope of the present invention and are usually, but not always, performed post-translationally. For example, several types of covalent modifications of antibodies are introduced into the molecule by reacting specific amino acid residues of the antibody with organic derivatizing agents that react with selected side chains or N-terminal or C-terminal residues.

[0152] In some embodiments, the anti-CD38 antibodies of the invention specifically bind to one or more residues or regions in CD38 and do 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).

[0153] Typically, lack of cross-reactivity means that there is less than about 5% relative competitive inhibition between the molecules when assessed by ELISA and / or FACS analysis using sufficient amounts of the molecules under appropriate assay conditions.

[0154] Reduce side effects

[0155] An adverse event (AE) is defined as any untoward medical occurrence in a clinical study subject administered a drug; it is not necessarily causally related to the treatment. A treatment-emergent adverse event (TEAE) is defined as an AE occurring after the first dose of study drug is received during the treatment period until the end of safety follow-up. In this document, the terms "serious TEAE" and "treatment-emergent SAE" and may be considered interchangeable. PTE and AE verbatim terms are coded by SOC and PT using MedDRA version 24.0. TEAEs are typically referred to as Grade 1, 2, 3, 4, and 5, with Grade 1 being the least severe and Grade 5 being the most severe TEAE. Based on other guidance from the FDA and Common Terminology Criteria for Oncology Adverse Events (CTCAE) criteria (see, e.g., https: / / evs.nci.nih.gov / ftp1 / CTCA E / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf; and Drug Inform. J. 35:1289-1299; which is incorporated herein by reference in its entirety), the following is how such grades are generally determined. Grade 1 is mild: no symptoms or mild symptoms; clinical or diagnostic observations only; no intervention is indicated. Grade 2 is moderate: minimal local or noninvasive intervention is indicated; age-appropriate instrumental activities of daily living ("ADL") are limited. Grade 3 is severe or medically significant, but not immediately life-threatening: hospitalization or prolonged hospitalization is indicated; disability; self-care ADL is limited. Grade 4 is life-threatening consequences: urgent intervention is indicated. Grade 5 is death associated with the AE.

[0156] Compared with the anti-CD38 antibodies of the prior art, the anti-CD38 antibodies of the present invention can reduce side effects. In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) do not induce TEAEs. In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) can reduce the incidence of TEAEs in the patient population compared with other anti-CD38 antibodies (e.g., MOR202). In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) can reduce the grade of TEAEs in the patient population compared with other anti-CD38 antibodies (e.g., MOR202). In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) can reduce the grade of TEAEs from grade 5 to grade 4 compared with other anti-CD38 antibodies. In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) can reduce the grade of TEAEs from grade 4 to grade 3 compared with other anti-CD38 antibodies. In some embodiments, the antibodies used according to the present invention (e.g., TAK-079) can reduce the grade of TEAEs from grade 3 to grade 2 compared with other anti-CD38 antibodies. In some embodiments, the antibodies used according to the present invention (eg, TAK-079) can reduce the grade of TEAEs from Grade 2 to Grade 1 compared to other anti-CD38 antibodies.

[0157] In some embodiments, the antibodies used in accordance with the present invention (e.g., TAK-079) may reduce the grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRR), leukopenia, lymphopenia, and nausea. In some embodiments, the antibodies used in accordance with the present invention (e.g., TAK-079) may reduce the incidence of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRR), leukopenia, lymphopenia, and nausea.

[0158] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the invention results in a Grade 3 or 4 incidence of one or more TRAEs or TEAEs of less than 10%; optionally wherein the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, infestation, pyrexia, herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / rigidity, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphocytopenia, cardiac disorders, palpitations and dyspnea.

[0159] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the invention results in one or more TRAEs or TEAEs of maximum intensity Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

[0160] Disease Indications

[0161] The antibodies or antigen-binding fragments thereof, methods and dosage units of the present invention can be used to treat patients with systemic lupus erythematosus (SLE), especially patients with moderate or severe SLE.

[0162] Systemic lupus erythematosus (SLE)

[0163] SLE is a heterogeneous autoimmune disease characterized by dysregulation of T and B lineage cells and other components of the innate immune system, production of autoantibodies, and formation of immune complexes, which lead to multi-organ damage and variable clinical symptoms. SLE was coined by the Systemic Lupus Erythematosus International Collaboration Clinics (SLICC) in 2012. https: / / sliccgroup.org / research / sle-criteria / ) or the American College of Rheumatology diagnostic criteria.

[0164] The 2012 SLICC classification criteria for SLE require: 1) at least four criteria are met, including at least one clinical criterion and one immunologic criterion, or 2) lupus nephritis is the only clinical criterion in the presence of ANA or anti-dsDNA antibodies.

[0165] Clinical criteria : (1) acute cutaneous lupus; (2) chronic cutaneous lupus; (3) oral ulcers: palate; (4) non-scarring alopecia (diffuse thinning or brittle hair with obvious hair breakage); (5) synovitis involving two or more joints, characterized by swelling or effusion or tenderness of two or more joints and morning stiffness for thirty minutes or longer; (6) serositis; (7) kidney; (8) nervous system; (9) hemolytic anemia; (10) leukopenia (<4000 / mm 3 at least once); or (11) thrombocytopenia (<100,000 / mm 3 ) at least once.

[0166] Immunological standards: (1) antinuclear antibodies (ANA) above the laboratory reference range; (2) anti-dsDNA above the laboratory reference range, except for ELISA (anti-Sm or anti-Smith); (3) antiphospholipid antibodies, (4) low complement; or (5) direct antiglobulin test (Direct Coombs Test) in the absence of hemolytic anemia.

[0167] Moderate to severe SLE

[0168] Subjects diagnosed as having "moderate SLE" were defined as those with a SLEDAI-2K score between 6 and 8.

[0169] Subjects diagnosed as having "severe SLE" were defined as those with a SLEDAI-2K score between 9 and 12.

[0170] The SLEDAI-2K disease assessment tool uses 24 items, 16 of which are clinical and 8 are based only on laboratory results (urine casts, hematuria, proteinuria, pyuria, low complement levels, increased DNA binding, thrombocytopenia, and leukopenia). See, e.g., Gladman et al., (2002). The Journal of rheumatology, 29(2): 288-291.

[0171] Due to the genetic and phenotypic heterogeneity of SLE, treating and identifying new therapies for SLE is challenging, which leaves a significant unmet medical need, especially for patients with moderate to severe SLE (Kiriakidou and Ching (2020) Ann. Intern. Med. 172(11):ITC81-ITC96; incorporated herein by reference).

[0172] Studies have shown that the number of PB in the blood of patients with active SLE is increased (D'Cruz (2006) Blood (ASH Annual Meeting Abstracts) 129: 2359-67; Clemens et al. (2017) Clin. Pharmacokinet. 56 (8): 915-24; Sanada et al. (2016) Blood 128 (7): 923-33; Wang et al. Arthrit. Rheumatol. 68 (suppl 10): 1085; which are incorporated by reference in their entirety). CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PB and plasma cells (Sullivan et al. (2017) Blood 129 (22): 3033-7; which is incorporated by reference in its entirety herein), making it a potential target for the treatment of SLE. In an in vitro study of CD38 expression on various immune cells in peripheral blood mononuclear cells from patients with SLE, the highest CD38 expression was observed on plasma cells and PB, followed by natural killer (NK) cells, plasmacytoid dendritic cells, regulatory T cell subsets, and naive T cells (Ramaschi et al., (1996) Blood 87(6):2308-13; which is incorporated herein by reference in its entirety). Compared with other immune cells, CD38 expression on plasma cells and PB is significantly higher, suggesting that it may be possible to selectively deplete these cells with anti-CD38 antibodies.

[0173] The therapeutic anti-CD38 antibodies of the invention bind to CD38-positive cells, leading to the depletion of these cells via multiple mechanisms of action including the CDC and ADCC pathways.

[0174] In some embodiments, the present invention provides a method for treating moderate or severe SLE in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (a) a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and (b) a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 mg to 140 mg.

[0175] In some embodiments, the present invention provides a method for reducing the level of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (a) a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and (b) a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 mg to 140 mg.

[0176] In some embodiments, the present invention provides a method of reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 mg to 140 mg.

[0177] In some embodiments, the invention provides methods as disclosed herein, wherein the immunoglobulin is IgA, IgG and / or IgM. In some embodiments, the immunoglobulin is IgA. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is IgM.

[0178] In some embodiments, the present invention provides a method for reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (a) a VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and (b) a VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 mg to 140 mg.

[0179] In some embodiments, the present invention provides a method as disclosed herein, wherein the one or more autoantibodies are selected from the group consisting of anti-dsDNA, anti-SmDp, beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A and Sjögren's syndrome SS-B.

[0180] In some embodiments, the present invention provides a method as disclosed herein, wherein the subject is diagnosed with severe SLE.

[0181] In some embodiments, the present invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms.

[0182] In some embodiments, the invention provides a method as disclosed herein, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, and wherein the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0183] In some embodiments, the invention provides a method as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0184] In some embodiments, the invention provides a method as disclosed herein, wherein the glycosylation is O-linked glycosylation.

[0185] In some embodiments, the present invention provides a method as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:10.

[0186] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:9.

[0187] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:10.

[0188] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:9.

[0189] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:10.

[0190] In some embodiments, the present invention provides a method as disclosed herein, wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:11.

[0191] In some embodiments, the present invention provides a method as disclosed herein, wherein the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:12.

[0192] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human sequence numbering.

[0193] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is 10 -8 M or greater, and wherein the affinity is measured by a standard Biacore assay.

[0194] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10.

[0195] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises the HC as shown in SEQ ID NO:11 and the LC as shown in SEQ ID NO:12.

[0196] In some embodiments, the present invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain.

[0197] In some embodiments, the invention provides a method as disclosed herein, wherein the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0198] In some embodiments, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0199] In some embodiments, the present invention provides a method as disclosed herein, wherein the subject is receiving one or more background SLE medications.

[0200] In some embodiments, the present invention provides a method as disclosed herein, wherein the one or more background SLE medications are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins.

[0201] In some embodiments, the present invention provides a method as disclosed herein, wherein the one or more background SLE drugs are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil and / or mycophenolic acid.

[0202] In some embodiments, the present invention provides a method as disclosed herein, wherein the one or more background SLE drugs are administered in combination with the antibody or antigen-binding fragment thereof.

[0203] In some embodiments, the present invention provides a method as disclosed herein, wherein the antibody or its antigen-binding fragment is administered at a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, and about 140 mg; in some embodiments, the antibody or its antigen-binding fragment is administered at a dose of about 45 mg. In some embodiments, wherein the antibody or its antigen-binding fragment is administered at a dose of about 90 mg. In some embodiments, wherein the antibody or its antigen-binding fragment is administered at a dose of about 135 mg.

[0204] In some embodiments, the invention provides a method as disclosed herein, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0205] In some embodiments, the present invention provides methods as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0206] In some embodiments, the present invention provides a method as disclosed herein, wherein the pharmaceutically acceptable composition comprises the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient or stabilizer.

[0207] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises a HC as shown in SEQ ID NO: 11 and a LC as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks. In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise glycosylation of one or more polypeptides, and the glycosylation is N-linked glycosylation.

[0208] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mazetuzumab.

[0209] In some embodiments, the present invention provides a method as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than 10% incidence of Grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, fever, herpes zoster, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphocytopenia, cardiac disorders, palpitations and dyspnea.

[0210] In some embodiments, the invention provides a method as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs of maximum intensity Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

[0211] Antibody compositions for in vivo administration

[0212] The preparation of the antibody or antigen-binding fragment thereof used according to the present invention is prepared by mixing the antibody having the desired purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition (1980) Osol, A. ed.; which is incorporated herein by reference in its entirety) in the form of a lyophilized preparation or an aqueous solution for storage.

[0213] The formulations herein may also contain more than one active compound required for the particular indication being treated, preferably compounds with complementary activities and which do not adversely affect each other. For example, it may be desirable to provide antibodies or antigen-binding fragments thereof with other specificities. Alternatively or in addition, the composition may include a cytotoxic agent, a cytokine, a growth inhibitor and / or a small molecule antagonist. Such molecules are appropriately combined in an amount effective for the intended purpose.

[0214] In some embodiments, two mazetuzumab drug product formulations have been developed, referred to as Process A and Process B disclosed herein.

[0215] In one embodiment, the process A mazetuzumab drug product is a clear to opalescent colorless solution containing an aqueous solution of TAK-079 (20 mg / mL) of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at a pH of about 6.5. The process placebo is a clear colorless solution containing an aqueous solution of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at a pH of about 6.5. The process A mazetuzumab drug product and placebo are supplied in sterile filled, single-use, clear, Type I borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip-top caps.

[0216] In another embodiment, the process B mazetuzumab drug product is made in 2 strengths (i.e., 5 mg / mL or 100 mg / mL). Each strength is a clear to opalescent, colorless to brownish yellow solution containing mazetuzumab in an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at a pH of about 5.9. The process B placebo is a clear, colorless solution containing histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at a pH of about 5.9. The process mazetuzumab drug product and placebo are supplied in sterile filled, disposable, clear, Type I borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip-top caps.

[0217] Subcutaneous administration

[0218] Anti-CD38 antibodies described herein (such as TAK-079) can be administered in a sufficient dose to be effective for treatment, thereby allowing subcutaneous administration. Subcutaneous administration is a minimally invasive mode of administration and is considered to be the most versatile and therefore desirable mode of administration that can be used for short-term and long-term therapies. In some embodiments, subcutaneous administration can be performed by injection. In some embodiments, when multiple injections or multiple devices are required, the site of the injection or device can be rotated.

[0219] Therefore, subcutaneous formulations are easier for patients to self-administer, especially since the formulations may have to be taken regularly throughout the patient's life. In addition, the ease and speed of subcutaneous delivery can increase patient compliance rates and enable faster access to medication when needed. Therefore, the subcutaneous formulations of anti-CD38 antibodies provided herein provide substantial benefits over the prior art and address certain unmet needs.

[0220] In some embodiments, the antibody of the present invention is administered to a subject via a subcutaneous route according to known methods. In some embodiments, the antibody of the present invention can be administered by subcutaneous injection. In a specific embodiment, the subcutaneous preparation is subcutaneously injected into the same part of the patient (e.g., administered to the upper arm, the front surface of the thigh, the lower part of the abdomen or the upper back) for repeated or continuous injection. In other embodiments, the subcutaneous preparation is subcutaneously injected into different or rotating parts of the patient. Single or multiple administrations of the preparation can be adopted.

[0221] In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat SLE. In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat moderate or severe SLE. In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat moderate SLE. In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat severe SLE.

[0222] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention result in depletion of plasmablasts, plasma cells, NK cells, B cells and / or T cells following subcutaneous administration to a subject. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention result in depletion of plasmablasts. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention result in depletion of plasma cells. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention allow for increased depletion of NK cells compared to depletion of B cells or T cells. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention allow for increased depletion of NK cells compared to B cells, and increased depletion of NK cells compared to T cells. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention allow for increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention allow for increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention allow for increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. Suitably, the antibodies or antigen-binding fragments thereof of the present invention may allow for increased depletion of NK cells compared to CD38 - Compared with the cells with increased CD38 + Cell depletion.

[0223] In some embodiments, the antibodies or antigen-binding fragments thereof of the invention result in a reduction in one or more immunoglobulin levels after subcutaneous administration to a subject. In some embodiments, the immunoglobulin is IgA, IgG, and / or IgM. In some embodiments, the immunoglobulin is IgA. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is IgM.

[0224] In some embodiments, the antibodies or antigen-binding fragments thereof of the invention result in a reduction in one or more autoantibodies after subcutaneous administration to a subject. In some embodiments, the one or more autoantibodies are selected from the group consisting of anti-dsDNA, anti-SmDp, beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A, and Sjögren's syndrome SS-B.

[0225] In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is between at least 50% and at least 80% compared to intravenous administration standardized for the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is between at least 60% and at least 80% compared to intravenous administration standardized for the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is between at least 50% and 70% compared to intravenous administration standardized for the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is between at least 55% and 65% compared to intravenous administration standardized for the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is between at least 55% and 70% compared to intravenous administration standardized for the same dose.

[0226] In certain embodiments, the bioavailability of an 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% compared to intravenous administration normalized to the same dose. Suitably, the bioavailability may be at least 50% compared to intravenous administration normalized to the same dose. Suitably, the bioavailability may be at least 60% compared to intravenous administration standardized for the same dose. Suitably, the bioavailability may be at least 70% compared to intravenous administration standardized for the same dose. Suitably, the bioavailability may be at least 80% compared to intravenous administration standardized for the same dose. Suitably, the bioavailability may be at least 90% compared to intravenous administration standardized for the same dose.

[0227] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is 50%-80% compared to intravenous administration normalized for the same dose.

[0228] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 50% compared to intravenous administration normalized to the same dose.

[0229] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 55% compared to intravenous administration normalized to the same dose.

[0230] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 60% compared to intravenous administration normalized to the same dose.

[0231] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 65% compared to intravenous administration normalized to the same dose.

[0232] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 70% compared to intravenous administration normalized to the same dose.

[0233] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 75% compared to intravenous administration normalized to the same dose.

[0234] In some embodiments, the disclosure provides a method wherein the bioavailability of an antibody of the invention following subcutaneous administration is at least 80% compared to intravenous administration normalized to the same dose.

[0235] In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously with a single bolus injection. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously monthly. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously weekly. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously twice a week. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously daily. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every 6 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every 4 hours. In certain embodiments, an anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every 2 hours. In certain embodiments, an anti-CD38 antibody or antigen-binding fragment thereof as described herein is administered subcutaneously every hour. In some embodiments, an antibody or antigen-binding fragment thereof as disclosed herein is administered subcutaneously once every 3 weeks for 12 weeks.

[0236] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as disclosed herein is administered subcutaneously at a dose of about 40 mg to about 140 mg. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof as disclosed herein is administered subcutaneously at a dose selected from the group consisting of: about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, and about 140 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg, about 90 mg, or about 135 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 90 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 135 mg.

[0237] Unit dosage form

[0238] In some embodiments, the therapeutic anti-CD38 antibody or antigen-binding fragment thereof is formulated as part of a unit dosage form. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises a HC comprising the following CDR amino acid sequences: GFTF DDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079) and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 TAK-079), or variants of those sequences with up to three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof comprises a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR 1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079) and QSYDSSL SGS (SEQ ID NO: 8; LCDR3 TAK-079), or variants of those sequences with up to three amino acid changes. In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCD R1 TAK-079), ISWNGGKT (SEQ ID NO:4; HCDR2 TAK-079), and ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 TAK-079), or variants of those sequences having up to three amino acid changes; and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 TAK-079), RDS (SEQ ID NO:7; LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 TAK-079), or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079), and ARGSLFHDSSG FYFGH (SEQ ID NO: 5; HCDR3 TAK-079).In some embodiments, the antibody comprises a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079). In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGK T (SEQ ID NO: 4; HCDR2 TAK-079) and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 TAK-079); and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079) and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079). In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Suitably, the HC may comprise the following CDR amino acid sequences: GF TFDDYG (SEQ ID NO: 3; HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4; HCDR2 TAK-079), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 TAK-079), and the remainder of the HC may have at least 80% sequence identity with SEQ ID NO 9. In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO: 9.

[0239] EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0240] In some embodiments, the antibody comprises a LC comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the LC may comprise the following CDR sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 TAK-079), RDS (SEQ ID NO: 7; LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 TAK-079), and the remainder of the LC may have at least 80% sequence identity to SEQ ID NO: 10. In some embodiments, the antibody comprises a LC comprising the VL region amino acid sequence of SEQ ID NO: 10.

[0241] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGDNYVSWYQQLPGT APKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC QSYDSSLGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (SEQ ID NO: 10).

[0242] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9 as described herein, or a variant thereof; and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10 as described herein, or a variant thereof.

[0243] As will be appreciated by those skilled in the art, the VH and VL regions may be linked to human IgG constant domain sequences (typically IgG1, IgG2 or IgG4). In some embodiments, the antibody comprises a HC having an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 11. Suitably, the HC may comprise CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, and the remainder of the HC may have at least 80% sequence identity with SEQ ID NO: 11. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11.

[0244] EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:11).

[0245] In some embodiments, the antibody comprises a LC having an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences as defined in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, and the remainder of the LC may have at least 80% sequence identity with SEQ ID NO: 12. In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12.

[0246] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLGSVFGGGTKLTVLG QPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQID NO:12).

[0247] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11 as described herein, or a variant thereof, and the LC amino acid sequence of SEQ ID NO: 12 as described herein, or a variant thereof.

[0248] In some embodiments, the preparation comprising an anti-CD38 antibody is a unit dosage form. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 40 mg to about 140 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 45 mg to about 135 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 45 mg to about 140 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 40 mg to about 135 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, and about 140 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg, about 90 mg, or about 135 mg.

[0249] In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 40 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 45 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 50 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 55 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 60 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 65 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 70 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 75 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 80 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 85 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 90 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose of about 95 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 105 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 110 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 115 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 120 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 125 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 130 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 135 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 140 mg.

[0250] In some embodiments, the anti-CD38 antibody unit dosage forms provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers and / or diluents. In some embodiments, the anti-CD38 antibody is provided in the form of a pharmaceutical composition comprising a unit dosage form according to the present invention. Suitably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, carriers and / or diluents.

[0251] The dosage regimen is adjusted to provide the optimal desired response (e.g., a 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 depending on the urgency of the therapeutic situation. The composition may be formulated in dosage unit form for ease of administration and uniformity of dosage. In some embodiments, a dosage unit form as used herein may refer to physically discrete units suitable as unit doses for a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with a desired pharmaceutical carrier.

[0252] The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of an individual.

[0253] The effective dosage and dosage regimen of the anti-CD38 antibody or antigen-binding fragment thereof used in the present invention depends on the severity of the disease or condition to be treated and can be determined by those skilled in the art.

[0254] In some embodiments, the anti-CD38 antibody or its antigen-binding fragment is administered once a week, once every two weeks, once every three weeks, or once every four weeks at a dose of about 40 mg to about 140 mg. In some embodiments, the anti-CD38 antibody or its antigen-binding fragment is administered once a week by subcutaneous administration at a dose of about 40 mg to about 140 mg. In some embodiments, the anti-CD38 antibody or its antigen-binding fragment is administered once every two weeks by subcutaneous administration at a dose of about 40 mg to about 140 mg. In some embodiments, the anti-CD38 antibody or its antigen-binding fragment is administered once every three weeks by subcutaneous administration at a dose of about 40 mg to about 140 mg. In some embodiments, the anti-CD38 antibody or its antigen-binding fragment is administered once every four weeks by subcutaneous administration at a dose of about 40 mg to about 140 mg.

[0255] Suitably, the dose every 3 weeks may be about 40 mg. Suitably, the dose every 3 weeks may be about 45 mg. Suitably, the dose every 3 weeks may be about 50 mg. Suitably, the dose every 3 weeks may be about 55 mg. Suitably, the dose every 3 weeks may be about 60 mg. Suitably, the dose every 3 weeks may be about 65 mg. Suitably, the dose every 3 weeks may be about 70 mg. Suitably, the dose every 3 weeks may be about 75 mg. Suitably, the dose every 3 weeks may be about 80 mg. Suitably, the dose every 3 weeks may be about 85 mg. Suitably, the dose every 3 weeks may be about 90 mg. Suitably, the dose every 3 weeks may be about 95 mg. Suitably, the dose every 3 weeks may be about 100 mg. Suitably, the dose every 3 weeks may be about 105 mg. Suitably, the dose every 3 weeks may be about 110 mg. Suitably, the dosage every 3 weeks may be about 115 mg. Suitably, the dosage every 3 weeks may be about 120 mg. Suitably, the dosage every 3 weeks may be about 125 mg. Suitably, the dosage every 3 weeks may be about 130 mg. Suitably, the dosage every 3 weeks may be about 135 mg. Suitably, the dosage every 3 weeks may be about 140 mg. Such administration as disclosed herein may be repeated, for example, 3 to 5 times. In some embodiments, such administration as disclosed herein may be repeated 3 times, i.e., repeated every 3 weeks, for a total of 9 weeks. In some embodiments, such administration as disclosed herein may be repeated 4 times, i.e., repeated every 3 weeks, for a total of 12 weeks. In some embodiments, such administration as disclosed herein may be repeated 5 times, i.e., repeated every 3 weeks, for a total of 15 weeks.

[0256] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered at a 3-week dose of about 40 to about 140 mg. Suitably, the 3-week dose may be about 45 mg to about 135 mg. Suitably, the 3-week dose may be about 45 mg. Suitably, the 3-week dose may be about 90 mg. Suitably, the 3-week dose may be about 135 mg. The dose may be determined or adjusted by measuring the amount of the compound of the invention in the blood after administration, for example by removing a biological sample and using an anti-idiotypic antibody targeting the antigen-binding region of the anti-CD38 antibody.

[0257] In one embodiment, the therapeutic antibody is prepared at a concentration of about 5 mg / ml. In another embodiment, the therapeutic antibody is prepared at a concentration of about 20 mg / ml. In another embodiment, the therapeutic antibody is prepared at a concentration of about 50 mg / ml. In some embodiments, a volume of 0.8 mL, 0.9 mL, 1.8 mL, 2.7 mL or 2.8 mL is injected in the thigh, abdomen or arm. In another embodiment, the therapeutic antibody is prepared at a concentration of about 75 mg / ml. In some embodiments, a volume of 0.53 mL, 0.6 mL, 1.2 mL, 1.8 mL or 1.87 mL is injected in the thigh, abdomen or arm. In another embodiment, the therapeutic antibody is prepared at a concentration of about 90 mg / ml. In some embodiments, a volume of 0.44 mL, 0.5 mL, 1.0 mL, 1.5 mL or 1.56 mL is injected in the thigh, abdomen or arm. In another embodiment, the therapeutic antibody is prepared at a concentration of about 100 mg / ml. In some embodiments, a volume of 0.4 mL, 0.45 mL, 0.9 mL, 1.35 mL, or 1.4 mL is injected into the thigh, abdomen, or arm. In some embodiments, the dose is administered over a period of 1, 2, 4, 6, 8, or 10 hours. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered every 2 weeks. In some embodiments, the dose is administered every 3 weeks. In some embodiments, the dose is administered every 4 weeks.

[0258] In some embodiments, the present invention provides a unit dosage form, comprising an isolated antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising a VH region, the VH region comprising a CDR1 having an amino acid sequence of SEQ ID NO:3, a CDR2 having an amino acid sequence of SEQ ID NO:4, and a CDR3 having an amino acid sequence of SEQ ID NO:5; and a VL region, the VL region comprising a CDR1 having an amino acid sequence of SEQ ID NO:6, a CDR2 having an amino acid sequence of SEQ ID NO:7, and a CDR3 having an amino acid sequence of SEQ ID NO:8; wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO:1), and the unit dosage form is formulated for subcutaneous administration of the antibody or antibody-binding fragment thereof at a dose of 40 mg to 140 mg to treat moderate or severe SLE.

[0259] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the unit dosage form is formulated for subcutaneous administration of the antibody or antigen-binding fragment thereof for the treatment of severe SLE.

[0260] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered sugar forms. In some embodiments, the engineered sugar form comprises glycosylation of one or more polypeptides, and the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. In some embodiments, the glycosylation is O-linked glycosylation.

[0261] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:10.

[0262] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein said VH region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:9.

[0263] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein said VL region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:10.

[0264] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein said VH region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:9.

[0265] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein said VL region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:10.

[0266] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:11.

[0267] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:12.

[0268] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human sequence numbering.

[0269] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is present in a dosage form of 10 -8 M or greater, and wherein the affinity is measured by a standard Biacore assay.

[0270] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10.

[0271] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises HC as shown in SEQ ID NO:11 and LC as shown in SEQ ID NO:12.

[0272] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain. In some embodiments, the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0273] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0274] In some embodiments, the present invention provides a unit dosage form as disclosed herein, further comprising one or more background SLE drugs.

[0275] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the separated antibody or its antigen-binding fragment is used in combination with one or more background SLE drugs. In some embodiments, the one or more background SLE drugs are selected from the group consisting of immunosuppressants, steroids and immunoglobulins. In some embodiments, the one or more background SLE drugs are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil and / or mycophenolic acid. In some embodiments, the unit dosage form disclosed herein comprises one or more background SLE drugs.

[0276] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the antibody or its antigen binding fragment is administered at a dose selected from the group consisting of: 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg and 140 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 40 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 45 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 50 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 55 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 60 mg. In some embodiments, the antibody or its antigen binding fragment is administered at a dose of 65 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 70 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 75 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 80 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 85 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 90 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 95 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 100 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 105 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 110 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 115 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 120 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 125 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of 130 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 135 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 140 mg.

[0277] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0278] In some embodiments, the present invention provides a unit dosage form as disclosed herein, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0279] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the administration of the antibody or antigen-binding fragment thereof results in a grade 3 or 4 incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of less than 10%. In some embodiments, the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, infection, fever, herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations and dyspnea. In some embodiments, the administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs with a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

[0280] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises HC as shown in SEQ ID NO: 11 and LC as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks. In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise glycosylation of one or more polypeptides, and the glycosylation is N-linked glycosylation.

[0281] Treatment

[0282] In the methods of the invention, therapy is used to provide a positive therapeutic response to a disease or disorder.The term "positive therapeutic response" refers to an improvement in a disease or disorder and / or an improvement in symptoms associated with a disease or disorder.

[0283] A positive therapeutic response for any given disease or condition can be determined by standardized response criteria specific to that disease or condition.In addition to this positive therapeutic response, the subject undergoing therapy may experience a beneficial effect of improvement in symptoms associated with the disease.

[0284] The measures of efficacy of treating SLE can be assessed based on the SLE disease activity scale according to the SOE study activity tables (Tables 4 and 5, Example 1). The SLE disease assessment is based on assessment tools, including but not limited to the SLEDAI-2K disease assessment tool, the cutaneous lupus erythematosus disease area and severity index, the 44 joint assessment, the physician's overall assessment of the disease (visual analog scale), as disclosed in Example 1.

[0285] Treatment according to the present invention includes a "therapeutically effective amount" of the drug used. The terms "therapeutically effective amount" and "therapeutically effective dose" refer to an amount of therapy sufficient to reduce or improve the severity and / or duration of a condition or one or more symptoms thereof; prevent the progression of a condition; cause regression of a condition; prevent the recurrence, development, onset or progression of one or more symptoms associated with a condition; or enhance or improve the preventive or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent) at a dosage and time period required to achieve the desired therapeutic result. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the antibody or antibody portion are exceeded by the therapeutically beneficial effects.

[0286] Anti-CD38 Antibody Kit

[0287] In another aspect of the present invention, a kit for treating SLE is provided. In some embodiments, a kit for treating moderate or severe SLE is provided. In some embodiments, a kit for treating severe SLE is provided. In one embodiment, the kit comprises a certain dose of an anti-CD38 antibody as described herein, such as TAK-079. In one embodiment, the kit comprises a certain dose of an anti-CD38 antibody as described herein, such as Mazettuzumab. In some embodiments, the kit provided herein may contain one or more doses of a liquid or lyophilized formulation as provided herein. When the kit comprises a lyophilized formulation of an anti-CD38 antibody as described herein (such as TAK-079), generally, the kit will also contain a suitable liquid for reconstructing a liquid formulation, such as sterile water or a pharmaceutically acceptable buffer. In some embodiments, the kit may include an anti-CD38 antibody formulation as described herein prepackaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0288] In certain embodiments, the kit will be used for a single administration or dose of an anti-CD38 antibody described herein, such as TAK-079. In other embodiments, the kit may contain multiple doses of an anti-CD38 antibody described herein, such as TAK-079, for subcutaneous administration. In one embodiment, the kit may contain an anti-CD38 antibody formulation described herein prepackaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0289] Products

[0290] In other embodiments, a product containing materials that can be used to treat the above-mentioned diseases is provided. The product includes a container and a label. Suitable containers include, for example, bottles, vials, syringes and test tubes. The container can be formed of a variety of materials, such as glass or plastic. The container holds a composition effective for treating the disease and can have a sterile access port (for example, the container can be an intravenous infusion bag or vial with a stopper that can be pierced by a hypodermic injection needle). The active agent in the composition is the antibody. The label on or associated with the container indicates that the composition is used to treat the selected disease. The product may also include a second container, which includes a pharmaceutically acceptable buffer such as phosphate-buffered saline, Ringer's solution or dextrose solution. The product may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes and package inserts with instructions for use.

[0291] Example

[0292] Example 1: A Phase 1B Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of TAK-079 in Combination with Standard Background Therapy in Patients with Moderate to Severe Systemic Lupus Erythematosus

[0293] Research objectives and research planning

[0294] This phase 1b, double-blind, placebo-controlled, multicenter study evaluated the safety, pharmacokinetics, and pharmacodynamics of mazezumab in a study population with moderate-to-severe SLE receiving background therapy guided by standard principal investigator guidelines.

[0295] The primary objective of this study is to evaluate the safety and tolerability of TAK-079 administered every 3 weeks over a 12-week dosing period compared to matching placebo in subjects with active SLE who are receiving stable SLE background therapy.

[0296] Secondary objectives of the study are to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of TAK-079 administered over a 12-week dosing period.

[0297] An exploratory objective was to evaluate the effect of repeated administration of TAK-079 on SLE disease activity using clinical rating scales and biomarkers.

[0298] This Phase 1b study is designed to evaluate the safety, PK, PD and immunogenicity of TAK-079. In addition, it is designed to better understand the mechanism proof and potential biological activity of TAK-079 in a patient population with specific, measurable SLE clinical manifestations. The study design allows subjects to continue to receive their SLE background therapy managed under the care of their physicians while evaluating the benefit-risk of TAK-079 as an investigational add-on therapy.

[0299] The study compared active TAK-079 in combination with background SLE standard therapy to matching placebo in combination with background SLE standard therapy across 3 sequentially enrolled cohorts in a double-blind study design ( Figure 1 and Figure 2 ). Subjects were randomly assigned within each cohort to: (1) TAK-079 administered as a subcutaneous (SC) injection every 3 weeks for 12 weeks (4 doses in total); or (2) a matching placebo given by the same route and schedule. Each cohort was designed to enroll 8 subjects; 6 subjects were randomly assigned to receive TAK-079 administration, and 2 subjects were randomly assigned to receive TAK-079 matching placebo. After each dosing day, the subjects returned for post-dose assessments as outlined in Tables 4 and 5.

[0300] After completion of the 12-week dosing period, subjects will be evaluated for an additional 12-week safety follow-up period, with safety visits completed every 4 weeks and ending this post-dosing study period with a safety visit at Week 24. Based on the clinical assessment at this visit, subjects may have completed the study or may have advanced to the long-term safety follow-up period to enter an additional 12-week on-study safety monitoring period (based on the end-of-study criteria outlined in Table 13), during which end-of-study parameters that were not met and deemed relevant to the study by the Principal Investigator will continue to be evaluated and tracked as outlined in the "End-of-Study Evaluations" section.

[0301] Sequential enrollment of double-blind cohorts allowed for evaluation of TAK-079 dosing in a stepwise double-blind design. In addition, the double-blind design provided support for unbiased safety and tolerability assessments as well as within-cohort and across-cohort analyses of PK, PD, immunogenicity, and efficacy endpoints of active TAK-079 and matching placebo. (See Figure 2 . )

[0302] Selection of study population

[0303] The study population was limited to subjects with SLE who presented with moderate to severe disease with persistent disease activity and had not adequately responded to standard SLE background therapy, but had not had a recent moderate to severe flare. All subjects had to be positive for anti-dsDNA antibodies and / or anti-extractable nuclear antigen (ENA) antibodies.

[0304] Based on findings from the first-in-human (FIH) study (TAK-079-101), most subjects will have detectable CD38 expression. The expression level of CD38 on PB cells was evaluated from samples obtained during screening for the TAK-079-101 study in healthy subjects (quantified as equivalent soluble fluorescent dye [MESF] molecular weight). A total of 129 evaluable subjects were analyzed for CD38 expression, of which 100% had detectable CD38 levels. The CD38 expression levels of these healthy subjects varied approximately within 5 times from 693,474 MESF units to 3,531,222 MESF units, with a mean of 1,747,840 MESF units. The minimum CD38 expression was approximately 7 times higher than the background, indicating that high levels of CD38 are expressed on the surface of peripheral blood PB in healthy subjects.

[0305] Inclusion criteria

[0306] Subjects eligible for inclusion in the study must meet the following criteria: (a) the subject understands and agrees to participate in the study by providing a signed and dated written ICF and any required privacy authorizations prior to initiating any study procedures (if applicable, the subject's legal representative may provide a written ICF in accordance with local and regional regulatory requirements), and is deemed by the investigator to be able to comply with the protocol requirements; (b) the subject is between 18 and 75 years of age at the time of signing the study ICF; (c) the subject has been diagnosed with SLE as defined by the 2012 International Collaborating Clinics for Systemic Lupus Erythematosus or the American College of Rheumatology diagnostic criteria; LE; (d) the subject has a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥6; (e) the subject is positive for anti-dsDNA antibodies and / or anti-ENA antibodies; (f) the subject is currently receiving concomitant medications consistent with the medication restrictions and limitations outlined in Tables 7 and 8, and based on the best medical judgment of the Principal Investigator, the subject is considered likely to be able to maintain dosing consistent with the protocol limits throughout the study dosing period unless unable to do so due to toxicity or the need for protocol-defined rescue therapy; and (g) the subject meets and / or agrees to the following birth control requirements.

[0307] Birth control requirements for males: (i) infertile, or (ii) if not infertile, agree to (1) maintain sexual abstinence or (2) use an appropriate method of birth control, including the use of a condom with spermicide, from the first dose of study drug on Day 1 until 90 days or 5 half-lives of study drug, whichever is longer, after the last dose of study drug. No restrictions are required for male subjects who have undergone a vasectomy procedure, provided that at least 1 year has passed since the subject had a bilateral vasectomy procedure before the first dose of study drug on Day 1. Male subjects who had a vasectomy procedure less than 4 months before the first dose of study drug on Day 1 must follow the same restrictions as males who have not undergone a vasectomy. Appropriate documentation of the surgical procedure should be provided. Agree not to donate sperm from the first dose of study drug on Day 1 until 90 days or 5 half-lives of study drug, whichever is longer, after the last dose of study drug.

[0308] Female birth control requirements: (i) Women of childbearing potential: (1) Female subjects of childbearing potential must agree to maintain abstinence or use double-barrier contraception consisting of a protocol-defined, medically acceptable method (such as implants, injections, oral contraceptives, intrauterine contraceptive devices), and must use contraception from the time of signing the ICF until 90 days or 5 half-lives of the study drug (whichever is longer) after the last dose of study drug administration; or (ii) Women of no childbearing potential are defined as meeting at least one of the following criteria: (1) postmenopausal (defined as spontaneous amenorrhea for women with serum follicle-stimulating hormone levels >40 mIU / mL for 12 months) with appropriate documentation of follicle-stimulating hormone levels; (2) surgical sterilization achieved by hysterectomy and / or bilateral oophorectomy with appropriate documentation of the surgical procedure; (3) previous tubal ligation with appropriate documentation of the surgical procedure; or (4) suffering from a congenital condition resulting in the absence of a uterus.

[0309] Exclusion criteria

[0310] Subjects who meet any of the following criteria are ineligible for study enrollment. (a) Subjects have participated in another investigational study within 4 weeks or 5 study drug half-lives (whichever is longer) prior to the screening visit (the 4-week window is derived from the date of the last study procedure and / or adverse event (AE) related to the study procedure in the previous study to the date of the screening visit for the current study). (b) Subjects have a positive pregnancy test. (c) Subjects are currently breastfeeding / lactating or plan to breastfeed during the study (including during the 12-week safety follow-up period of the study). (d) Subjects have a history of chronic alcohol or drug abuse ≤12 months prior to the screening visit. (e) Subjects have a history of malignant disease (except successfully treated basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the cervix) ≤5 years prior to the screening visit. (f) Subjects have chronic obstructive pulmonary disease (COPD) or asthma with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note: FEV1 testing is required for subjects suspected of having COPD or asthma. (g) Subjects have undergone major surgery and / or donated or lost ≥1 unit (approximately 500 mL) of blood within ≤4 weeks prior to the screening visit. (h) Subjects have had opportunistic infections ≤12 weeks prior to initial study dosing, or are currently receiving treatment for chronic opportunistic infections (such as tuberculosis (TB), Pneumocystis jiroveci pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria). (i) Subjects currently or recently have an acute or chronic infection requiring one or more of the following interventions: (1) hospitalization ≤30 days prior to the screening visit or (2) administration of parenteral (IV or intramuscular) antibacterial, antiviral, antifungal, or antiparasitic agents ≤30 days prior to the screening visit. (j) Subjects with a positive T-cell interferon-gamma release assay (TIGRA) (by QuantiFERON TB Gold test or T-Spot / Elispot) at the screening visit (pending analysis by local laboratory), noting the following: (1) If TIGRA testing is not available, a purified protein derivative skin test may be used as an alternative; or (2) Subjects with indeterminate TIGRA results must meet the following criteria: (i) negative purified protein derivative skin test (defined as induration <5 mm); or (ii) low risk of acquiring TB (e.g. avoiding close contact with TB-positive individuals) and / or chest x-ray results consistent with no evidence of latent or active TB within ≤6 months prior to the screening visit. (k) Subjects with drug-induced SLE or any other rheumatic or autoimmune disease (excluding secondary Sjögren's syndrome or mixed connective tissue disease).(l) Subjects who required therapeutic intervention for active neuropsychiatric SLE within 60 days prior to initial study dosing, as evidenced by (but not limited to) the following: (1) new or worsening impaired level of consciousness, (2) psychosis, (3) delirium or confusional state, (4) grand mal seizure (including status epilepticus), (5) aseptic meningitis, (6) ascending or transverse myelitis, or (7) chorea, cerebellar ataxia, or demyelinating syndrome. (m) Subjects with active glomerulonephritis (i.e., concurrent acute renal episode or documentation of an acute renal episode in the past 3 months that required induction therapy for lupus nephritis) and met at least one of the following criteria: (1) proteinuria (protein >3000 mg / 24 hours), (2) urine protein to creatinine ratio >300 mg / mmol, or (3) estimated glomerular filtration rate (GFR) <30 mL / min / 1.73 m2. 2 (e.g., calculated using the Modification of Diet in Renal Disease [MDRD] formula; see the Laboratory Evaluation section). (n) Subjects had at least one of the following laboratory test values: (1) alanine aminotransferase or aspartate aminotransferase > 3 times the upper limit of normal, (2) total bilirubin > 1.5 times the upper limit of normal (Note: Subjects with a documented diagnosis of Gilbert syndrome in their medical records were not excluded based on this criterion), (3) platelets < 75,000 / mm 3 , (4) Neutrophils <1500 / mm 3 , (5) hemoglobin <8 g / dL, or (6) IgG below the lower limit of normal. (o) The subject tested positive for hepatitis B surface antigen or hepatitis C antibody or HIV antibody / antigen at screening. (p) The subject has a concurrent disease that the investigator believes may confound the interpretation of the results or affect the subject's ability to fully participate in the study. (q) The subject has a history of severe allergic or anaphylactic reaction to the recombinant proteins or excipients used in the TAK-079 formulation.

[0311] Removal of a subject from treatment or evaluation

[0312] Table 11 summarizes laboratory findings that require temporary suspension or permanent discontinuation of TAK-079 administration. Subjects who exhibit these or other clinical findings (for which the investigator believes that continued administration of TAK-079 may expose the subject to undue risk) immediately suspend further TAK-079 administration and continue to be tracked for safety. In such cases, TAK-079 can be resumed according to the dosing criteria defined in the protocol in consultation with the study medical monitor (MM).

[0313] Treatment with study drug may be permanently discontinued for any of the following reasons: (a) AEs and / or serious adverse events (SAEs); (b) subject withdrawal; (c) protocol violation; (d) study discontinuation by the sponsor; (e) loss to follow-up; or (f) other.

[0314] Once study drug has been discontinued, all study procedures outlined for follow-up are completed as specified in the Schedule of Events (SOE) (Tables 4 and 5). Subjects who withdraw from study treatment are asked if they would allow follow-up assessments. If the subject withdraws consent in full, no further follow-up assessments will be completed. The main reason for discontinuation of study drug is recorded on the electronic case report form (eCRF).

[0315]

[0316]

[0317]

[0318] Table 5. Study Event Schedule: Safety Follow-up and Long-term Safety Follow-up Period

[0319]

[0320] AE: adverse event; CLASI: cutaneous lupus erythematosus disease area and severity index; HV: home visit; ICF: informed consent; IRB: institutional review board; SLE: systemic lupus erythematosus; V: visit; VAS: visual analog scale.

[0321] a Clinical parameters that do not meet the study end criteria as outlined in Table 10 and are deemed study related by the Principal Investigator will continue to be assessed no less than every 4 weeks until resolved, as outlined in the "Study End Evaluations" section.

[0322] b SLE assessment tools include: CLASI, Systemic Lupus Erythematosus Disease Activity Index 2000, 44-joint assessment, and physician's global disease assessment (VAS).

[0323] c AE assessment will include a symptom review of the subject's current disease state, condition, and treatment.

[0324] d Pregnancy testing is completed. If menstruation is delayed or upon request of the IRB, additional testing must be evaluated.

[0325] eUrinalysis (including protein to creatinine ratio and nitrates) will be performed by the central laboratory; additional protein and nitrate assessments will be performed at each clinical visit; abnormal findings from local laboratory assessments must be confirmed by central laboratory evaluation. Further details are provided in the Laboratory Evaluation section.

[0326] Demographic and medical history data collection

[0327] A complete medical history was compiled for each subject during the screening period (i.e., ≤28 days prior to study day 1), which included an assessment and documentation of prior medical history, comorbidities, and concomitant treatment. This included an assessment of current SLE signs, symptoms, incidence as assessed and scored by the Disease Activity Tool, and prior and current SLE therapy (see the Efficacy Measures section). Demographic data included the subject's date of birth, race, ethnicity, and sex during the screening period.

[0328] treat

[0329] Treatment Administered

[0330] As part of each study cohort, TAK-079 or matching placebo was administered as a single SC injection every 21 days (i.e., 3 weeks) for 12 weeks, for a total of 4 doses. Subjects in cohorts A, B, and C received 45 mg, 90 mg, and 135 mg of TAK-079, or matching placebo, respectively.

[0331] The selection of the dose and frequency of administration of TAK-079 was based on a comprehensive review and analysis of data from: (1) TAK-079 dosing in healthy subjects (Study TAK-079-101); (2) nonclinical repeat TAK-079 dosing studies in cynomolgus monkeys (TAK-079-10015, TAK-079-1018, and TAK-079-10019); and (3) data from daratumumab. Data from repeated dosing of daratumumab, a related anti-CD38 cytolytic antibody approved for the treatment of multiple myeloma.

[0332] Based on the good safety profile and PD target effect (i.e., sustained reduction in PB) observed after administration of a 0.6 mg / kg dose to healthy subjects (study TAK-079-101), the starting dose of the initial dosing cohort (i.e., cohort A) was selected to be 45 mg. A single SC dose of 0.6 mg / kg reduced PB levels in peripheral blood by >90% and NK cell levels by >80%, without comparable reductions in monocytes and B and T cells. 21 days after administration, PB and NK cell levels returned to an average of 50% of baseline levels. At this dose, there were no SAEs, deaths in the study, or AEs that led to study discontinuation. No significant findings in laboratory tests, electrocardiograms (ECGs), vital signs, or physical examinations related to the administration of TAK-079 were reported. Two subsequent dosing cohorts with doses of 90 mg (a 2-fold increase compared to the first dose cohort) and 135 mg (a 50% increase compared to the previous cohort) are planned. Because patients with lupus often exhibit higher levels of CD38-expressing PB than healthy study subjects, higher doses may be required to achieve comparable PD effects; subjects will be carefully monitored to maintain a benefit-risk balance.

[0333] Identity of the study drug

[0334] Study drug was supplied as 100 mg TAK-079 (Table 6) in 1 mL (100 mg / mL) of an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and pH 5.9 buffer to be administered as a single SC injection.

[0335] Table 6. Identity of study drugs

[0336]

[0337] NA: not applicable; SC: subcutaneous.

[0338] Packaging, labeling and storage

[0339] TAK-079 drug product and matching placebo are supplied in aseptically filled, single-use, clear, Type I borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip-top caps.

[0340] Supplies of TAK-079 and matching placebo were labeled according to current ICH guidance on GCP and Good Manufacturing Practices and included any locally required statements.

[0341] TAK-079 and matching placebo were stored as specified by the manufacturer (as specified on the label) and remained in the original container until dispensed. A daily temperature log was maintained for the medication storage area.

[0342] Research Reference Product Ingredients

[0343] The matching placebo product is composed of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20 and pH 5.9 buffer, and is administered via SC injection following the same procedure as the TAK-079 drug product. The process B maize to monoclonal antibody drug product is made with 2 strengths (i.e., 5 mg / mL or 100 mg / mL). Each strength is a transparent to milky white, colorless to brownish yellow solution containing maize to monoclonal antibody in an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20 and water for injection having a pH value of about 5.9. The process B placebo is a transparent colorless solution containing histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20 and an aqueous solution of water for injection having a pH value of about 5.9. Process Mazetuzumab drug product and placebo are supplied in aseptically filled, single-use, clear, Type I borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip-top caps.

[0344] Methods of Assigning Subjects to Treatments

[0345] Assignment of study subjects to 1 of 2 study arms in each sequentially enrolled cohort was maintained by a blinded randomization schedule generated and maintained by an interactive voice / web response system (IXRS).

[0346] Selection and scheduling of doses for each subject

[0347] Since infusion reactions and other antibody-mediated hypersensitivity reactions have been reported with other biologics, similar AEs may also occur following treatment with TAK-079. To prevent potential infusion-related reactions (IRRs), all patients must receive premedication prior to each study dose. Post-dose medication should be administered at the investigator's discretion to further minimize delayed IRRs as clinically indicated.

[0348] Precursor drugs

[0349] On each dosing day, subjects were given premedications 1 to 3 hours prior to TAK-079 administration using a regimen consistent with (but not limited to) the following: (1) antipyretics: oral acetaminophen (650 mg to 1000 mg) and (2) antihistamines: oral or IV diphenhydramine (25 mg to 50 mg, or equivalent). Clinical sites were responsible for procuring premedications as outlined in the protocol.

[0350] Study Drug Administration

[0351] After the subject receives premedication, the TAK-079 dose or matching placebo is administered as a SC injection with a syringe to a maximum volume of 2 mL, so that the full planned dose is administered. The time and anatomical site of the SC injection are recorded for each administration, and the injection site is rotated for each administration (injection sites in the abdomen, thigh, arm, and upper buttocks area are all acceptable).

[0352] After administration of medication

[0353] Subjects may receive low-dose methylprednisolone (<20 mg) to prevent delayed injection-related reactions, as clinically indicated and at the discretion of the principal investigator.

[0354] Subjects at increased risk for respiratory complications (e.g., subjects with a history of COPD and subjects with asthma) may be administered the following medications after each study dose (at the discretion of the investigator) to further prevent IRRs: (a) antihistamines (diphenhydramine or equivalent) on the first and second days after study dosing; (b) short-acting β2-adrenergic receptor agonists, such as albuterol (salbutamol) aerosol, or (c) pulmonary disease control medications, such as the following: (i) inhaled corticosteroids (with or without long-acting β2-adrenergic receptor agonists) for subjects with asthma, or (ii) long-acting bronchodilators, such as tiotropium or salmeterol (with or without inhaled corticosteroids) for subjects with COPD.

[0355] Based on emerging data, the Takeda physician / designee may enhance the administration of therapy prior to or after TAK-079 injection to ensure the safety of the subject.

[0356] Blind

[0357] Randomization and medication schedules are generated and maintained by IXRS. All randomization information is stored in a secure area with access only by authorized personnel.

[0358] To maintain the integrity of the study, treatment assignment was blinded to all investigators (including investigators, site personnel, contract research organizations MM, study clinicians, and sponsors) during the treatment period. Treatment assignment was obtained through IXRS according to the procedures outlined in the study manual. Information on treatment assignment was securely stored at Takeda or designated personnel in accordance with its standard operating procedures.

[0359] The study site maintained records of the subject number, date the study drug was dispensed, and treatment assignment.

[0360] If necessary, emergency unblinding can be performed via IXRS. No emergency unblinding occurred during this study.

[0361] Treatment assignments to Cohorts A and B were unblinded after all subjects in Cohorts A and B had completed the study and all data were verified with source data. This unblinding was considered appropriate because, at the time of unblinding, (1) subjects in Cohorts A and B had completed their participation in the study (i.e., completed the study or discontinued the study early); (2) the ongoing Cohort C followed a separate randomization schedule and was therefore unaffected; (3) for this small, early-stage study, the information collected in this interim analysis was unlikely to introduce bias into the ongoing Cohort C; and (4) the initial statistical analysis plan (SAP) had been completed and approved.

[0362] Prior and concomitant therapy

[0363] Background SLE therapy

[0364] Eligible subjects were on background SLE therapy for ≥12 weeks prior to screening (including ≥8 weeks of stable dosing). Once enrolled in the study, subjects remained on background therapy managed by their principal investigator throughout their study participation, according to local institutional practice and consistent with the study protocol. Ongoing background SLE therapy at screening and any changes made to this therapy were recorded in the eCRF.

[0365] Rescue therapy

[0366] Rescue therapy was defined as additional concomitant medications given according to institutional practice or the physician's best medical judgment to control and manage the underlying SLE disorder.

[0367] Subjects remained on their stable doses of immunosuppressive and corticosteroid therapy throughout the study. Dose reductions of immunosuppressive agents were permitted at the investigator's discretion due to toxicity. Increasing, adding, or changing background immunosuppressive therapy, or adding medications that were not originally within the protocol limits as deemed necessary by the principal investigator to treat the SLE manifestations resulted in subjects discontinuing study dosing and advancing to safety follow-up; these subjects will be classified as study nonresponders.

[0368] NOTE: Subjects who required an increase in corticosteroid dose to greater than 0.5 mg / kg / day (or 40 mg / day of prednisone) or equivalent during the study to control SLE activity or manage a new SLE flare discontinued study medication. Prednisone dose or equivalent may be increased to a dose less than or equal to 0.5 mg / kg / day or 40 mg / day (whichever is lower). However, dosing should be tapered to pre-flare levels or 20 mg / day (whichever is greater) over 4 weeks or less. If tapering is not possible and a higher dose is required to treat SLE manifestations, the subject discontinued study medication, advanced to safety follow-up, and was designated as a study nonresponder.

[0369] Exclusion and dose-limiting drugs

[0370] Tables 7 and 8 list the excluded and dose-limited concomitant medications.

[0371] Table 7. Excluded drugs

[0372]

[0373] AE: adverse event

[0374] a Exceptions to excluded drugs may be permitted to treat AEs after discussion and agreement between the sponsor and the principal investigator.

[0375] Table 8. Dose-limiting concomitant medications

[0376]

[0377] a Dosage restrictions do not apply to topical agents.

[0378] Documentation of accompanying medications

[0379] Concomitant medications, blood products, and procedures were recorded from the first dose of TAK-079 or matching placebo until the end of the safety follow-up period (i.e., the end of the safety follow-up visit in Week 24 or, when applicable, the end of the long-term safety follow-up visit in Week 36). The trade name and international nonproprietary name (if any), indication, and start and end dates of the administered medication were recorded.

[0380] Treatment compliance rate

[0381] Study medication will be administered in the clinic. Treatment compliance rates will be calculated as outlined in the "Extent of Exposure and Compliance" section.

[0382] Efficacy, PK, PD, biomarkers, and safety variables

[0383] Measurements and flow chart for evaluation

[0384] The study procedure schedule for the dosing phase is presented in Table 4 and the study procedure schedule for the safety / long-term safety follow-up phase is presented in Table 5. Table 9 provides additional information on PK, CD38, T lymphocyte, B lymphocyte, and NK cell samples, and ECG timing.

[0385] Table 9. PK, CD38, TBNK samples and ECG time (by visit)

[0386]

[0387] D: day; ECG: electrocardiogram; hr: hour; HV: home visit; MM: medical monitoring; NA: not applicable; PK: pharmacokinetics; TBNK: T lymphocytes, B lymphocytes, and natural killer cells.

[0388] a An ECG must be obtained prior to PK sampling scheduled on the same day; a single ECG (read locally) must be obtained and evaluated as part of study screening and at the end of the safety follow-up visit; during study treatment, triplicate 12-lead ECGs (read locally) should be obtained and one copy submitted centrally for future analysis. (See ECG section).

[0389] b Performed prior to study dosing.

[0390] c MM may request additional PK sampling.

[0391] Efficacy Measurement

[0392] The study principal investigator or appropriately trained authorized study site staff assessed each subject's disease activity based on the SLE Disease Activity Scale according to the SOE Study Activity Table (Tables 4 and 5).

[0393] SLEDAI-2K

[0394] The SLEDAI-2K disease assessment tool uses 24 items, 16 of which are clinical items and 8 are based only on laboratory results (urine casts, hematuria, proteinuria, pyuria, low complement levels, increased DNA binding, thrombocytopenia, and leukopenia). Manifestations that occur within 10 days of the assessment time are recorded regardless of their severity or whether they have improved or worsened. Individual item scores range from 1 to 8 points, and the total score ranges from 0 to 105 points. See, for example, Gladman et al., (2002). The Journal of rheumatology, 29 (2): 288-291.

[0395] For the purpose of this study, items for which laboratory results were unavailable were scored as negative or as normal values.

[0396] Cutaneous Lupus Erythematosus Disease Area and Severity Index

[0397] The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) consists of 2 scores: the first score summarizes the activity of the disease, while the second is a measure of the damage caused by the disease. Activity is scored based on erythema, scaling / hyperkeratosis, mucosal involvement, acute alopecia, and non-scarring. Lesions are scored for pigmentation and scarring (including scarring alopecia). Pigmentation associated with SLE lesions is classified as permanent and the score is doubled if it remains visible for more than 12 months.

[0398] 44-Joint Assessment

[0399] 44-Joint Assessment The number of tender and swollen joints is assessed according to location as outlined in the disease assessment tool.

[0400] Physician's global assessment of illness (visual analog scale)

[0401] The Physician's Global Assessment (PGA) is a visual analog scale (VAS) that reflects the clinician's judgment of overall SLE disease activity. The disease activity index scored on the VAS ranges from 0 to 3, with an increase of ≥1.0 since the last visit indicating a flare.

[0402] PK measurements

[0403] Blood samples were collected by venipuncture or indwelling catheter at the time points detailed in the SOE (Table 4) to measure serum concentrations of TAK-079. The samples were tested at a central laboratory.

[0404] If a change in the sampling schedule is deemed necessary to better characterize the PK profile of TAK-079, the timing of samples may be modified during the study based on emerging PK data. Additional PK samples may be requested for specific events or AEs of clinical concern if deemed necessary by the MM.

[0405] Immunogenicity samples

[0406] Serum samples for measurement of anti-TAK-079 antibodies (ie, antidrug antibodies [ADA]) were collected at various time points as specified in the SOE (Table 4).

[0407] Samples are collected before each administration. Immunogenicity samples are screened to identify potential ADA-positive samples, which are then further verified by the bioanalytical laboratory for their true positive rate and titer. The relationship between immunogenic response, efficacy, and safety can be explored.

[0408] Biomarker Measurements

[0409] In this study, several biomarkers were evaluated to test their association with safety, PK, and, if possible, efficacy. Biomarkers of disease activity included anti-dsDNA, anti-ENA antibodies, complement C3, C4, urine protein to creatinine ratio, and / or CD38 pathway regulatory markers. These biomarkers are intended to identify subjects with a higher probability of response or adverse reaction to TAK-079.

[0410] Blood samples were collected by venipuncture or indwelling catheter at the time points detailed in the SOE (Table 4) for measurement of biomarkers. The samples were tested at a central laboratory.

[0411] PK, IgG, and autoantibody quantification

[0412] TAK-079 serum concentrations were quantified by a clinically validated electrochemiluminescent immunoassay. The lower limit of quantification (LLOQ) for this assay was 5 ng / mL. IgG measurements were obtained from a Roche Cobas 8000 analyzer in a central laboratory. SLE-related autoantibodies were quantified in a central laboratory using a clinically validated enzyme-linked immunosorbent assay via a Thermo Scientific Phadia250 analyzer.

[0413] CyTOF analysis

[0414] CyTOF analysis was performed at CellCarta (Fremont CA). Samples were run in batches of approximately ten. Each sample was thawed and washed, stained with a dye indicating cell viability, and then hybridized with a defined antibody panel. After washing, the samples were fixed and incubated with a DNA intercalator at 4°C for 3-7 days. The fixative was then removed and the samples were suspended in water for CyTOF analysis. 100,000-250,000 events were analyzed for each sample. In addition to viability assessment, we also performed an immuno-oncology panel containing 39 metal ion-conjugated antibodies. This panel was modified to include TSF-19 as a non-competing antibody against CD38. Samples were collected at baseline (during screening until 28 days before initiation of mazetuzumab) and on days 15, 36, 57, and 85. Data were collected as FCS plots and evaluated based on the analysis of a random selection of 100,000 cells per patient sample.

[0415] Cluster identification and analysis were performed using the R package CyTofWorkflow (Nowicka et al. (2017) F1000Res 6: p. 748). Different cell populations were identified based on expression profiles using FlowSOM (Van Gassen et al. (2015) Cytometry A 87(7): p. 636-45) and ConsensusClusterPlus (Wilkerson, MD and DNHayes (2010) Bioinformatics 26(12): p. 1572-3), and the results were visualized using TSNE plots (Amir el et al. (2013) Nat. Biotechnol, 31(6): p. 545-52). FlowSOM uses a self-organizing map algorithm to cluster cells into metaclusters, while ConsensusClusterPlus uses a consensus clustering method to identify stable clusters. Additional analyses were performed in-house. Data are presented as median CD38 expression and percentage of the parent population (+ / - standard error of the mean when applicable). Statistical analysis and graph generation were performed using Excel, GraphPad Prism 9, and R code. Flow cytometry subplots were generated using FlowJo 10.

[0416] Safety Measurement

[0417] Safety measurements were performed at the times specified in the SOE (Tables 4 and 5).

[0418] Takeda clinicians reviewed AEs, SAEs, and relevant clinical parameters to ensure consistency with an acceptable benefit-risk ratio throughout the study. At the subject level, each subject's safety and tolerability were closely monitored at the completion of each dose and before the next subsequent dose to ensure that clinical dosing criteria were met before each subsequent administration of TAK-079 or matching placebo. In addition, a comprehensive safety assessment was performed at the end of treatment in each cohort, enabling decisions to be made about whether to be included in subsequent cohorts. The 12-week post-dose safety follow-up period enables continued observation and evaluation of the safety and sustainability of biological activity. Subjects whose safety parameters have not recovered to sufficient protocol-defined rebound levels by the end of the safety follow-up period will be advanced to the long-term follow-up period for continued monitoring (Table 5, Table 11). These ongoing safety observation periods provide optimal monitoring and evaluation for any ongoing study-related sequelae.

[0419] Physical examination

[0420] A symptom-oriented physical examination and assessment for SLE signs and symptoms were completed according to standard of care.

[0421] Vital signs

[0422] Vital signs included temperature, pulse, respiratory rate (RR), and blood pressure (BP). As part of the post-dose assessment, vital signs were assessed before and 4 hours after each study dose. Pulse and BP were assessed at similar locations at each study assessment.

[0423] In addition to the assessments planned in the SOE, vital signs were assessed whenever clinically necessary (ie, the subject exhibited signs or symptoms of an injection reaction, CRS, or hypersensitivity reaction) in either the clinic or home visit setting.

[0424] Clinically significant values ​​as determined by the Principal Investigator were recorded as AEs and were closely monitored for follow-up.

[0425] NOTE: When subjects reported symptoms consistent with an infusion reaction, additional vital signs including BP measurement were assessed. If subjects experienced hypotension (with or without symptoms), intensive BP monitoring was performed according to local practice. Subjects were not allowed to leave the study site until BP values ​​had returned to Grade 1 or baseline for at least 1 hour.

[0426] Laboratory evaluation

[0427] Unless otherwise stated in the protocol, all laboratory samples will be sent to the study center laboratory for analysis, except for the Coombs test, which is performed locally.

[0428] Clinical chemistry and hematology measurements are summarized in Table 10, and urinalysis measurements are summarized in Table 12. The timing of these assessments is summarized in the SOE (Tables 4 and 5).

[0429] Table 10. Clinical chemistry and hematology evaluation

[0430]

[0431] ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: aspartate aminotransferase; BUN: blood urea nitrogen; CRP: C-reactive protein; LDH: lactate dehydrogenase; WBC: white blood cell.

[0432] GFR is calculated using the MDRD formula as follows:

[0433] GFR = 175 × (serum creatinine) -1.154 ×(age) -0.023

[0434] For female subjects, multiply the product by 0.742. For African American subjects, multiply the product by 1.212.

[0435] A complete urinalysis and urine protein-to-creatinine ratio were performed by the site laboratory as part of the predose assessment 1 week prior to each dosing day and at each follow-up safety visit (Table 12). Subsequently, urine was assessed for the presence of protein and nitrates as analyzed by local laboratory analysis (i.e., dipstick analysis) prior to dosing on each dosing day and at each follow-up safety visit.

[0436] Any abnormal findings from the local laboratory urine protein to creatinine ratio assessment will be confirmed by the site laboratory. If the urinalysis is abnormal, the central laboratory will perform a urine microscopic examination. The microscopic examination consists of red blood cells / high power field, white blood cells / high power field, and casts.

[0437] Prior to each study dose, the principal investigator provided the MM with a summary of the assessment results related to dosing criteria for review and approval. In the event that clinical parameters did not meet dosing criteria, study dosing was temporarily withheld until the parameters reached dosing levels or dosing was discontinued, as summarized in Table 11. Subjects returned every 3 weeks for reassessment of dosing criteria until completion of Week 12 of the dosing period, at which time the subjects began the safety follow-up period.

[0438] Table 11. Summary of dosing criteria

[0439]

[0440]

[0441] ANC: absolute neutrophil count; CRS: cytokine release syndrome; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; Hgb: hemoglobin; IRR: infusion-related reaction; LLN: lower limit of normal; SLE: systemic lupus erythematosus.

[0442] a Subjects whose clinical parameters met the criteria for a dose hold did not receive the next scheduled cohort dose (ie, TAK-079 or matching placebo) but returned for the next scheduled dose-criteria assessment for reassessment and evaluation of subsequent dosing.

[0443] b Subjects whose clinical parameters meet dose discontinuation criteria will permanently discontinue study dosing (i.e., TAK-079 or matching placebo); subjects will then advance to the safety follow-up period of the study and complete all relevant assessments while continuing to receive standard background therapy for SLE, based on the judgment of the Principal Investigator and local institutional practice.

[0444] c Laboratory grading, allergy, and infection grading were based on the NCI CTCAE version 4.03.

[0445] d A complete cytokine panel was obtained for any suspected event of CRS of any grade.

[0446] e No further information regarding study-related hypersensitivity reactions is shown here.

[0447] f Further details regarding the grading and clinical signs and symptoms of CRS are not shown here.

[0448] g Lee et al. (2014) Blood 124(2): 188-95; which is incorporated herein by reference in its entirety.

[0449] h Regan and Markowitt (2016) Advancing Transfusion and Cellular Therapies Worldwide Association Bulletin #16-02: 1-4; which is incorporated herein by reference in its entirety.

[0450] Table 12. Clinical Urinalysis Evaluation

[0451]

[0452]

[0453] a Protein and nitrate were assessed as part of a complete urinalysis performed by a central laboratory 1 week prior to each dosing. In addition, protein and nitrate were assessed by a local laboratory (i.e., test strips) prior to dosing on study dosing days. Abnormal findings assessed by the local laboratory were confirmed by a complete urinalysis performed by the central laboratory. Tables 5 and 6 provide further details on the timing of the assessments.

[0454] ECG

[0455] Each ECG recording was performed according to standard institutional practices.

[0456] All study ECGs (including triplicate repeat ECGs) were interpreted by qualified personnel (ie, read locally). In addition, triplicate 12-lead ECGs were recorded electronically and submitted to a central vendor for storage and future analysis.

[0457] ECGs with clinically significant findings as judged by the investigator were considered treatment-emergent adverse events (TEAEs); (with the exception of ECGs obtained as part of the screening visit, which were considered part of the medical history). Clinically significant findings were recorded in the source documents and eCRF and were subject to ongoing monitoring.

[0458] AE

[0459] An adverse event (AE) is defined as any untoward medical occurrence in a clinical study subject who has signed an ICF and is participating in the study; it does not necessarily have a causal relationship with treatment. Therefore, an AE may be any unfavorable and unexpected sign (e.g., clinically significant abnormal laboratory findings), symptom, or disease temporally associated with drug use, regardless of whether it is considered to be related to the drug.

[0460] AEs (i.e., AEs, SAEs, AEs of clinical concern, and liver function test abnormalities) will be collected starting from the time the subject signs the ICF. AEs that persist beyond the end of treatment will be monitored until they resolve, return to baseline, are clearly determined to be due to the subject's stable or chronic condition or intercurrent illness, or 6 months after the end of treatment (whichever comes first). For subjects who withdraw before the administration of study drug, AEs will be followed until the subject discontinues participation in the study.

[0461] All AEs are recorded on the AE page of the eCRF.

[0462] Pregnant

[0463] Urine or serum pregnancy testing is performed as outlined in Tables 4 and 5. Study pregnancy testing may be performed at a designated local laboratory as determined and confirmed by the Sponsor, with appropriate laboratory documentation provided prior to study testing.

[0464] End of study assessment

[0465] End-of-study clinical parameters were assessed at Week 24 (end of safety follow-up period) as summarized in Table 13. If clinical findings and parameters did not meet the end-of-study criteria and were considered study-related by the Principal Investigator, the subject was required to remain in the study and complete a 12-week long-term safety follow-up period, during which study-related parameters that did not meet the end-of-study criteria would continue to be assessed.

[0466] Table 13. Clinical parameters at the end of the study

[0467]

[0468] CRS: cytokine release syndrome; CTCAE: Common Terminology Criteria for Adverse Events; Hgb: hemoglobin; LLN: lower limit of normal.

[0469] a Based on Lee, 2014 rating.

[0470] Appropriateness of measurement

[0471] All assessments used in this study were appropriate for the subject population and are widely used in studies of subjects with SLE.

[0472] end

[0473] Primary End Point

[0474] The primary endpoint evaluated the safety and tolerability of TAK-079, including the incidence, type, and grade of AEs, and the percentage of subjects experiencing ≥1 AE leading to discontinuation of study treatment.

[0475] Secondary End Points

[0476] Secondary endpoints include: (a) PK evaluation of TAK-079; (b) PD evaluation of TAK-079; and (c) immunogenicity assessment of TAK-079.

[0477] Exploratory End Points

[0478] Exploratory Objectives The effect of repeated administration of TAK-079 on disease activity was evaluated using the following clinical rating scales: (a) CLASI, (b) SLEDAI-2K, (c) PGA of Disease (VAS), and (d) 44-Joint Assessment.

[0479] Additionally, biomarkers of disease activity (eg, anti-dsDNA, anti-ENA antibodies), complement C3 and C4, urine protein to creatinine ratio, and / or specific markers of CD38 pathway modulation were evaluated.

[0480] Drug concentration measurement

[0481] For drug concentration measurements, see the “PK Measurements” section.

[0482] Management of events of clinical concern

[0483] Hypersensitivity reactions: infusion and injection site reactions

[0484] Since infusion reactions and other antibody-mediated hypersensitivity reactions have been reported with other biologics, similar AEs may have been seen with TAK-079. Infusion reactions are potentially dose-limiting AEs, but are not uncommon with IV administration of biologics, but are less frequently associated with SC injections of these therapies.

[0485] Symptoms of hypersensitivity reactions can range from a mild rash to more severe reactions, wheezing, hypotension, poor perfusion, respiratory arrest, and even death. Non-allergic clinical hypersensitivity reactions usually occur within the first hour; however, delayed responses have been reported in the literature. Anaphylaxis is a potentially life-threatening condition with symptoms ranging from swelling, angioedema, bronchospasm, respiratory distress, and shock. Hypersensitivity reactions in the literature often occur within a few hours of taking the drug. Based on results from studies of daratumumab, patients with pre-existing COPD or asthma may be at particular risk for developing respiratory complications such as bronchospasm if an infusion reaction event occurs. Therefore, the forced expiratory volume in 1 second (FEV 1 ) below 50% of predicted normal will be excluded from study participation. Eligible patients with a history of COPD may have required additional post-dose medications to manage respiratory complications.

[0486] To date, no subjects who have been administered TAK-079 have experienced allergic symptoms. In a clinical study in healthy subjects (TAK-079-101), infusion-related reactions (IRRs) were defined as treatment-emergent adverse events (TEAEs) occurring within 2 hours of the start of infusion; no IRRs occurred in this study because no allergic reactions or cytokine release reactions were observed within this time period.

[0487] Cytokine Release Syndrome (CRS)

[0488] CRS represents an important infusion reaction that is frequently associated with the use of monoclonal antibodies used in anti-inflammatory and anti-neoplastic therapies. Onset of CRS may occur early in therapy, often after the first infusion of the drug, due to a high level of immune system activation and engagement and proliferation of T cells, which may result in increased cytokine release.

[0489] Nonclinical studies have shown that TAK-079 does not have agonist activity, suggesting that TAK-079 is unlikely to cause cytokine release due to cell activation. At 0.1 mg / kg, no cytokine increases associated with TAK-079 were observed. At >0.3 mg / kg, dose-related increases in tumor necrosis factor (TNF-α) were observed 30 minutes after the first dose of TAK-079 (up to 29.5-fold for any single monkey). These increases are considered small compared to the elevations observed during cytokine storm events, were not accompanied by changes in other cytokines, and did not translate into clinical manifestations of IRR. The increase in serum TNF-α may be related to TAK-079-mediated lysis of CD38+ lymphocytes.

[0490] In the FIH study in healthy subjects, symptoms consistent with mild CRS were rarely observed, especially at higher doses; no dose adjustment or interruption was required.

[0491] The hallmark of CRS is fever. CRS can also present with rash, urticaria, headache, chills, fatigue, nausea, and / or vomiting. Severe CRS is characterized by severe dyspnea, often with bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. Acute respiratory failure may be accompanied by events such as interstitial pulmonary infiltrates or edema visible on chest x-ray. The syndrome often manifests within 1 or 2 hours after the first infusion. Patients with a history of pulmonary insufficiency or those with lung tumor infiltration may be at greater risk for adverse outcomes and should be treated more cautiously. Based on results from studies of the anti-CD38 mAb daratumumab, patients with pre-existing COPD or asthma may be at particular risk for respiratory complications such as bronchospasm if an infusion reaction or CRS event occurs.

[0492] Therefore, if a patient's FEV 1 less than 50% of predicted normal, they will be excluded from study participation. Eligible patients with a history of COPD may have required additional post-infusion medications to manage respiratory complications.

[0493] Hematological effects

[0494] In nonclinical studies, platelet, lymphocyte, and red blood cell (RBC) decreases were observed in some animals at TAK-079 doses above the no observed adverse effect level (NOAEL) of 0.3 mg / kg. In the FIH study, no RBC or platelet decreases were observed, although decreases in these cell counts were observed after repeated dosing at higher dose levels (≥1 mg / kg) in monkey toxicology studies.

[0495] Throughout this clinical study, patients were closely monitored, including testing of hematological parameters. In the event that clinical parameters did not meet dosing criteria, study dosing would be temporarily or permanently discontinued. Medical interventions were administered according to institutional guidelines.

[0496] Infect

[0497] In a 13-week toxicology study in accordance with good laboratory practice (GLP), bacterial and / or viral infections secondary to immunosuppression were observed in cynomolgus monkeys administered IV doses of 3, 30, and 80 mg / kg every 2 weeks. The NOAEL dose of 0.3 mg / kg administered IV once weekly was not associated with infection. In the FIH study, mild infections, particularly nasopharyngitis, were reported.

[0498] Patients were monitored for any signs and symptoms of infection throughout this clinical study. In the event that clinical parameters do not meet dosing criteria, study dosing will be temporarily or permanently discontinued. Standard medical care management of infection is recommended.

[0499] Anti-drug antibody interactions

[0500] Antidrug antibody (ADA) responses were detected in most monkeys in single-dose PK studies and 4-week (non-GLP) and 13-week (GLP) toxicology studies. Stronger positive ADA responses were generally associated with lower TAK-09 serum concentrations, which was particularly evident in the 13-week repeated dose toxicity study and at lower doses. In a single-dose healthy subject study (TAK-079-1001), 5 of 54 subjects treated with TAK-079 were positive for ADA (3 subjects had transient ADA and 2 subjects had persistent ADA). Among them, one subject received 0.06mg IV cohort treatment, and the remaining 4 subjects received 0.03mg / kg (2 subjects), 0.1mg / kg (1 subject) or 0.6mg / kg (1 subject) SC TAK-079 treatment. Immunogenicity was not associated with clinically significant AEs, even in 2 subjects with persistent immunogenicity.

[0501] Overdose

[0502] Overdose is the known intentional or accidental administration of an investigational drug to or by a research subject at a dose higher than the dose assigned to that individual subject according to the study protocol.

[0503] To date, there has been no experience of overdose. If an overdose has occurred, close monitoring and supportive care as medically indicated is recommended.

[0504] Statistical methods and sample size determination

[0505] Analysis Set

[0506] Safety Analysis Set: The safety analysis set included all subjects who were enrolled and received at least 1 dose of study drug. This analysis set was used for demographics, baseline characteristics, efficacy, and safety summaries.

[0507] PK Analysis Set: The PK analysis set included all subjects who received study drug and had at least 1 measurable serum concentration.

[0508] PD Analysis Set: The PD analysis set included all subjects who received study drug and underwent at least 1 post-dose PD measurement.

[0509] Immunogenicity Analysis Set: The immunogenicity analysis set included all subjects from the safety population who had a baseline immunogenicity sample and underwent at least 1 post-dose immunogenicity sample assessment.

[0510] General Notes

[0511] Continuous data were summarized using the following descriptive statistics: number of subjects, mean, SD, median, minimum, and maximum values ​​(where applicable). Continuous data were summarized with the percent coefficient of variation (%CV) and geometric mean (where indicated). Where appropriate, the arithmetic mean, geometric mean, and median were presented to one more decimal place than the data was recorded, and the SD was presented to two more decimal places than the data was recorded.

[0512] For PK-related tables, mean, SD, median, minimum, and maximum values ​​were rounded to 3 significant figures, and %CV was presented to 1 decimal place.

[0513] Categorical data were summarised using the number and percentage of subjects in each category, where appropriate. Percentages were reported to one decimal place.

[0514] Unless otherwise stated, baseline values ​​were defined as the last observation before the first dose of study drug.

[0515] There are no visit windows for dosing visits, safety follow-up periods, and long-term safety follow-up periods. The window period for all non-dosing visits during the dosing period is + / - 1 day.

[0516] For values ​​with several non-missing measurements, such as triplicate ECGs, the mean of the triplicate assessments was used.

[0517] Subjects who received placebo within each cohort were pooled across cohorts. All summaries are presented separately by pooled placebo group, TAK-079 dose, and total TAK-079 subjects across studies.

[0518] For analyses based on the safety, PK, PD, or immunogenicity analysis sets, subjects were analyzed as treated (i.e., actual treatment). For analyses based on all randomized subjects, subjects were analyzed as randomized (i.e., planned treatment).

[0519] Disposition of subjects

[0520] The summary and tabulation of the disposition of the subject is based on all randomized subjects. The number of subjects in the safety analysis set is presented. The disposition is tabulated by subjects who prematurely discontinued study treatment, subjects who completed study treatment, subjects who prematurely discontinued the study, and subjects who completed the study. The main reasons for premature discontinuation of the study or study treatment as entered on the eCRF are tabulated. The percentages are based on the number of subjects in the safety analysis set.

[0521] In addition, the number of randomized participants was summarized for each country and site.

[0522] Major protocol deviations were summarized and listed based on all randomized subjects. Protocol deviations related to coronavirus disease 2019 (COVID-19) were summarized.

[0523] The date of first dose, date of last dose, duration of treatment, and reason for premature discontinuation of study drug / study visit are presented in a table for each subject.

[0524] Demographic and other baseline characteristics

[0525] Demographics

[0526] Summary statistics are presented for continuous variables (e.g., age and weight). The number and percentage of subjects within each category are presented for categorical variables (e.g., race and sex). Demographic and baseline characteristic data for individual subjects are presented. Placebo data were pooled across cohorts.

[0527] Demographic variables for subjects who failed screening and reasons for screening failure were summarized for subjects who underwent screening but were not enrolled in the study.

[0528] Individual demographic characteristics, ICF dates, and reasons for screening failure are listed.

[0529] Demographic data and baseline characteristics were analyzed and presented based on the safety analysis set.

[0530] Medical history

[0531] Medical history refers to any significant illness or disease that had ceased at or before the time of informed consent or was ongoing at the time of informed consent.

[0532] Medical history was coded using the Medical Dictionary for Regulatory Activities (MedDRA, Version 24.0) and summarized by treatment using System Organ Class (SOC) and MedDRA Preferred Term (PT). The table includes the number and percentage of subjects and is sorted alphabetically by SOC. Within the SOC, PTs are sorted in descending order of frequency based on the total number of subjects. Even if a subject has multiple disorders / symptoms, they are only counted once in a particular category. The summary is based on the safety analysis set.

[0533] All medical history data are presented in a table based on the safety analysis set.

[0534] Previous and concomitant medications

[0535] Concomitant medications, blood products, and procedures were recorded from the first dose of TAK-079 or matching placebo until the end of the safety follow-up period (i.e., the end of the safety follow-up visit in Week 24 or, when applicable, the end of the long-term safety follow-up visit in Week 36). The trade name and international nonproprietary name (if any), indication, and start and end dates of the administered medication were recorded. Medication was coded using the World Health Organization Drug Dictionary (B3 Global Version SEP2018 or higher). Based on the safety analysis set, the number and percentage of subjects taking previous medications and concomitant medications were tabulated according to the World Health Organization Drug Dictionary Common Terms.

[0536] Data for all prior and concomitant medications were presented in a table based on the safety analysis set. No imputation was performed for missing concomitant medication dates.

[0537] Efficacy analysis

[0538] Exploratory efficacy endpoints were summarized by descriptive statistics. In addition, analyses of treatment effects were presented as point estimates and two-sided 95% CIs, where applicable. All efficacy analyses used the safety analysis set.

[0539] Rating scales were also analyzed using longitudinal modeling and respondent analysis.

[0540] Vertical Modeling

[0541] Changes from baseline in CLASI, SLEDAI-2K, PGA of disease (VAS), and 44-joint assessment were calculated at each planned visit.

[0542] The changes from baseline in the rating scales by visit were analyzed using a mixed model (MMRM) analysis for repeated measures, which included treatment, visit, and (treatment × visit) interaction terms as factors and baseline values ​​as covariates, and were further adjusted by the baseline-by-visit interaction. Unstructured covariance was used as the default structure for the model. If there were convergence issues, alternative covariance structures were evaluated. The mean changes from baseline between different doses of TAK-079 and placebo were compared for all planned post-baseline assessment time points. The CI for the differences between the groups based on the least squares means is presented. Based on the "missing at random" assumption, only observed case data were used for this analysis.

[0543] The observed rating scale values ​​and the changes from baseline by visit were summarized descriptively. The observed and MMRM model-based mean changes from baseline for each treatment group were plotted. The rating scales are provided in a per-subject tabulation. Individual subject profiles over time for selected rating scales or subscales can be plotted as desired.

[0544] Respondent Analysis

[0545] For each planned assessment, the percentage of subjects meeting the following clinical response criteria for each clinical rating scale was calculated:

[0546] CLASI total activity score: a decrease of ≥4 points or a decrease of ≥20% from baseline (only subjects with a baseline score >0 were analyzed).

[0547] SLEDAI-2K total score: score decrease of ≥4 points from baseline.

[0548] PGA of disease (VAS): score decrease from baseline by ≥ 0.3 points.

[0549] Subjects who met the clinical response criteria in each clinical rating scale were considered responders for the clinical rating scale. The responder rate (responder rate) between different doses of TAK-079 and placebo was compared for all planned post-baseline assessment time points. The CI of the proportion difference is presented. This analysis is based only on the observed data at each time point (i.e., complete case analysis). Missing data was not imputed.

[0550] The observed percentage of responders by visit was summarized descriptively. The 95% CI for the percentage of responders by treatment group could have been generated. The observed percentage of responders over time could have been plotted.

[0551] Security Analysis

[0552] AE

[0553] TEAEs were defined as AEs occurring after the first dose of study drug during the treatment period until the end of safety follow-up.

[0554] TEAEs were presented by intensity. Treatment-emergent SAEs, TEAEs leading to study drug discontinuation, TEAEs leading to dose modification (e.g., described as dose delay, dose skipped), and TEAEs leading to death were also summarized using the SOC and PT.

[0555] When calculating the frequency and percentage of subjects who reported a TEAE, when multiple TEAEs were coded to the same SOC or PT, each SOC or PT was counted only once for a subject. For the intensity or relevance summary, if a subject reported multiple TEAEs coded to the same SOC or PT, the TEAE with the greatest intensity or strongest relevance was included.

[0556] AEs with missing intensity are listed as such in the AE list, but are summarized as severe in the summary table. Similarly, if the relationship of an event is missing, the event is considered relevant, but it is presented as missing in the list.

[0557] Missing AE dates were not imputed.

[0558] Clinical laboratory evaluation

[0559] If a subject had duplicate laboratory values ​​for a given time point, the value from the last evaluation was used.

[0560] All laboratory test parameters are presented in both International System of Units (SI) units and conventional (CV) units in individual subject data listings. For test results in non-SI units, conversion to SI units was performed using known conversion factors. If necessary, SI units at the central laboratory may have been converted to Takeda's preferred SI units. All summaries and analyses are based on values ​​using preferred SI units; data are presented in both SI and conventional units in data listings.

[0561] The Common Terminology Criteria for Adverse Events (CTCAE) grading (version 4.03) of laboratory values ​​was summarized by creating a table of toxicity grade transition from baseline to the worst toxicity grade after baseline.

[0562] Vital signs

[0563] The investigator recorded each vital sign result that met abnormal criteria and was clinically significant according to the PI as an AE.

[0564] 12-lead ECG

[0565] The overall ECG interpretation category (normal, clinically insignificant abnormal, clinically significant abnormal, not evaluable) was collected via the eCRF at baseline and at each scheduled post-baseline visit. Changes in ECG interpretation were presented as a cross-tabulation (baseline vs. each post-baseline visit) of the number of subjects with normal, clinically insignificant abnormal, and clinically significant abnormal interpretations, not evaluable, with missing (if applicable) and the total overall category.

[0566] If necessary, calculate the heart rate-corrected QT interval (milliseconds) (corrected QT [QTc]) from the ECG using the Bazett correction and Fridericia correction. The formula is:

[0567] QTc(Bazett)=QT / (RR^0.5)

[0568] QTc(Fridericia)=QT / (RR^0.33)

[0569] Where RR = 60 / heart rate (heart beats per minute). All ECG parameters are listed in the data table.

[0570] Exposure and compliance rates

[0571] The total number of doses taken and the total number of doses taken were summarized descriptively in the pooled placebo and TAK-079 arms.

[0572] Treatment compliance rates were summarized as the percentage of planned doses received in the pooled placebo and TAK-079 arms. The percentage of planned doses received for each subject was defined as: [(actual total number of doses taken) / (planned number of doses taken)]×100.

[0573] The date and time of each dose for each subject are reported in the data tabulation.

[0574] PK, PD and biomarker analysis

[0575] PD and biomarker analysis

[0576] Individual values, changes from baseline, mean changes from baseline, and / or percentage changes from baseline were calculated for various immune cell subsets (including plasma cells, PB, NK cells, B cells, T cells, monocytes, and total lymphocytes) at different time points for placebo and each TAK-079 dose level. CD38 expression and receptor occupancy of plasma cells, PB, NK cells, B cells, T cells, and monocytes were also evaluated. Cytokine measurements and changes from baseline were calculated for each subject at different time points for placebo and each TAK-079 dose level. Individual values ​​and changes in autoantibody, immunoglobulin, and complement protein levels were summarized.

[0577] Descriptive summaries included geometric means and %CV (where available).

[0578] Plots of means and mean percent changes from baseline were generated. Rather than plotting mean percent changes from baseline for measurements related to receptor occupancy, mean changes from baseline were generated. Individual subject profiles over time for selected parameters can be plotted as desired.

[0579] PK analysis

[0580] Type and methods of PK analysis: TAK-079 concentrations in serum and whole blood were summarized by TAK-079 dose level at each scheduled sampling time using descriptive statistics (N, arithmetic mean, SD, median, maximum, and percent coefficient of variation [%CV]). Individual plasma concentration data versus time are presented in data tables. PK parameters of TAK-079 for each dose level were summarized using descriptive statistics. Maximum observed concentration (C max ) and the geometric mean of the area under the concentration-time curve (AUC). Dose proportionality was assessed graphically and using a power model. max and AUC and dose-normalized C max and AUC versus dose. Other analyses or approaches were also considered if appropriate.

[0581] Due to sparse PK sampling, non-compartmental analyses were not performed. TAK-079 concentration-time profiles were summarized using descriptive statistics. Individual TAK-079 concentration-time data, individual data on the last concentration achieved before the next dose (C 谷值 ) and the individual maximum observed concentration (C max ) were presented in a table and tabulated by treatment group using summary statistics. Individual and mean concentration-time curves were plotted by treatment group. PK parameters were summarized and analyzed using the PK analysis set.

[0582] A population PK model may be developed. If developed, the population PK model will be reported separately. The analysis plan for the population PK analyses will be defined separately, and the results of these analyses will be reported separately.

[0583] PK-PD relationships can be explored graphically. A PK / PD model can be developed to explore the relationship between TAK-079 serum concentrations and cell counts (e.g., plasma cells, PB, NK cells, B cells, T cells, monocytes, and total lymphocytes). If developed, the results will be reported in a separate report. PD parameters will also be listed in the data table. If appropriate, additional PD analyses can be performed to evaluate dose effects.

[0584] Immunogenicity analysis

[0585] Immunogenicity analyses (ADA transient, persistent, negative, and titer) were summarized using descriptive statistics where applicable. The relationship between immunogenic responses and efficacy and safety can be explored.

[0586] A transient positive ADA response was defined in SAP as a subject whose ADA status was confirmed to be positive in 1 or 2 post-baseline assessments.

[0587] Sustained positive ADA response was defined in SAP as subjects with confirmed positive ADA status in >2 post-baseline assessments.

[0588] A positive ADA assessment at each post-baseline visit was defined in SAP as having: (1) a negative assessment at baseline and a positive assessment value, or (2) a positive value at baseline and a assessment value that met criteria for a treatment-enhanced ADA response (≥4 times the baseline value).

[0589] During the actual analysis of the study data, changes and additions were made to the SAP-defined ADA responses outlined above. These changes are described in detail in the section “Changes Made to Immunogenicity Analysis”.

[0590] Interim Analysis

[0591] The sponsor may have conducted an unblinded review or analysis of data from one or more dose cohorts after all subjects enrolled in these cohorts completed the safety follow-up period or prematurely discontinued the study. The sponsor received only the treatment assignment of each subject within the relevant cohort, while the treatment assignment of other subjects remained blinded to the sponsor.

[0592] Determination of sample size

[0593] This study did not have a statistical basis to conduct any hypothesis testing. The sample size of 6 active subjects and 2 placebo subjects in each of the 3 cohorts (resulting in 6 subjects receiving placebo or 45 mg, 90 mg, or 135 mg TAK-079 treatment) was considered sufficient to achieve the study objectives of evaluating safety, tolerability, and PK in each cohort.

[0594] Example 2: Study Subjects

[0595] Disposition of subjects

[0596] A total of 35 subjects were screened but did not enter the study. The reasons for screening failure were: failure to meet the entry criteria (28 subjects), subject withdrawal (5 subjects), and other reasons (2 subjects).

[0597] The study was planned to randomize 24 subjects; however, enrollment was ended early due to a high study screening failure rate and operational challenges in subject recruitment.

[0598] Twenty-three subjects were randomized to 13 study sites in the U.S. One randomized subject discontinued the study before receiving study drug, and 22 randomized subjects received at least 1 dose of study drug and were included in the safety analysis set (Table 14).

[0599] The mean age in the placebo group (36.4 years) was lower than in the mazetuzumab group (pooled mazetuzumab groups: 49.1 years). The mean baseline weight was higher in the placebo (87.3 kg) and mazetuzumab 90 mg (85.6 kg) groups, whereas it was lower in the mazetuzumab 45 mg (75.0 kg) and mazetuzumab 135 mg (64.6 kg) groups. Other demographic variables were similar between treatment groups. The majority of study subjects were female, and the percentages of African American and white study subjects were nearly equal.

[0600] Table 14. Summary of Subject Disposition (All Randomly Assigned Subjects)

[0601]

[0602] AE: adverse event

[0603] a The safety analysis set consisted of all subjects who were enrolled and received at least 1 dose of study drug.

[0604] b Subjects who completed the Week 24 visit were considered to have completed the study. All other subjects were considered to have discontinued the study prematurely.

[0605] Protocol Deviation

[0606] A total of 3 subjects reported major protocol deviations, 1 in the informed consent category and 2 in the study treatment administration / assignment category.

[0607] Impact of the COVID-19 Pandemic on Research Participants

[0608] A total of 2 subjects reported protocol deviations related to COVID-19. One subject in the TAK-079 90 mg group reported deviations in 2 categories of study procedures / assessments and visit schedule, and one subject in the TAK-079 135 mg group reported deviations in 2 categories of study treatment adherence rate and visit schedule.

[0609] Example 3: PK, PD, Immunology and Efficacy Evaluation

[0610] Analyzed datasets

[0611] The number of subjects in each analysis set is shown in Table 15. The safety analysis set was used for demographics, baseline characteristics, efficacy, and safety summaries.

[0612] Table 15. Summary of Analysis Set (All Randomly Assigned Subjects)

[0613]

[0614] PK: pharmacokinetics; PD: pharmacodynamics.

[0615] Percentages are based on all subjects randomized. One subject was randomized but did not receive any dose.

[0616] a The safety analysis set consisted of all subjects who were enrolled and received at least 1 dose of study drug.

[0617] b The PK set consisted of all subjects who received study drug and had at least 1 measurable serum concentration.

[0618] c The PD set consisted of all subjects who received study drug and underwent at least 1 post-dose PD measurement.

[0619] d The immunogenicity set consisted of all subjects who received study drug and underwent baseline and at least 1 post-baseline immunogenicity sample assessment.

[0620] Demographic characteristics

[0621] The demographic characteristics are summarized in Table 16.

[0622] The mean age of the placebo group (36.4 years) was lower than that of the TAK-079 group (pooled TAK-079 group: 49.1 years). Other demographic variables were similar between treatment groups. The majority of study subjects were female, and the percentages of African American and white study subjects were nearly equal.

[0623] Table 16. Demographic Data (Safety Analysis Set)

[0624]

[0625] Max: maximum value; min: minimum value.

[0626] a Subjects may have more than 1 race. Those who selected more than one race were counted only under "Multiple Races."

[0627] Medical history and other baseline characteristics

[0628] All 22 subjects (100%) had a reported medical history. Common medical histories other than SLE (≥25% of all subjects) included gastroesophageal reflux disease (13 subjects [59.1%]), hypertension (11 [50.0%]), depression (10 subjects [45.5%]), anxiety (9 subjects [40.9%]), hyperthyroidism (7 subjects [31.8%]), and migraine, insomnia, and vitamin D deficiency (6 subjects [27.3%] each).

[0629] Medication history and concomitant medications

[0630] Drug history

[0631] All 22 subjects (100%) had at least 1 prior medication. Common prior medications (≥25% of total subjects) included hydroxychloroquine (13 subjects, 59.1%), prednisone (9 subjects, 40.9%), gabapentin (8 subjects, 36.4%), and hydroxychloroquine sulfate (6 subjects, 27.3%).

[0632] Concomitant medications

[0633] All 22 (100%) subjects had at least 1 concomitant medication, reflecting the fact that all subjects were required to be on stable background SLE therapy throughout the study. The most common background SLE medications in this study included:

[0634] Antimalarials: Pooled placebo, 4 subjects (80.0%); TAK-079 45 mg, 5 subjects (83.3%); TAK-079 90 mg, 6 subjects (100%); TAK-079 135 mg, 4 subjects (80.0%). Hydroxychloroquine (13 subjects, 59.1%): Pooled placebo, 3 subjects (60.0%); TAK-079 45 mg, 3 subjects (50.0%); TAK-079 90 mg, 4 subjects (66.7%); TAK-079 135 mg, 3 subjects (60.0%). Hydroxychloroquine sulfate (6 subjects, 27.3%): pooled placebo, 1 subject (20.0%); TAK-079 45 mg, 2 subjects (33.3%); TAK-079 90 mg, 2 subjects (33.3%); TAK-079 135 mg, 1 subject (20.0%).

[0635] Corticosteroids [mean dose, mg]: pooled placebo, 3 subjects (60.0%) [8.3 mg]; TAK-079 45 mg, 2 subjects (33.3%) [10 mg]; TAK-079 90 mg, 2 subjects (33.3%) [7 mg]; TAK-079 135 mg, 3 subjects (60.0%) [4.6 mg]. Prednisone (9 subjects, 40.9%): pooled placebo, 3 subjects (60.0%); TAK-079 45 mg, 2 subjects (33.3%); TAK-079 90 mg, 1 subject (16.7%); TAK-079 135 mg, 2 subjects (60.0%). Methylprednisolone (1 subject, 4.5%): pooled placebo, 0 subjects; TAK-079 45 mg, 0 subjects; TAK-079 90 mg, 1 subject (16.7%); TAK-079 135 mg, 0 subjects.

[0636] Gabapentin (8 subjects, 36.4%): pooled placebo, 2 subjects (40%); TAK-079 45 mg, 3 subjects (50%); TAK-079 90 mg, 1 subject (16.7%); TAK-079 135 mg, 2 subjects (40%).

[0637] Mycophenolate mofetil: Pooled placebo, 1 subject (20.0%); TAK-079 45 mg, 2 subjects (33%); TAK-079 90 mg, 1 subject (16.7%); TAK-079 135 mg, 3 subjects (60.0%). Mycophenolate mofetil: Pooled placebo, 1 subject (20.0%); TAK-079 45 mg, 1 subject (16.7%); TAK-079 90 mg, 0 subjects; TAK-079 135 mg, 2 subjects (40.0%). Mycophenolate sodium: Pooled placebo, 0 subjects; TAK-079 45 mg, 0 subjects; TAK-079 90 mg, 1 subject (16.7%); TAK-079 135 mg, 0 subjects. Mycophenolic acid: pooled placebo, 0 subjects; TAK-079 45 mg, 1 subject (16.7%); TAK-079 90 mg, 0 subjects; TAK-079 135 mg, 1 subject (20.0%).

[0638] Methotrexate: pooled placebo, 1 subject (20.0%); TAK-079 45 mg, 2 subjects (33.3%); TAK-079 90 mg, 0 subjects; TAK-079 135 mg, 0 subjects.

[0639] Overall, background medications were balanced across treatment groups and did not change during the treatment period. Among subjects receiving corticosteroids (prednisone and methylprednisolone), the mean daily dose during the treatment period was slightly higher in the placebo (8.3 mg) group and the TAK-079 45 mg (10.0 mg) group than in the TAK-079 90 mg (7.0 mg) group and the TAK-079 135 mg (4.7 mg) group.

[0640] Measurement of treatment adherence

[0641] Study medication adherence rate data are provided in Table 17.

[0642] Table 17. Study Drug Exposure and Adherence Rate (Safety Analysis Set)

[0643]

[0644] a The treatment compliance rate (%) was calculated as (number of doses actually taken) / (number of planned doses) × 100

[0645] Analysis of PK, PD, immunology, and efficacy results

[0646] PK Results - TAK-079 Serum Concentrations

[0647] Serum concentrations of TAK-079 were detectable in all subjects at all dose levels. However, many subjects had TAK-079 concentrations below the lower limit of quantitation after dosing, especially in the 45 mg dose group. Serum PK data excluded from PK analysis and / or reporting were due to dose suspension and premature discontinuation (“Exposure” section), as well as other reasons related to sample availability and conditions.

[0648] Figure 3A and Figure 3B Log-linear plots of mean / SD serum concentrations of TAK-079 versus time following multiple dose administration of TAK-079 at 45, 90, and 135 mg SC injections are presented in Table 1. max (maximum observed plasma concentration) and amounts are presented in Tables 18 and 19, respectively.

[0649] Table 18. C of TAK-079 max (maximum observed plasma concentration) (PK analysis set).

[0650]

[0651] a The pharmacokinetic analysis set consisted of all participants who received study drug and had at least 1 measurable serum concentration.

[0652] b The number analyzed was the number of participants available for analysis at a given time point.

[0653] Table 19. Number of Participants with Changes from Baseline in (Cluster of Differentiation 38) CD38 Expression Levels and Receptor Occupancy (PK Analysis Set).

[0654]

[0655]

[0656] a The pharmacokinetic analysis set consisted of all participants who received study drug and had at least 1 measurable serum concentration.

[0657] b Reported as a count of participants who experienced a change relative to baseline.

[0658] c Baseline until Day 85 (EOT).

[0659] TAK-079 peak exposure was greater than dose proportional across the dose range tested (45 mg to 135 mg). After the first administration, a 3-fold increase in the dose resulted in a mean C max The increase was approximately 100-fold, from 57.5 ng / mL to 6130 ng / mL. This greater than dose-proportional increase in exposure was generally maintained over subsequent dosing intervals.

[0660] For subjects with available and measurable concentration data, at each dosing interval, the C max The time (t max ) ranged from 33 to 168 hours after injection. Most subjects in all dose groups reached maximum drug concentrations at 108 hours after the first and second doses of TAK-079. No PK collection was specified between 5 hours and 168 hours after the third and fourth doses, and all but two subjects had apparent t max Both are 168 hours.

[0661] Biomarker Validation

[0662] Completed the pre-validation characterization and technical verification of flow cytometry assay, to evaluate the CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, PB and plasma cells in whole blood. In addition, this assay has been verified to quantitatively determine the CD38 receptor occupancy rate and receptor density of each cell type. The quantity of the participants whose immune cells (i.e. plasma cells, plasmablasts, NK cells, B cells, T cells, monocytes and lymphocytes) changed relative to baseline is presented in Table 20.

[0663] Table 20. Number of participants with changes from baseline in immune cell subsets at end of treatment (EOT) from baseline to day 85 (PD analysis set).

[0664]

[0665] a The PD analysis set included all participants who received study drug and underwent at least 1 postdose PD measurement.

[0666] b Reported as a count of participants who experienced a change relative to baseline.

[0667] c Baseline until Day 85 (EOT).

[0668] Target engagement based on receptor occupancy flow cytometric analysis

[0669] The CD38 receptor occupancy assay was developed to evaluate changes in CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, PB, and plasma cells in whole blood. In addition, CD38 expression and TAK-079 receptor occupancy of all corresponding cell types were evaluated by comparing the CD38 fluorescence signal of 2 independent flow cytometry samples containing labeled TAK-079 (for quantification of "free" CD38 receptors) or labeled TSF-19 (a non-competitive CD38 antibody for quantification of "total" CD38 receptors).

[0670] Trends in the PD profile were most evident after the first dose. Data in subsequent dosing intervals were confounded by dose pauses and premature discontinuations (“Exposure” section) and other reasons related to sample availability and conditions.

[0671] The NK cell population is the most abundant CD38-expressing cell population in the peripheral blood, and receptor occupancy on this cell type can be used as a surrogate marker for CD38 engagement on target cells. TAK-079 engaged the CD38 target on CD38+ NK cells in a dose-dependent manner, with median receptor occupancy increasing from 43.8% to 88.4% one day after the first dose across the studied dose range of 45 mg to 135 mg. The trend for dose-dependent target engagement was less pronounced at subsequent doses, such that the 90 mg dose achieved similar or higher mean receptor occupancy compared to the 135 mg dose. Maximum receptor occupancy for all dose groups was reached approximately 4 to 7 days after administration and returned to near baseline before the next dosing interval, except for the 90 mg dose group, in which receptor occupancy did not fully return to baseline from the second dosing interval.

[0672] Target engagement was accompanied by changes in absolute cell counts of CD38+ NK cells. The corresponding reductions in CD38+ NK cells were roughly similar across all TAK-079 dose groups, with median changes from baseline observed for 45 mg, 90 mg, and 135 mg of -71.5%, -65.5%, and -90.0%, respectively ( Figure 4A ). These reductions occurred 2 days after the first dose and did not show a complete recovery to baseline by the time of the next dose. Similar trends were observed during subsequent dosing intervals. In each pooled TAK-079 group, CD38+ NK cells were depleted of a 33.7% change from baseline at the end of treatment (Day 85). Throughout the study, subjects receiving placebo did not show a decrease in CD38+ NK cells from baseline.

[0673] Changes in absolute PB counts were examined because these cells represent target cells for TAK-079 that can be quantified in peripheral blood. Reductions in absolute PB counts were similar across TAK-079 dose groups. The maximum effect occurred one day after the first dose, with median changes from baseline of -87.0%, -69.4%, and -75.8% for 45 mg, 90 mg, and 135 mg, respectively ( Figure 4B ). PB counts returned to baseline before the second dose was administered. Similar trends were observed during subsequent dosing intervals, although PB depletion was less pronounced.

[0674] Downstream pharmacology targeting CD38

[0675] Potential effects on plasma cells are assessed indirectly because these cells are primarily found in tissues (e.g., bone marrow) and are present in small numbers in peripheral blood. Therefore, serum concentrations of total IgA, IgG, and IgM were evaluated as surrogate biomarkers for the effects of TAK-079 on plasma cells in tissues.

[0676] Multiple doses of TAK-079 at either 45 mg or 90 mg resulted in modest decreases in IgG, with mean decreases from baseline at any given time being less than 10% and not substantially different from placebo, which had a maximum mean decrease from baseline of approximately 5% during the dosing period ( Figure 4C and Figure 4D The maximum mean decrease in IgG from baseline caused by a 135 mg dose of TAK-079 was 18.8%. IgA depletion showed a dose-dependent trend, with the maximum mean decreases from baseline in IgA achieved with 45 mg, 90 mg, and 135 mg being 11.3%, 17.1%, and 32.6%, respectively. Figure 5 ). The reduction in IgM concentrations was similar across all dose groups, with mean decreases from baseline of approximately 11.3% to 16.7% across the pooled TAK-079 groups during the dosing period. Reductions in immunoglobulins generally did not return to baseline levels by Day 85, the last time point examined in the study.

[0677] In addition to changes in total immunoglobulin concentrations, the effect of TAK-079 on changes in serum autoantibody concentrations in subjects who were positive for a given autoantibody at baseline was also evaluated. The subjects were positive for six main autoantibodies: anti-dsDNA, anti-SmD p, beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A antibody, and Sjögren's syndrome SS-B antibody. Many subjects were positive for anti-dsDNA (9 of 22 subjects) or for Sjögren's syndrome SS-A (14 of 22 subjects). Changes in autoantibody concentrations did not appear to be dose-dependent and generally did not show strong concordance with changes in total immunoglobulins ( Fig. 6A and Figure 6B ). For all autoantibodies evaluated, the maximum reduction in autoantibody concentrations was a mean decrease from baseline of approximately 20%.

[0678] CyTOF

[0679] To further understand the broad immune landscape changes caused by mazetzumab, CyTOF analysis was performed on PBMC samples collected during the study. These results showed a general trend that CD38 expression correlated with the degree of cell exhaustion ( Fig. 7A ). Plasma cells, Bregs, NK cells, and plasmablasts were among the most affected populations, consistent with the receptor occupancy data for subsets of these cells. In addition, the unsorted CyTOF data were subjected to FlowSOM clustering and tSNE visualization ( Figure 7B , Figure 7C , Fig. 8A and Figure 8B These data show changes in cluster size, specifically around clusters expressing high levels of CD38. To obtain more information about specific clusters that underwent substantial changes, the number of clusters was increased from 20 to 50 ( Fig. 9A This more fine-grained analysis revealed two CD8+ and CD4+ clusters (32 and 34, Fig. 9B and 9C ), they express granzymes, are CCR7-, and are CD45RAlo / -. Evaluation of the treatment effect on this population revealed an increase in the prevalence of these populations that appeared to be dependent on treatment duration and / or dose. Taken together, the data suggest that mazetuzumab targets high CD38 expressing cells, leading to their depletion and an overall reduction in CD38 signaling in immune cells.

[0680] IFN gene signature

[0681] Whole blood RNA samples were collected at discrete time points throughout mazetzumab treatment and subjected to the nanostring autoimmune profiling panel. Genes associated with type 1 IFN responses were identified as downregulated in patients in the 135 mg cohort compared to placebo ( Fig.10). This response was most pronounced in patients who experienced a strong skin response based on CLASI scores.

[0682] Immunogenicity results

[0683] Changes made to the immunogenicity assay after the final SAP are described in the “Changes Made to the Immunogenicity Assay” section.

[0684] Twenty-one subjects in the immunogenicity set had baseline and at least 1 post-baseline ADA assessment. One subject was missing an assessment at baseline and was therefore not included in the immunogenicity set.

[0685] Subjects with a positive baseline ADA result were considered to have pre-existing ADA. Three subjects in the placebo group had pre-existing ADA, no subjects in the TAK-079 45 mg group had pre-existing ADA, and 1 subject in each of the TAK-079 90 mg and 135 mg groups had pre-existing ADA, so the overall pre-existing ADA incidence was 23.8% (Table 21). The high proportion of subjects with pre-existing ADA may be the result of active autoimmune disease in these subjects with SLE (Faustini et al. (2021) Arthritis Res. Ther. 23 (1): 211-23).

[0686] Subjects with a positive baseline ADA result and a post-baseline titer increase of ≥4-fold compared to the baseline titer were considered to have treatment-enhanced ADA; however, no subjects met these criteria in this study. Subjects with a negative baseline ADA result and a positive ADA result after any administration were considered to have treatment-emergent ADA. No subject in the placebo group had treatment-emergent ADA, 2 subjects in each of the TAK-079 45mg and 135mg groups had treatment-emergent ADA, and 1 subject in the TAK-079 90mg group had treatment-emergent ADA, with an overall treatment-induced ADA incidence of 23.8% (Table 21). Among the subjects with treatment-emergent ADA, 4 (19% of the total number of subjects) were transiently ADA-positive, and only 1 (4.8% of the total number of subjects) was persistently ADA-positive.

[0687] The overall ADA prevalence (including pre-existing ADA at any time point and treatment-emergent ADA) was 47.6% (10 of 21 subjects) (Table 21). The proportions were similar in each treatment group, including the placebo group.

[0688] The minimum dilution or minimum titer required in this study was 20, and only ADA positive samples were evaluated for titer. Among all subjects with ADA that emerged during treatment, the median titer was 200 and ranged from 20 to 327,680 (Table 21). No correlation between ADA titer and administered dose was observed.

[0689] Immunogenicity was not associated with clinically significant AEs or hypersensitivity reactions, even in subjects with persistently positive ADA responses. AEs and efficacy results were carefully evaluated in 2 subjects with ADA titers >40,000 (1 subject in the TAK-079 45 mg group and 1 subject in the TAK-079 135 mg group). Both subjects were ADA negative at baseline, but based on their medical history, they showed immune dysfunction at the beginning of the study, which may partially explain the development of high ADA titers. No clinically relevant AEs or hypersensitivity reactions were observed in these subjects, and the efficacy results were consistent with the study group responses. Due to the limited number of subjects, the drug dose dependence of immunogenicity could not be assessed, but there was no significant difference in ADA positive responses among the different treatment dosing groups (Table 21).

[0690] Neither the individual subject figures for serum TAK-079 concentrations over time nor the ADA results revealed C max At the individual level, C in subjects with a positive (transient or persistent) ADA response that emerged during treatment max The C values ​​were generally lower after a positive ADA assessment. However, comparable decreases in drug concentrations with continued dosing were also observed in subjects with a negative ADA response. In addition, C values ​​were similar across subjects regardless of ADA. max There was considerable variability, for example, a geometric %CV of 186.3% was reported for the TAK-079 45 mg group at Dose 1, in which all subjects had negative ADA status. Overall, the data were too limited and too variable to determine the impact of immunogenicity on TAK-079 PK, but there was no clear trend toward differences in exposure in subjects with positive ADA responses compared to those with negative ADA responses.

[0691] Table 21. Summary of ADA responses (immunogenicity set)

[0692]

[0693]

[0694] ADA: anti-drug antibodies.

[0695] The baseline value was defined as the last observation before the first dose of study drug.

[0696] a A pre-existing ADA response was defined as any subject with a positive ADA status at baseline and a negative post-baseline sample or a positive post-baseline sample with no more than a 4-fold increase in volume per liter relative to baseline.

[0697] b A treatment-emergent transient ADA response was defined as a subject with a negative ADA status at baseline and a confirmed positive ADA status at 1 or 2 post-baseline assessments.

[0698] c A treatment-emergent sustained ADA response was defined as a subject with a negative ADA status at baseline and confirmed positive ADA status in >2 post-baseline assessments.

[0699] d ADA prevalence is the proportion of the study population with ADA (including pre-existing ADA) at any point in time.

[0700] e The ADA incidence rate is the proportion of the study population with treatment-emergent ADA (including transient and persistent ADA) or treatment-enhanced ADA at any time point. Treatment-enhanced ADA is defined as a >4-fold increase in titer after baseline compared to baseline titer; however, no subject in this study met the criteria for treatment-enhanced ADA.

[0701] Table 22. Summary of ADA titers (immunogenicity set)

[0702]

[0703]

[0704] ADA: anti-drug antibody; D: study day; max: maximum value; min: minimum value.

[0705] The baseline value was defined as the last observation before the first dose of study drug.

[0706] Efficacy analysis

[0707] Exploratory Objectives The effect of repeated administration of TAK-079 on disease activity was evaluated using a clinical rating scale.

[0708] CLASI

[0709] There was a moderate improvement in CLASI total activity scores from baseline to the end of treatment, and no significant change in CLASI total impairment scores, with no observable differences between treatment groups. At baseline, mean CLASI total activity scores were lower in the placebo group (4.8), TAK-079 45 mg group (7.2), and TAK-079 90 mg group (5.2) than in the TAK-079 135 mg group (11.8) (Table 23). At the end of treatment on Day 85, the change from baseline in total activity scores (LS mean) was similar in the placebo group (-3.7) and the TAK-079 treatment groups (TAK-079 45 mg: -4.3; TAK-079 90 mg: -3.9; TAK-079 135 mg: -3.6) (Tables 23 and Fig.11 The number of responders (defined as subjects with a score reduction of at least 4 points or at least 20% from baseline) was also similar in each treatment group at this time (Table 23). When a single total activity score was assessed, all subjects with a baseline CLASI score >10 met responder criteria at the end of treatment ( Fig.12 , Table 24). At the end of treatment on Day 85, the total injury scores (LS mean) in the placebo group (0.0) and the TAK-079 treatment group (TAK-079 45 mg: -1.3; TAK-079 90 mg: 0.0; TAK-079 135 mg: 0.4) were almost unchanged from baseline.

[0710] Table 23. Summary and Analysis of CLASI Total Activity Scores by Visit (Safety Analysis Set)

[0711]

[0712] CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; max: maximum value; min: minimum value.

[0713] MMRM: mixed effects model for repeated measures.

[0714] The baseline value was defined as the last observation before the first dose of study drug.

[0715] a According to the MMRM analysis of all post-baseline visits, the analysis used the change from baseline as the outcome, treatment, visit and (treatment × visit) interaction terms as factors, and the baseline value and (baseline × visit) interaction as covariates. The degrees of freedom were calculated using the Kenward-Rogers method, and the covariance matrix was based on an autoregressive (1) covariance structure. The pooled placebo group was used as the control group for the difference (active - placebo) in the LS means and their 95% CIs.

[0716] b Only patients with a baseline score above zero were included.

[0717] c Responders were defined as subjects with a score reduction of at least 4 points or at least 20% from baseline. Comparable The 95% CI is based on the Wilson method.

[0718] Table 24. CLASI responder analysis

[0719]

[0720]

[0721] EOT was visit on Day 85. For patient 58007-002: Data on Day 85 were not available, the indicated values ​​are based on the follow-up visit.

[0722] SLEDAI-2K

[0723] Mild to moderate improvements in SLEDAI-2K total scores from baseline to end of treatment were observed in this study. There were no observable differences between the treatment groups. At baseline, mean SLEDAI-2K total scores were similar for the placebo group (8.4), TAK-079 45 mg group (9.7), TAK-079 90 mg group (9.7), and TAK-079 135 mg group (8.8) (Table 25). At the end of treatment on Day 85, the change from baseline in total score (LS mean) in the placebo group (5.2) was similar to that in the TAK-079 treatment groups (TAK-079 45 mg: -3.1; TAK-079 90 mg: -2.5; TAK-079 135 mg: -4.2) (Tables 25 and 25). Fig.13 The number of responders (defined as subjects whose scores decreased by at least 4 points from baseline) was similar in each treatment group at this time (Table 25). No trends were observed in the individual SLEDAI-2K total scores ( Fig.14 ).

[0724] Table 25. Summary and Analysis of SLEDAI-2K Total Scores by Visit (Safety Analysis Set)

[0725]

[0726] Max: maximum value; min: minimum value; MMRM: mixed effects model for repeated measures; SLEDAI-2K: systemic lupus erythematosus disease activity index-2000.

[0727] The baseline value was defined as the last observation before the first dose of study drug.

[0728] a According to the MMRM analysis of all post-baseline visits, the analysis used the change from baseline as the outcome, treatment, visit and (treatment × visit) interaction as factors, and baseline value and (baseline × visit) interaction as covariates. Degrees of freedom were calculated using the Kenward-Rogers method, and the covariance matrix was based on an autoregressive (1) covariance structure. The pooled placebo group was used as the control group for the difference (active - placebo) in the LS means and their 95% CIs.

[0729] b Responders were defined as subjects with a score reduction of at least 4 points from baseline.

[0730] Disease PGA (VAS)

[0731] Mild to moderate improvements in disease PGA scores from baseline to end of treatment were detected. No differences were observed between treatment groups.

[0732] At baseline, the mean disease PGA score, presented as disease severity on a 3-point scale, was similar in the placebo group (1.48), the TAK-079 45 mg group (1.70), the TAK-079 90 mg group (2.02), and the TAK-079 135 mg group (1.84) (Table 25).

[0733] At the end of treatment on Day 85, the change in score from baseline (LS mean) was similar in the placebo group (-0.58) and the TAK-079 treatment groups (TAK-079 45 mg: -0.71; TAK-079 90 mg: -0.48; TAK-079 135 mg: -0.90) (Table 26). The number of responders (defined as subjects with a score decrease of at least 0.3 points from baseline) was similar in each treatment group at this time (Table 26).

[0734] No trends were observed for individual disease PGA scores.

[0735] Similar results were observed when disease PGA was presented as disease severity on the VAS scale.

[0736] Table 26. Summary and Analysis of Disease PGA (Disease Severity on a 3-Point Scale) by Visit (Safety Analysis Set)

[0737]

[0738] Max: maximum value; min: minimum value; MMRM: mixed effects model for repeated measures; PGA: physician global assessment; SLEDAI-2K: systemic lupus erythematosus disease activity index-2000. The baseline value was defined as the last observation before the first dose of study drug.

[0739] a According to the MMRM analysis of all post-baseline visits, the analysis used the change from baseline as the outcome, treatment, visit and (treatment × visit) interaction as factors, and baseline value and (baseline × visit) interaction as covariates. Degrees of freedom were calculated using the Kenward-Rogers method, and the covariance matrix was based on an autoregressive (1) covariance structure. The pooled placebo group was used as the control group for the difference (active - placebo) in the LS means and their 95% CIs.

[0740] b Responders were defined as subjects whose scores decreased by at least 0.3 points from baseline.

[0741] 44-Joint Assessment

[0742] Overall, there were moderate improvements in total tender joint counts, total swollen joint counts, and total movable joint counts from baseline to the end of treatment, with no observable differences between treatment groups.

[0743] At baseline, mean total tender joint counts were similar across treatment groups. At the end of treatment on Day 85, the change from baseline (LS mean) was similar in the placebo group (-9.5) and the TAK-079 treatment groups (TAK-079 45 mg: -7.9; TAK-079 90 mg: -14.2; TAK-079 135 mg: -10.1).

[0744] At baseline, mean total swollen joint counts were similar across treatment groups. At the end of treatment on Day 85, the change from baseline (LS mean) was similar in the placebo group (-5.8) and the TAK-079 treatment groups (TAK-079 45 mg: -3.1; TAK-079 90 mg: -2.1; TAK-079 135 mg: -7.1).

[0745] At baseline, mean total active joint counts were similar across treatment groups. At the end of treatment on Day 85, the change from baseline (LS mean) was similar in the placebo group (-6.1) and the TAK-079 treatment groups (TAK-079 45 mg: -4.0; TAK-079 90 mg: -6.4; TAK-079 135 mg: -6.7).

[0746] Statistical and analytical issues

[0747] Handling of missing or missing data

[0748] Efficacy data were analyzed using observed case data only, based on the “missing at random” assumption.

[0749] Interim analysis and data monitoring

[0750] No interim analysis was performed for this study.

[0751] Treatment assignments for Cohorts A and B were unblinded after all subjects in Cohorts A and B had completed the study and all data were verified by the source data. The Sponsor received only the treatment assignments for each subject within the relevant cohort, while the treatment assignments for subjects in other cohorts remained blinded to the Sponsor. Details on the unblinding process and steps used to minimize bias are described in the "Blinding" section.

[0752] Multicenter study

[0753] This was a multicentre study. No adjustment was made for study centre.

[0754] Multiple comparisons / multiplicity

[0755] No multiplicity adjustments were made.

[0756] Use of efficacy subsets of subjects

[0757] No efficacy subset of subjects was used in this study.

[0758] Active substance-controlled studies to demonstrate equivalence

[0759] This was not an active-controlled study designed to demonstrate equivalence.

[0760] Subgroup Examination

[0761] No subgroup analysis was performed in this study.

[0762] PK, PD, immunogenicity, and efficacy conclusions

[0763] Consistent with the literature and other SLE studies, the majority of study subjects were female. Racial representation in this study was well balanced, with nearly equal percentages of African American and white study subjects.

[0764] TAK-079 exposure increased more than dose proportionally across the dose range tested (45 mg to 135 mg). After the first administration, a 3-fold increase in the dose resulted in a mean C max The increase was approximately 100-fold. This greater than dose-proportional increase in exposure was generally maintained with subsequent dosing intervals.

[0765] The majority of subjects in all dose groups achieved maximum drug concentrations at 108 hours after the first and second doses of TAK-079.

[0766] TAK-079 engages with the CD38 target on CD38+NK cells in a dose-dependent manner after the first dose. All dose groups reached maximum receptor occupancy about 4 to 7 days after drug administration. In the pooled TAK-079 group, CD38+NK cells were depleted of 33.7% change relative to baseline at the end of treatment (Day 85). Throughout the study, subjects receiving placebo treatment did not show a decrease in CD38+NK cells relative to baseline.

[0767] The reduction in absolute PB counts was similar across TAK-079 dose groups. The maximum effect was observed on day 2 after the first dose and reached a mean change of -74.0% in the pooled TAK-079 groups.

[0768] The IgG decrease was most pronounced in the TAK-079 135 mg group, with a maximum mean decrease of 18.8% from baseline. IgA depletion showed a dose-dependent trend, with the maximum mean decreases from baseline achieved in IgA with 45 mg, 90 mg, and 135 mg TAK-079 doses of 11.3%, 17.1%, and 32.6%, respectively. The reduction in IgM concentrations was similar across all dose groups, with the pooled TAK-079 groups having a mean decrease from baseline of approximately 11.3% to 16.7% during the dosing period.

[0769] Changes in autoantibody concentrations did not appear to be dose-dependent and generally did not show strong concordance with changes in total immunoglobulins. The maximum reduction in autoantibody concentrations was a mean decrease of approximately 20% from baseline for all autoantibodies evaluated.

[0770] A total of 5 subjects from each placebo group and TAK-079 treatment group had pre-existing ADA, with an overall mean rate of 23.8%. An additional 5 subjects from the TAK-079 treatment group had treatment-emergent ADA, with an incidence of 23.8%. Immunogenicity was not associated with clinically significant AEs or hypersensitivity reactions, and the dose dependence of immunogenicity could not be assessed due to the limited number of subjects.

[0771] Exploratory efficacy was assessed in this study using four clinical rating scales: CLASI, SLEDAI-2K, PGA, and 44 joint assessment (total tender joint count, total swollen joint count, and total active joint count). No differences were observed between treatment groups for any of these clinical rating scales. When a single CLASI total activity score was assessed, all patients with a baseline CLASI score >10 met responder criteria at the end of treatment, indicating a trend toward more profound responses in patients with higher CLASI scores at baseline.

[0772] Overall, responder analyses of CLASI, SLEDAI-2K, and PGA did not reveal any observable differences among treatment groups.

[0773] Example 4: Safety and Safety Biomarker Assessment

[0774] Exposure

[0775] A summary of study drug exposure and compliance rates is provided in Table 17. A total of 17 subjects were exposed to TAK-079. The mean compliance rate for the placebo group was 80.0%, while the mean compliance rate for the pooled (total) TAK-079 group was 70.6%.

[0776] Due to a variety of factors, including the COVID-19 pandemic (see the “Impact of the COVID-19 pandemic on study subjects” section) and dose suspensions (see the “Dose suspensions” section), many subjects did not receive all 4 doses of study drug. A small number of subjects in each treatment group received all 4 doses of study drug: 2 of 5 subjects in the placebo group, 2 of 6 subjects in the TAK-079 45 and 90 mg groups, and 1 of 5 subjects in the TAK-079 135 mg group.

[0777] Dosage suspension

[0778] Prior to receiving each dose of study drug, subjects underwent an evaluation of dosing criteria based on laboratory evaluations and events of clinical interest as defined in Table 11.

[0779] Overall, the number of dose interruptions was balanced across treatment groups: 3 subjects in the placebo group, 2 subjects in each of the TAK-079 45 mg and 135 mg groups, and 1 subject in the TAK-079 90 mg group had dose interruptions based on laboratory evaluations, and 1 subject in the TAK-079 45 mg group had a dose interruption based on an event of clinical concern.

[0780] AE

[0781] A pre-treatment event (PTE) is defined as any adverse medical event that occurs before the administration of any study drug to a clinical study subject who has given informed consent to participate in the study; the event does not necessarily have a causal relationship with participation in the study.

[0782] An AE is defined as any adverse medical event that occurs in a clinical study subject to whom a drug is administered; it does not necessarily have a causal relationship with this treatment. Therefore, an AE may be any unfavorable and unexpected sign (e.g., clinically significant abnormal laboratory findings), symptom, or disease that is temporarily associated with drug use, regardless of whether it is considered to be drug-related. TEAEs are defined as AEs that occur after receiving a study drug. SAEs are adverse events that result in any of the following outcomes or are considered significant for any other reason: death; initial or prolonged hospitalization; life-threatening experience (risk of immediate death); persistent or significant disability / incapacity; congenital malformations; any events or symptoms described in Table 27. TEAEs are defined as AEs that occur after receiving the first dose of study drug during the treatment period until the end of safety follow-up. In this document, the terms "serious TEAE" and "treatment-emergent SAE" can be considered interchangeable. The severity of TEAEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, grade 1 to 5 definitions. Grade 1 is mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; intervention not indicated. Grade 2 is moderate: minimal local or noninvasive intervention indicated; limitation of age-appropriate instrumental activities of daily living. Grade 3 is severe or medically significant but not immediately life-threatening: hospitalization or prolonged hospitalization indicated; disability; limitation of self-care activities of daily living. Grade 4 is life-threatening consequences: urgent intervention indicated. Grade 5 is death related to the AE.

[0783] Table 27. Takeda's General List of Medically Significant AEs

[0784]

[0785]

[0786] PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0.

[0787] A summary of TEAEs is presented in Table 28.

[0788] Table 28. Summary of TEAEs (Safety Analysis Set)

[0789]

[0790] SAE: serious adverse event; TEAE: treatment-emergent adverse event.

[0791] a Dose modifications include dose interruptions and drug withdrawal.

[0792] The most common TEAEs (occurring in more than 2 subjects in the total TAK-079 group) are presented by SOC and PT in Table 29.

[0793] Table 29. Common (N>2) non-serious TEAEs by SOC and PT (Safety Analysis Set)

[0794]

[0795] MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; SOC: System Organ Class; TEAE: Treatment-emergent adverse event.

[0796] PTs occurring in more than 2 subjects in the total TAK-079 group were included. Subjects were counted once for each PT and SOC.

[0797] Adverse events were coded using MedDRA version 24.0.

[0798] Analysis of AE

[0799] TEAEs were uncommon among study participants. Regardless of causality, the 2 most common TEAEs were nausea and urinary tract infection. No subject in the placebo group reported a TEAE of urinary tract infection, and 4 subjects (23.5%) in the pooled TAK-079 group reported a TEAE of urinary tract infection, and 1 subject in the placebo group (20.0%) reported a TEAE of nausea, and 3 subjects (17.6%) in the pooled TAK-079 group reported a TEAE of nausea (Table 31). Other TEAEs were reported by 2 or fewer subjects.

[0800] The maximum intensity of all TEAEs was CTCAE grade 1 or 2.

[0801] Death, other SAEs, and other significant AEs

[0802] List of deaths, other SAEs, and other significant AEs

[0803] die

[0804] No deaths occurred during the study period.

[0805] Other SAEs

[0806] Two treatment-emergent SAEs occurred during the study: palpitations were reported by one subject in the TAK-079 45 mg group and dyspnea was reported by one subject in the TAK-079 135 mg group (Table 30). Both treatment-emergent SAEs were CTCAE Grade 2, judged to be unrelated to study drug, and had a recovery / resolved outcome. The palpitations event did not lead to any change in study drug, and the dyspnea event led to withdrawal of study drug.

[0807] Table 30. Treatment-emergent SAEs by SOC and PT (Safety Analysis Set)

[0808]

[0809] MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; SAE: Serious Adverse Event; SOC: System Organ Class.

[0810] Subjects were counted once for each PT and SOC.

[0811] Adverse events were coded using MedDRA version 24.0.

[0812] Other significant AEs

[0813] The most common non-serious adverse events (AEs) are presented in Table 31.

[0814] Table 31. Most common non-serious adverse events (AEs) by SOC and PT (Safety Analysis Set).

[0815]

[0816]

[0817]

[0818] MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; AE: Adverse Event; SOC: System Organ Class.

[0819] The safety analysis set included all subjects who were enrolled and received at least 1 dose of study drug.

[0820] Subjects were counted once for each PT and SOC.

[0821] Adverse events were coded using MedDRA version 24.0.

[0822] Frequency threshold for reporting other AEs: >5%

[0823] Drug-related TEAEs

[0824] Overall, 1 subject in the placebo group (20.0%) and 3 subjects in the pooled TAK-079 groups (1 in each dose group) (17.6%) experienced a TEAE that was considered by the investigator to be related to study drug (Table 32).

[0825] Table 32. Drug-related TEAEs by SOC and PT (Safety Analysis Set)

[0826]

[0827] MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; SOC: System Organ Class; TEAE: Treatment-emergent adverse event.

[0828] TEAEs were defined as adverse events occurring after the first dose of study drug during the treatment period until the end of safety follow-up.

[0829] Subjects were counted once for each PT and SOC. Events with missing relationships were included.

[0830] Adverse events were coded using MedDRA version 24.0.

[0831] TEAEs leading to study drug discontinuation

[0832] One (20.0%) subject in the TAK-079 135 mg group reported a TEAE that led to study drug discontinuation. This dyspnea event is further described in the “Other SAEs” section.

[0833] TEAEs leading to dose modification

[0834] Dose modifications in this study consisted of dose interruptions or withdrawals. No subject in the placebo group reported TEAEs leading to dose modifications, while 2 subjects (11.8%) in the pooled TAK-079 groups reported TEAEs leading to dose modifications, including 1 diarrhea TEAE in the TAK-079 45 mg group and 1 dyspnea TEAE in the TAK-079 135 mg group. Dyspnea events were serious, also led to study drug discontinuation, and are further described in the “Other SAEs” section.

[0835] Analysis and discussion of deaths, other SAEs, and other significant AEs

[0836] No subject reported life-threatening or fatal AEs, and 2 subjects reported serious TEAEs. No serious TEAEs were considered related to study drug.

[0837] There were no cases of CRS or local injection site reactions in this study. From a systemic perspective, one subject in the TAK-0791 35 mg group experienced 1 CTCAE Grade 2 TEAE febrile event on the day after the first dose. This event was considered a hypersensitivity reaction. It was considered related to the study drug, did not result in a dose change, was treated with 1000 mg acetaminophen, and had a recovery / resolved outcome.

[0838] Serum chemistry

[0839] No trends in means or changes from baseline were observed in serum chemistry parameters. The higher mean serum creatinine observed in the TAK-079 135 mg group compared to the other treatment groups was driven by 1 subject who had high serum creatinine at baseline, which did not worsen but persisted throughout the study. This subject had underlying chronic kidney disease at study entry.

[0840] There was no shift of >1 CTCAE grade in any serum chemistry parameter from baseline to postbaseline.

[0841] No AEs related to serum chemistry parameters occurred during the study period.

[0842] hematology

[0843] No trends were observed in the means or changes from baseline in hematologic parameters.

[0844] Changes from baseline to >1 CTCAE grade post-baseline for hematologic parameters included a change from baseline grade 0 to worst post-baseline grade 2 for blood neutrophils in 1 subject in the placebo group and 1 subject in the TAK-079 45 mg group, and a change from baseline grade 0 to worst post-baseline grade 2 for blood lymphocytes in 1 subject in the TAK-079 45 mg group.

[0845] No AEs related to hematological parameters occurred during the study.

[0846] Urinalysis

[0847] No trends were observed in the mean or change from baseline in urinalysis parameters, except that the urine protein / creatinine ratio (UPCR) was higher in the TAK 135 mg group than in the other treatment groups. The higher mean UPCR in this treatment group was driven by 2 subjects who demonstrated high UPCR values ​​at baseline, which persisted throughout the study. One of these 2 subjects had been diagnosed with chronic kidney disease at the start of the study.

[0848] Changes from baseline to >1 CTCAE grade post-baseline in urinalysis parameters included a change from baseline grade 0 to worst post-baseline grade 2 in elevated proteinuria in 1 subject in the placebo group, 2 subjects in the TAK-079 45 mg group, and 1 subject in the TAK-079 135 mg group:

[0849] No AEs related to urinalysis parameters occurred during the study period.

[0850] Other laboratory results

[0851] No significant results were observed with respect to other laboratory results.

[0852] Vital signs

[0853] No trends were observed in the means or changes from baseline in vital sign parameters.

[0854] Physical examination

[0855] The physical examination was guided by symptoms and SLE disease. Any significant clinical findings were recorded as AEs (see the "AEs" section for AEs).

[0856] ECG

[0857] No trends were observed in the means or changes from baseline in ECG parameters.

[0858] At baseline, all subjects reported normal or non-clinically significant abnormal ECG results. No subject reported a transition to a clinically significant abnormal post-baseline result at any time point.

[0859] Safety biomarkers

[0860] Biomarkers associated with safety were based on flow cytometric analysis of A167 QTBNK. CD3 + Total T cells, CD8 + Cytotoxic T cells, CD4 + Helper T cells, B cells, and monocytes for safety evaluation related to potential depletion of immune cell populations.

[0861] The overall effect of TAK-079 on cell counts of these cell types was modest and did not appear to differ between doses. + Total CD4 + Helper T cells, B cells, and monocytes showed a mean decrease of less than 20.0% from baseline.+ Cytotoxic T cells demonstrated a maximum mean reduction of 32.8% from baseline, which was observed on day 2 after the first dose and was transient as cell counts returned to baseline prior to dosing on day 22. The placebo group did not demonstrate any significant depletion of any of the aforementioned cell populations.

[0862] Pregnant

[0863] No pregnancies were reported during the study period.

[0864] Safety Conclusion

[0865] Overall, TAK-079 was well tolerated. There were no substantial imbalances in AEs between treatment groups, and no dose-dependent effects or safety issues were identified.

[0866] Seventeen subjects were exposed to TAK-079 during the study period.

[0867] The reported AE events were balanced across placebo and treatment groups and were consistent with the reported safety profiles for each agent (hydroxychloroquine, prednisone, gabapentin, and mycophenolic acid). Infections and cytopenias did not represent clinical problems in this study.

[0868] Urinary tract infection and nausea were reported by 4 subjects each as TEAEs; other TEAEs were reported by 2 subjects or fewer.

[0869] The maximum intensity of all TEAEs was CTCAE grade 1 or 2. There were no life-threatening or fatal AEs.

[0870] Two subjects reported treatment-emergent SAEs, including palpitations reported by one subject in the TAK-079 45 mg group and dyspnea reported by one subject in the TAK-079 135 mg group. Neither was related to study drug. The dyspnea event led to withdrawal of study drug. A total of 4 subjects (1 in each treatment group) experienced TEAEs that were considered by the investigator to be related to study drug.

[0871] There was one case of hypersensitivity reaction and no cases of cytokine release syndrome or injection site reactions.

[0872] There were no clinically significant findings related to laboratory evaluations, vital signs, or ECGs.

[0873] The overall effects of TAK-079 on cell counts of CD3+ total T cells, CD8+ cytotoxic T cells, CD4+ helper T cells, B cells, and monocytes were modest and did not appear to differ between doses.

[0874] Overall, TAK-079 was well tolerated. There were no substantial imbalances in AEs between treatment groups, and no dose-dependent effects or safety issues were identified.

[0875] Discussion and overall conclusions

[0876] discuss

[0877] The main goal of this study is to evaluate the safety and tolerability of TAK-079 in patients with SLE. For this reason, TAK-079 is well tolerated, and no safety issues were identified in this study. The safety profile of TAK-079 is consistent with the safety profile observed in the first human study (TAK-079_101) in healthy volunteers. There is no substantial imbalance in the AE between the treatment groups. The maximum intensity of all TEAEs is CTCAE grade 1 or 2. Four subjects (1 in each treatment group) experienced non-serious TEAEs that the researcher believed were related to the study drug. The SAEs that occurred in the 2 reported treatments were not considered relevant. The most commonly reported adverse AEs were urinary tract infections and nausea, reported by a total of 4 subjects, respectively. There were no cases of CRS or local injection site reactions in this study, and there was 1 case of hypersensitivity. The safety dose suspension between the treatment groups was balanced, and there was no dose-dependent trend of increased safety-related dose suspension in the group treated with TAK-079.

[0878] The secondary objective of this study is to evaluate the PK, PD and immunogenicity of TAK-079 in patients with SLE.TAK-079 exposure appears to increase in a greater than dose ratio within the tested dose range, which is consistent with observations from the first human study (TAK-079-101) and non-clinical studies (TAK-079-10666).The obvious nonlinearity in TAK-079PK is consistent with the target-mediated drug disposal often observed in mAb, and is caused by the combination with abundant cell receptors (such as CD38).Peak concentrations are usually observed 108 hours (4.5 days) after administration, which is consistent with expectations for SC drug administration.Due to limited data, other PK parameters were not evaluated in this study.The concentration-time curves of most subjects are incomplete, which makes it impossible to properly evaluate the drug accumulation after multiple doses and to determine the effect of ADA on exposure.In general, there is a great variability in serum TAK-079 concentrations, and dose suspension, premature termination and excluded samples can confuse the interpretation of PK data.

[0879] The target engagement of TAK-079 on the CD38 antigen was evaluated via the receptor occupancy on CD38+NK cells. Although NK cells are not target cells responsible for the production of autoantibodies, they are abundant in peripheral blood and their receptors are highly expressed, so they serve as alternative PD markers. The target engagement of TAK-079 on CD38+NK cells is dose-dependent, with the peak occupancy rate being consistent with the maximum CD38+NK cell depletion. The receptor occupancy rate did not reach saturation at the tested dose and failed to continue within the dosing interval. The receptor occupancy rate on CD38+NK cells returned to the baseline level consistent with the partial recovery of this cell population when the next dose was administered, which may be beneficial to the cytotoxicity of TAK-079 against cells producing antibodies, because these effector cells are important in driving the ADCC effect.

[0880] Limited reductions in immunoglobulins were observed, with the best responses seen for IgA. The greatest IgG changes were observed at the 135 mg TAK-079 dose, with the other 2 dose levels showing minimal differences compared to the placebo group. Reductions in total immunoglobulins were generally not accompanied by changes in autoantibody concentrations at the individual level, which can be attributed in part to the overall modest immunoglobulin response. In addition, dose suspensions and small sample sizes also confounded the results.

[0881] The therapeutic hypothesis for studying TAK-079 in SLE is based on targeting CD38 expressing cells, such as plasma cells and PB, thereby reducing the production of pathogenic autoantibodies. In this study, subjects must be positive for at least 1 of the following autoantibodies to be enrolled: anti-dsDNA, anti-SmD p, ribonucleoprotein-70, Sjögren's syndrome SS-A or Sjögren's syndrome SS-B. In addition, five other lupus-related autoantibodies were evaluated. The reduction in autoantibodies for which patients were positive at baseline did not appear to be associated with efficacy measures such as those assessed by clinical rating scales such as CLASI, SLEDAI-2K, and PGA of disease, which seems consistent with literature reports (Marks and Tullus (2012) Pediatr. Nephrol. 27 (10): 1855-68; Pisetsky (2020) J. Autoimmun. 110: 102356). The lack of clear consistency may also be due to limited reductions in immunoglobulins due to insufficient plasma cell depletion. Furthermore, given that each autoantibody may have a different pathogenic contribution to disease activity (Dema and Charles (2016) Antibodies (Basel) 5(1):2) and that many subjects are positive for more than 1 autoantibody, more uniform suppression of all autoantibodies in a given patient may be necessary to observe a correlation between autoantibody reduction and clinical improvement. Some subjects experience clinical responses in the absence of PD effects, making it necessary to investigate the potential contribution of additional mechanisms unrelated to the antibody-producing target cells to better understand the link between the downstream pharmacology of targeting CD38 and clinical efficacy.

[0882] Overall, the PD results suggest that the dosing regimen of TAK-079 in SLE could potentially be optimized, such that higher doses and / or more frequent dosing schedules could result in robust PD effects. The observed extent of depletion of CD38-expressing cells (i.e., PB and NK cells) in peripheral blood is consistent with the results from the first human study (TAK-079_101), which provided a reference for dose selection in this study. However, the reduction in total immunoglobulins in SLE was not as large as that in healthy subjects, which may be due to changes in the immune landscape in the disease state.

[0883] The incidence of ADA that emerged during treatment and pre-existing ADA was 23.8%, respectively, resulting in an overall ADA prevalence of 47.6% in this study. No significant association was observed between immunogenicity and PK / PD, efficacy, or safety. The relatively high ADA prevalence in this study may be attributed to the active immune state of patients with SLE autoimmune disease (Faustini et al. (2021) Arthritis Res. Ther. 23 (1): 211-23). ​​In addition, planned interruptions in drug administration may also lead to the development of ADA: 3 of 5 subjects with ADA responses that emerged during treatment had detectable titers after TAK-079 dose suspension. In studies using biologics where treatment is intermittent or includes extended drug holidays, a high frequency of ADA formation in autoimmune patients has been observed (Atiqi et al., (2020) Front. Immunol. 11: 312). The immunogenicity results may also be due in part to the low doses investigated in this study, which are associated with a higher risk of ADA responses (Mok et al. (2016) Expert Opin. Biol. Ther. 16(2):201-11).

[0884] The exploratory objective of this study was to evaluate the effect of repeated administration of TAK-079 on disease activity using various SLE clinical rating scales. The biggest limitation of this study with respect to this objective was that it was not powered enough to assess the significance of clinical scores in each group. In addition, the COVID-19 pandemic resulted in a large number of discontinuations and missed doses, further reducing the number of subjects available for efficacy evaluation within each cohort.

[0885] An additional limitation regarding efficacy exploration endpoints is the relatively high placebo response observed in this study. This phenomenon is not uncommon in SLE studies due to the allowance of concomitant background therapy, the administration of rescue medications, inadequate clinical rating scales, reporter bias, and heterogeneity of the patient population (Mahieu et al. (2016) Lupus 25(10):1122-40). In SLE clinical trials, the use of rescue therapy both interferes with measuring the true effect of the investigational drug and increases the placebo response (Mahieu et al. (2016) Lupus 25(10):1122-40). Although this study was designed to recruit subjects who had an inadequate response to standard SLE background therapy and had not recently experienced a moderate to severe acute attack, all subjects participating in this study received stable SLE background therapy for the duration of the study. Although no background medications were added during the treatment period and the dose of ongoing background medications was not increased, the patients in the study were receiving a variety of different SLE medications and doses, which made it difficult to distinguish the true effect of the investigational drug from the effect of the ongoing background medication. Therefore, it is plausible that stable background medication use contributed to the efficacy results of this study, in which mild to moderate improvements in SLE symptoms were observed in the placebo group regardless of the assessment tool used. The slightly higher mean corticosteroid dose used in the placebo group compared with the 90 mg and 135 mg TAK-079 groups may have further supported the positive results observed in the placebo group.

[0886] There is a lack of consensus among drug developers on the best way to conduct research on the efficacy of SLE. Currently available and most commonly used outcome measures (such as SLEDAI-2K) are mostly designed from observational data sets rather than prospective randomized clinical studies. Therefore, they are not optimally designed to capture multi-organ clinical responses in heterogeneous SLE patient populations (Mahieu et al. (2016) Lupus 25(10): 1122-40). The clinical rating scales used in this study have different advantages and disadvantages. SLEDAI-2K is an effective tool for measuring changes in overall disease activity, but is insensitive to deterioration or improvement of a single organ system (Mahieu et al. (2016) Lupus 25(10): 1122-40; Ohmura (2021) Mod. Rheumatol. 31(1): 20-8). The CLASI is a well-validated tool for assessing cutaneous aspects of the disease other than the classic “rash” that exhibits high specificity but low sensitivity (Klein et al. (2011) Arch. Dermatol. 147(2):203-8); however, the lack of a minimum CLASI requirement as part of the study and the high number of patients with a CLASI<5 limited the availability of this scale during this study and led to a floor effect. 44 Evaluations of joint assessment scales aim to more accurately characterize joint involvement and the benefits of related treatments on the joints. However, this scale was originally developed for patients with rheumatoid arthritis and has not been validated in patients with SLE. Finally, although the PGA is considered the most comprehensive disease activity index (Ohmura (2021) Mod. Rheumatol. 31(1):20-8), in this study it exhibited poor sensitivity, with approximately 70% of study patients in each treatment group meeting responder criteria; of these, 100% of placebo study patients met the PGA responder criteria at the end of treatment.

[0887] In future studies, more severe SLE patient populations with specific clinical manifestations would be more appropriate to assess efficacy and / or proof of mechanism. Enrollment of patients with higher baseline SLEDAI-2K scores and lupus nephritis may help validate the mechanism of action of TAK-079 in reducing anti-dsDNA antibodies, as shown in another SLE study utilizing an anti-CD38 antibody (Ostendorf et al. (2020) N. Engl. J. Med. 383(12):1149-55). In addition, assessment of more targeted biomarkers of cutaneous lupus disease, such as a type I interferon gene signature, would provide a better mechanistic understanding of the trends observed in patients with higher CLASI scores at baseline. Requiring a minimum CLASI score in future studies may also help minimize the floor effect observed in this study and thereby help assess whether patients with more severe skin disease can effectively benefit from TAK-079 treatment.

[0888] Although a potential trend toward more profound CLASI responses was identified in patients with higher baseline scores, there was a lack of relevant PD effects supporting the observed clinically relevant improvements in skin manifestations. This warrants further investigation of the potential contribution of additional mechanisms of TAK-079 that are unrelated to the antibody-producing target cells. More targeted in vitro and in vivo...

Claims

1. A method for treating moderate or severe systemic lupus erythematosus (SLE) in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, The antibody or antigen-binding fragment thereof comprises: a variable heavy chain region comprising 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; and a variable light chain region comprising 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; and The antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

2. A method of reducing the level of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or an antigen-binding fragment thereof, The antibody or antigen-binding fragment thereof comprises: a variable heavy chain region comprising 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; and a variable light chain region comprising 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; and The antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

3. A method of reducing the level of one or more immunoglobulins in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, The antibody or antigen-binding fragment thereof comprises: a variable heavy chain region comprising 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; and a variable light chain region comprising 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; and The antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

4. The method of claim 3, wherein the immunoglobulin is IgA, IgG and / or IgM.

5. A method of reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, The antibody or antigen-binding fragment thereof comprises: a variable heavy chain region comprising 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; and a variable light chain region comprising 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; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg.

6. The method of claim 5, wherein the one or more autoantibodies are selected from anti-dsDNA, anti-SmD p , β-2 glycoprotein 1IgM, ribonucleoprotein-70, Sjögren's syndrome SS-A and Sjögren's syndrome SS-B.

7. The method of any one of the preceding claims, wherein the subject is diagnosed with severe SLE.

8. The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

9. The method of any of the preceding claims, wherein the variable heavy chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 9, and / or the variable light chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 10; Optionally wherein the variable heavy chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9, and / or the variable light chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 10; Optionally wherein the variable heavy chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 9, and / or the variable light chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 10; Optionally, the heavy chain of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 11; and / or the light chain of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 12; Optionally wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human sequence numbering; Optionally, the isolated antibody or antigen-binding fragment thereof is 10 -8 M or greater affinity to human CD38 (SEQ ID NO: 1), and wherein the affinity is measured by a standard Biacore assay; Optionally wherein the variable heavy chain region comprises SEQ ID NO: 9, and the variable light chain region comprises SEQ ID NO: 10; and Optionally, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO:11 and a light chain as shown in SEQ ID NO:

12.

10. The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain; Optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and Optionally wherein the isolated antibody or antigen-binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgG1 antibody.

11. The method of any of the preceding claims, wherein the subject receives one or more background SLE medications, optionally wherein the one or more background SLE medications are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins; and optionally wherein the one or more background SLE medications are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil, and / or mycophenolic acid.

12. The method of claim 11, wherein the one or more background SLE drugs are administered in combination with the antibody or antigen-binding fragment thereof.

13. The method of any of the preceding claims, wherein administration of the antibody or antigen-binding fragment thereof results in a Grade 3 or 4 incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of less than 10%; Optionally wherein the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, infestation, pyrexia, herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / rigidity, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphocytopenia, cardiac disorders, palpitations and dyspnea; and Optionally wherein administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs of maximum intensity Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

14. The method of any of the preceding claims, wherein the antibody, or antigen-binding fragment thereof, is administered at a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, and about 140 mg; and optionally wherein the antibody, or antigen-binding fragment thereof, is administered at a dose of about 45 mg, about 90 mg, or about 135 mg.

15. The method of any one of the preceding claims, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

16. The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition, and optionally wherein the pharmaceutically acceptable composition comprises the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient or stabilizer.

17. The method of any of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO: 11 and a light chain as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks.

18. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof is mazetuzumab.

19. A unit dosage form comprising an isolated antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising a variable heavy chain region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 3, a CDR2 having an amino acid sequence of SEQ ID NO: 4, and a CDR3 having an amino acid sequence of SEQ ID NO: 5; and a variable light chain region comprising a CDR1 having an amino acid sequence of SEQ ID NO: 6, a CDR2 having an amino acid sequence of SEQ ID NO: 7, and a CDR3 having an amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the antibody or antigen-binding fragment thereof at a dose of 40 mg to 140 mg to treat moderate or severe systemic lupus erythematosus (SLE).

20. The unit dosage form of claim 19, wherein the unit dosage form is formulated for subcutaneous administration of the antibody or antigen-binding fragment thereof to treat severe SLE.

21. The unit dosage form of claim 19 or claim 20, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

22. The unit dosage form of any one of claims 19-21, wherein the variable heavy chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 9, and / or the variable light chain region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 10; Optionally wherein the variable heavy chain region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 10; Optionally wherein the variable heavy chain region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 10; Optionally wherein the heavy chain of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 11, and / or the light chain of the antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 12; Optionally wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human sequence numbering; Optionally, the isolated antibody or antigen-binding fragment thereof is 10 -8 M or greater affinity to human CD38 (SEQ ID NO: 1), and wherein the affinity is measured by a standard Biacore assay; Optionally wherein the variable heavy chain region comprises SEQ ID NO: 9, and the variable light chain region comprises SEQ ID NO: 10; and Optionally, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO:11 and a light chain as shown in SEQ ID NO:

12.

23. The unit dosage form of any one of claims 19-22, wherein the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain, optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and Optionally wherein the isolated antibody or antigen-binding fragment is a human IgG antibody, Optionally wherein the human IgG antibody is a human IgG1 antibody.

24. The unit dosage form of any one of claims 19-23, wherein the isolated antibody or antigen-binding fragment thereof is used in combination with one or more background SLE drugs, optionally wherein the one or more background SLE drugs are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins; optionally wherein the one or more background SLE drugs are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil and / or mycophenolic acid; and optionally wherein the unit dosage form further comprises the one or more background SLE drugs.

25. The unit dosage form of any one of claims 19-24, wherein administration of the antibody or antigen-binding fragment thereof results in a Grade 3 or 4 incidence of less than 10% for one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs); Optionally wherein the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, infestation, pyrexia, herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / rigidity, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest and mediastinal disorders, thrombocytopenia, leukopenia, lymphocytopenia, cardiac disorders, palpitations and dyspnea; and Optionally wherein administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs of maximum intensity Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2.

26. The unit dosage form of any one of claims 19-25, wherein the antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, and about 140 mg; and optionally wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 45 mg, about 90 mg, or about 135 mg.

27. The unit dosage form of any one of claims 19-26, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

28. The unit dosage form of any one of claims 19-27, further comprising at least one pharmaceutically acceptable carrier, excipient or stabilizer.

29. The unit dosage form of any one of claims 19-28, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO: 11 and a light chain as shown in SEQ ID NO: 12; and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every 3 weeks for 12 weeks.

30. The unit dosage form of any one of claims 19-29, wherein the isolated antibody or antigen-binding fragment thereof is mazetuzumab.

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