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

Abstract

A method for treating patients with moderate to severe systemic lupus erythematosus (SLE) by subcutaneous administration of an isolated anti-CD38 antibody is disclosed. Also disclosed is a unit dosage form of the anti-CD38 antibody for use in treating patients with moderate to severe SLE.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 375,197, filed September 9, 2022, U.S. Provisional Application No. 63 / 381,128, filed October 26, 2022, U.S. Provisional Application No. 63 / 382,275, filed November 3, 2022, and U.S. Provisional Application No. 63 / 519,535, filed August 14, 2023, the entire disclosures of which are incorporated herein by reference.

[0002] Incorporation by Reference of Electronically Submitted Materials This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML file, created on August 31, 2023, is named 101588-5016-WO Sequence Listing.xml and is 16,384 bytes in size.

[0003] A method for treating patients with moderate to severe systemic lupus erythematosus (SLE) by subcutaneous administration of an isolated anti-CD38 antibody is disclosed. Also disclosed is a unit dosage form of the anti-CD38 antibody for use in treating patients with moderate to severe SLE. [Background technology]

[0004] Systemic lupus erythematosus (SLE) is a severe autoimmune rheumatic disease that has defying efforts to develop effective therapies, and there remains a significant unmet medical need for patients with moderate to severe disease.

[0005] 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) (incorporated herein by reference in their entireties)). The disease is characterized by 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) (incorporated herein by reference in their entireties)). Tissue damage in SLE is primarily caused by these pathogenic autoantibodies through immune complex deposition accompanied by Fc- and complement-mediated inflammation, as well as direct antibody-target interactions. Virtually any organ or system in the body can be affected by SLE.

[0006] The clinical course of SLE is abrupt, with flares of disease activity leading to increasing disability and organ damage over time. For moderate to severe cases, current standard treatments include immunosuppressants (e.g., azathioprine, cyclophosphamide, and mycophenolate mofetil), antimalarials (e.g., hydroxychloroquine and chloroquine phosphate), corticosteroids (e.g., prednisone), and off-label therapies including high-dose intravenous immunoglobulin (IVIg).

[0007] Therapeutic agents used to treat SLE have had limited success in targeting autoantibody production. Short-lived plasmablasts (PBs), plasma cells (i.e., terminally differentiated B cells), and long-lived plasma cells produce characteristic pathogenic autoantibodies and are therefore highly involved in the pathogenesis of SLE. Studies have shown increased PBs in the blood of patients with active SLE (Dorner et al. (2011) Arthritis. Res. Ther. 13(5):p.243 (incorporated herein by reference in its entirety)).

[0008] To avoid the toxicity associated with general immunosuppression, trials using biologics aimed at selective B cell depletion have been developed. However, most of these trials have had disappointing results (Cinquina et al. (2022) Curr. Rheumatol. Res. 3(1):1-3) (incorporated herein by reference in its entirety). These failures, which may be due in part to the heterogeneity of the pathophysiology of SLE, indicate the need for the development of more effective targeted therapies.

[0009] 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 (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 subpopulations, and naive T cells (Burns et al. (2021) Int. J. Mol. Sci. 22(5) (incorporated herein by reference in its entirety)).

[0010] Other studies have confirmed that the levels of CD38-expressing PBs 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 (incorporated herein by reference in their entirety). Daratumumab, a commercially available CD38 antibody approved for the treatment of multiple myeloma, effectively depleted plasma cells and PBs 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 (incorporated herein by reference in their entirety).

[0011] AB79 (the active pharmaceutical ingredient of mezagitamab (also known as TAK-079)) is a fully human IgG1 monoclonal antibody (mAb) that specifically binds to CD38 with high affinity (Kd = 3.5 nM) (U.S. Patent No. 8,362,211, the contents of which are incorporated herein by reference in their entirety). Available first-in-human nonclinical data have demonstrated an acceptable safety profile and promising pharmacodynamic (PD) effects in depleting CD38-expressing target cells (Korver et al. (2019) J. Pharmacol. Exp. Ther. 370(2): pp. 182-196; Fedyk et al. (2020) Br. J. Clin. Pharmacol. 86(7): pp. 1314-1325, the entire contents of which are incorporated herein by reference). AB79 reduces the levels of plasma cells and plasmablasts in blood isolated from healthy subjects and patients with systemic lupus erythematosus (SLE). In SLE, plasma cell populations, including short-lived and long-lived plasma cells, are reduced by 80%. Additionally, the number of cells producing pathogenic autoantibodies, including VH4-34 9G4+ antibodies (70% reduction), anti-Ro antibodies (70% reduction), and anti-dsDNA antibodies (80% reduction), is also reduced.

[0012] The level of unmet need in the treatment of patients with moderate to severe SLE remains high, and therapies with novel mechanisms of action are needed to provide improved efficacy in reducing disease activity, help reduce corticosteroid use, and improve the quality of life of patients with SLE.

[0013] The object of the present invention is to provide a method for treating patients with moderate to severe SLE by subcutaneous administration of AB79 (as the active pharmaceutical ingredient of mezagitamab), a fully human IgG1 mAb that binds to CD38 with high affinity. Summary of the Invention

[0014] Provided herein are methods and unit dosage forms comprising an anti-CD38 antibody or antigen-binding fragment thereof for use in treating patients with moderate to severe SLE.

[0015] In one aspect, the 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 antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. In some embodiments, the subject is diagnosed with severe SLE.

[0016] In another aspect, the invention provides a method of reducing plasmablast and / or plasma cell levels 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, wherein the antibody or antigen-binding fragment thereof comprises a VH region comprising 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 SEQ ID NO: 5, and a VL region comprising 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. In some embodiments, the subject is diagnosed with severe SLE.

[0017] In one aspect, the invention provides a method of reducing immunoglobulin(s) levels 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, wherein the antibody or antigen-binding fragment thereof comprises a VH region comprising 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 VL region comprising 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, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. 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 immunoglobulin(s) in a subject diagnosed with moderate or severe SLE as disclosed herein, wherein the immunoglobulin is IgA, IgG, and / or IgM.

[0019] In one aspect, the 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 antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises (a) a VH 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 (b) a VL 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, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. 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 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, Sjogren's SS-A, and Sjogren's SS-B.

[0021] 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 one or more polypeptide glycosylation, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

[0022] In another aspect, the invention relates to a method disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to 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 to SEQ ID NO: 10, optionally wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to 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 95% identity to SEQ ID NO: 10, optionally wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 9, and / or wherein the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 10, and optionally the heavy chain (HC) of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 11, and / or the light chain (LC) of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 12, optionally 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, and optionally the isolated antibody or antigen-binding fragment thereof -8 and wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10; and optionally, the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0023] In one aspect, the 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, and optionally wherein the human IgG antibody is a human IgG1 antibody.

[0024] In another aspect, the invention provides a method as disclosed herein, wherein the subject receives background SLE medication(s), optionally wherein the background SLE medication(s) is / are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins, and optionally wherein the background SLE medication(s) is / are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil, and / or mycophenolic acid.

[0025] In one aspect, the invention provides a method as disclosed herein, wherein the background SLE drug(s) are administered in combination with the antibody or antigen-binding fragment thereof.

[0026] In another aspect, the invention provides a method disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than a 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4; optionally, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infestation, pyrexia, shingles, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea; and optionally, administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs having a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0027] In one aspect, the invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered at a dosage 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, optionally wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 45 mg, about 90 mg, or about 135 mg.

[0028] In another aspect, the invention provides a method as disclosed herein, wherein the dosage is administered once per week, once every two weeks, once every three weeks, or once every four weeks.

[0029] In one aspect, the 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, optionally the pharmaceutically acceptable composition comprising the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0030] In another aspect, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12, and the antibody or antigen-binding fragment thereof is administered subcutaneously once every three weeks for 12 weeks.

[0031] In one aspect, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

[0032] In another aspect, the invention provides a unit dosage form comprising an isolated antibody or antigen-binding fragment thereof, wherein the unit dosage form comprises a VH 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 VL 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, 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 milligrams to 140 milligrams in the treatment of moderate or severe systemic lupus erythematosus (SLE).

[0033] In one aspect, the invention provides a unit dosage form as disclosed herein, wherein the unit dosage form is formulated for subcutaneous administration of an antibody or antigen-binding fragment thereof in the treatment of severe SLE. In another aspect, the invention provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoforms comprise one or more polypeptide glycosylation, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

[0034] In one aspect, the invention relates to 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 to 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 to SEQ ID NO: 10, optionally wherein the VH region comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 9, and / or the VL region comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 10, optionally wherein the VH region comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 9, and / or the VL region comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 9. and / or the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 12; optionally, 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; and optionally, the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 10; -8 and optionally, the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10; and optionally, the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0035] In another aspect, the 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, 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.

[0036] In one aspect, the 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 medications, optionally wherein the background SLE medication(s) is / are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins, optionally wherein the background SLE medication(s) is / 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 one or more background SLE medications.

[0037] In another aspect, the invention provides a unit dosage form disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than a 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) Grade 3 or 4, optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infestation, pyrexia, shingles, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic, 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 having a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0038] 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 dosage 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, optionally wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 45 mg, about 90 mg, or about 135 mg.

[0039] In another aspect, the present invention provides a unit dosage form as disclosed herein, wherein the dosage is administered once per week, once every two weeks, once every three weeks, or once every four weeks.

[0040] In one aspect, the present invention provides a unit dosage form as disclosed herein, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0041] In another aspect, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12, and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously once every three weeks for 12 weeks.

[0042] In a further aspect, the present invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

[0043] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in 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 immunoglobulin(s) 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 antigen-binding fragment thereof comprises a VH 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 SEQ ID NO: 5, and a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams.

[0044] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in treating moderate or severe systemic lupus erythematosus (SLE), wherein the antibody or antigen-binding fragment comprises a VH region comprising 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 SEQ ID NO: 5, and a VL region comprising 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 SEQ ID NO: 8; and the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams.

[0045] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in reducing plasmablast and / or plasma cell levels in a subject diagnosed with moderate or severe SLE, wherein the antibody or antigen-binding fragment thereof comprises a VH region comprising 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 SEQ ID NO: 5, and a VL region comprising 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 SEQ ID NO: 8, and the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams.

[0046] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in reducing levels of immunoglobulin(s) in a subject diagnosed with moderate or severe SLE, wherein the antibody or antigen-binding fragment comprises a VH 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 SEQ ID NO: 5, and a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. In some embodiments, the immunoglobulin is IgA, IgG, and / or IgM.

[0047] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in reducing the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, wherein the antibody or antigen-binding fragment comprises a VH 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 SEQ ID NO: 5, and a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. 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, Sjogren's SS-A, and Sjogren's SS-B.

[0048] In one aspect, the invention provides a human anti-CD38 antibody or antigen-binding fragment thereof for use in 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 immunoglobulin(s) in the subject is reduced, and / or (iii) the level of one or more autoantibodies in the subject is reduced, wherein the antibody or antigen-binding fragment thereof comprises a VH 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 SEQ ID NO: 5, and a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. 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, Sjogren's SS-A, and Sjogren's SS-B. [Brief explanation of the drawings]

[0049] The objects and features of the present invention may be better understood by referring to the drawings described below.

[0050] [Figure 1] A schematic diagram of the TAK-079-2001 study design is shown. This Phase 1b study compared active mezagitamab in combination with background SLE standard of care with matching placebo across three consecutively 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 (four total doses), a 12-week safety follow-up (FU) period, and a 12-week long-term safety follow-up period. [Figure 2] TAK-079-2001 Study Cohort Review: This phase 1b study compared active mezagitamab in combination with background SLE standard of care with matching placebo across three sequentially enrolled cohorts in a double-blind design, with safety review at the end of each cohort and 3:1 randomization to mezagitamab:placebo. [Figure 3A] The pharmacokinetics (PK) of mezagitamab in patients with SLE demonstrates a nonlinear increase in exposure within the dose range studied. Treatment-specific mean (±SD) serum TAK-079 concentration-time profiles (pharmacokinetic analysis set) are shown, aligned across dosing intervals 1-4. Vertical lines at each nominal time point represent ±SD. The lower SD bar is presented on a semi-logarithmic scale when the mean-SD was ≤0 on the original scale. Unscheduled visits are not included. [Figure 3B] The pharmacokinetics (PK) of mezagitamab in patients with SLE demonstrates a nonlinear increase in exposure within the dose range studied. Treatment-specific mean (±SD) serum TAK-079 concentration-time profiles (pharmacokinetic analysis set) are shown aligned for dosing intervals 1 and 2. Vertical lines at each nominal time point represent ±SD. The lower SD bar is presented on a semi-logarithmic scale when the mean-SD was ≤0 on the original scale. Unscheduled visits are not included. [Figure 4A]Pharmacodynamics of mezagitamab in patients with SLE. Receptor occupancy and population changes in NK cells are shown. Baseline is considered Day 1 of the study. *Day 85 is the end-of-treatment visit. [Figure 4B] Pharmacodynamics of mezagitamab in patients with SLE. Receptor occupancy in plasmablasts (PB) is shown. Baseline is considered Day 1 of the study. *Day 85 is the end-of-treatment visit. [Figure 4C] Figure 1 shows the pharmacodynamics of mezagitamab in patients with SLE. Dose-dependent longitudinal changes in serum IgG levels are shown, expressed as the mean percent change from pretreatment baseline (pharmacodynamic analysis set) ± SD. Baseline is considered study day 1. *Day 85 is the end-of-treatment visit. [Figure 4D] Dose-dependent longitudinal changes in serum IgG levels, expressed as the mean percent change ± SEM from pretreatment baseline, demonstrate the pharmacodynamics of mezagitamab in patients with SLE. Baseline is considered Day 1 of the study. *Day 85 is the end-of-treatment visit. [Figure 5] Percent changes in serum immunoglobulin A (pharmacodynamic analysis set) are shown. Vertical lines at each nominal time point represent SD. Baseline is considered Day 1 of the study. *Day 85 is the end-of-treatment visit. [Figure 6A] Temporal profiles of IgG, autoantibodies, and clinical scores are shown. The decreases in serum IgG and autoantibodies were modest and did not appear to correlate with each other or with clinical response. Data from subjects at the highest tested dose of 135 mg are shown. [Figure 6B] Temporal profiles of IgG, autoantibodies, and clinical scores are shown. The declines in serum IgG and autoantibodies were modest and did not appear to correlate with each other or with clinical response. Data from CLASI responders in the mezagitamab-treated group are shown. [Figure 7A] Figure 1 shows mezagitamab-depleted populations in a largely CD38-dependent manner. Depletion of selected CD38-positive cell populations (labeled) plotted against baseline CD38 expression. [Figure 7B]Figure 8 shows mezagitamab-depleted populations in a largely CD38-dependent manner. Figure 8 shows that 20-cluster TSNE cluster mapping identified after CyTOF analysis reveals distinct populations (as shown in Figures 8A and 8B) that were maintained over the course of the study. [Figure 7C] Figure 1 shows the populations depleted by mezagitamab in a largely CD38-dependent manner. CD38 heatmap expression across the entire study is shown. [Figure 8A] 20 cluster analysis using a phenotypic heat map of PBMCs from mezagitamab-treated patients. [Figure 8B] Labeled TSNE plots are shown. [Figure 9A] Figure 9B shows a 50-cluster analysis of PBMCs from mezagitamab-treated patients. Phenotypic heatmaps and cluster sizes (as % of selected events) are shown. Treatment efficacy assessment identified two clusters with phenotypes consistent with effector-like CD8 T cells (cluster 32, Figure 9B) and CD4 T cells (cluster 34, Figure 9C). p-values ​​for the 135 mg dose compared to placebo were <0.05 (*), 0.01 (**), or 0.001 (***). [Figure 9B] Figure 9C shows a 50-cluster analysis of PBMCs from mezagitamab-treated patients. Treatment efficacy assessment identified two clusters with phenotypes consistent with effector-like CD8 T cells (cluster 32, Figure 9B) and CD4 T cells (cluster 34, Figure 9C). p-values ​​for the 135 mg dose compared to placebo were <0.05 (*), 0.01 (**), or 0.001 (***). [Figure 9C] Figure 9C shows a 50-cluster analysis of PBMCs from mezagitamab-treated patients. Treatment efficacy assessment identified two clusters with phenotypes consistent with effector-like CD8 T cells (cluster 32, Figure 9B) and CD4 T cells (cluster 34, Figure 9C). p-values ​​for the 135 mg dose compared to placebo were <0.05 (*), 0.01 (**), or 0.001 (***). [Figure 10] The pharmacokinetics of mezagitamab in SLE patients showed a nonlinear increase in exposure within the dose range tested. [Figure 11] LS mean change from baseline in CLASI total activity score by treatment group - MMRM (safety analysis set). CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; MMRM: Repeated Measures Mixed-Effects Model. From the MMRM analysis across all post-baseline visits, change from baseline is shown as the outcome, with treatment, visit, and the (treatment x visit) interaction term shown as factors, and baseline value and the (baseline x visit) interaction shown as covariates. The Kenward-Roger method was used to calculate degrees of freedom, and the covariance matrix is ​​based on an autoregressive (1) covariance structure. Vertical lines at each study day represent ± SEM. *Day 85 is the end-of-treatment visit. [Figure 12] Individual CLASI observations (safety analysis set) by baseline total activity score category are shown. CLASI responders demonstrated substantial and clinically meaningful improvement in skin symptoms by the end of treatment. Subgroup analysis of total activity score revealed that all subjects with a baseline CLASI score >10 met responder criteria at the end of treatment. CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index. Baseline is considered day 1 of the study. [Figure 13] LS mean change from baseline in SLEDAI-2K total score by treatment group - MMRM (safety analysis set). MMRM: repeated measures mixed-effects model; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index-2000. From the MMRM analysis across all post-baseline visits, change from baseline is shown as the outcome; treatment, visit, and the (treatment x visit) interaction term are shown as factors; baseline value and the (baseline x visit) interaction are shown as covariates. The Kenward-Roger method was used to calculate degrees of freedom, and the covariance matrix is ​​based on an autoregressive (1) covariance structure. Vertical lines at each study day represent ± SEM. *Day 85 is the end-of-treatment visit. [Figure 14] Individual SLEDAI-2K observations (safety analysis set) by baseline total score category are shown. SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index-2000. Baseline is treated as Day 1 of the study. DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention relates to methods and unit dosage forms for the subcutaneous administration of a therapeutically effective amount of an isolated anti-CD38 antibody to treat patients with moderate or severe systemic lupus erythematosus (SLE).

[0052] SLE is a serious condition characterized by abnormal immune system activity, leading to a variety of clinical symptoms. Treating SLE and identifying novel therapies therefor is challenging due to its genetic and phenotypic heterogeneity, and significant unmet medical needs remain, particularly for patients with moderate to severe SLE (Kiriakidou and Ching (2020) Ann. Intern. Med. 172(11):ITC81-ITC96, incorporated herein by reference in its entirety).

[0053] SLE is characterized by dysregulation of T and B lineage cells and other components of the innate immune system. The disease is characterized by the production of pathogenic autoantibodies against double-stranded DNA (dsDNA), phospholipids, blood cells, and other targets. Tissue damage in SLE is primarily caused by these pathogenic autoantibodies through immune complex deposition accompanied by Fc- and complement-mediated inflammation and direct antibody-target interactions (Rahman and Isenberg (2008) N. Engl. J. Med. 358(9):929-39, incorporated herein by reference in their entireties). Virtually any organ or system in the body can 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, incorporated herein by reference in their entireties).

[0054] The clinical course of SLE is episodic, with flares of disease activity leading to increasing disability and organ damage over time. For moderate to severe cases, the current standard of care includes immunosuppressants (azathioprine, cyclophosphamide, and mycophenolate mofetil), high-dose steroids, and off-label therapies, including intravenous (IV) immunoglobulin for cytopenias. Therapeutic agents used to treat SLE have met with limited success. Short-lived plasmablasts (PBs), plasma cells (i.e., terminally differentiated B cells), and long-lived plasma cells produce characteristic pathogenic autoantibodies and are therefore highly involved in the pathogenesis of SLE.

[0055] Studies have shown an increase in the number of plasmablasts (PBs) in the blood of patients with active SLE (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 (incorporated by reference in their entirety)). CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PBs and plasma cells (Sullivan et al. (2017) Blood 129(22):3033-7 (incorporated by reference in their entirety)) and may be a 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 PBs, followed by natural killer (NK) cells, plasmacytoid dendritic cells, regulatory T cell subpopulations, and naive T cells (Ramaschi et al. (1996) Blood 87(6):2308-13, incorporated herein by reference in its entirety).

[0056] The significantly higher CD38 expression on plasma cells and PBs compared to other immune cells suggests the possibility of selectively depleting these cells with anti-CD38 antibodies. Daratumumab, a commercially available anti-CD38 antibody, effectively depleted plasma cells and PBs 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 (incorporated herein by reference in its entirety)). Intravenous daratumumab has been approved for patients with multiple myeloma (relapsed and newly diagnosed). However, the most frequent adverse reactions (≥20%) associated with daratumumab monotherapy or in combination with standard antimyeloma regimens are infusion-related reactions (IRRs), 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 anaphylactic reactions, which have been reported in approximately 30% of all patients (Darzalex USPI). Importantly, attention must also be paid to daratumumab's interference with certain clinical laboratory assays, which may complicate hemocompatibility testing (Darzalex USPI).

[0057] Other Morphosys antibodies targeting CD38 are known (see, e.g., WO 2006 / 125640, incorporated herein by reference in its entirety, which discloses 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 various reasons. MOR03080 binds to human CD38 and cynomolgus monkey CD38, but with low affinity to human CD38 (Biacore KD = 27.5 nm). OKT10 binds to human CD38 and cynomolgus monkey CD38, but with low / moderate affinity to human CD38 (Biacore KD = 8.28 nm). MOR03079 binds to human CD38 with high affinity (Biacore KD = 2.4 nm), but not to cynomolgus monkey CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD = 10 nm and 56 nm, respectively). In comparison, TAK-079 binds to human CD38 and cynomolgus monkey CD38 with high affinity (Biacore KD = 5.4 nm for human CD38). Furthermore, prior art antibodies have insufficient ADCC and CDC activity.

[0058] The advantage of more efficient ADCC is the ability to deliver anti-CD38 therapeutics as small injections. A safety profile and PD-targeting efficacy were observed following subcutaneous administration of TAK-079 at doses up to 0.6 mg / kg in healthy subjects. A single subcutaneous dose of 0.6 mg / kg of TAK-079 reduced peripheral blood PB levels by more than 90% and NK cell levels by more than 80%, without comparable reductions in monocytes, B cells, and T cells. On average, PB and NK cell levels recovered to 50% of baseline levels 21 days after administration. At this dose, there were no serious adverse events (SAEs), on-study deaths, or adverse events (AEs) leading to study discontinuation (WO2019 / 140410, incorporated herein by reference in its entirety). Further studies have shown that following subcutaneous administration of TAK-079 at doses of 45 mg, 135 mg, 300 mg, or 600 mg to patients with relapsed and / or refractory multiple myeloma (RRMM), no drug-related serious adverse events (SAEs), on-study deaths, or AEs leading to study discontinuation were reported. Administration of TAK-079 dose-dependently reduced plasmablast levels in blood and bone marrow aspirates, as well as plasma cell levels in bone marrow aspirates. In patients with advanced RRMM, TAK-079 also demonstrated early signs of antitumor activity, as evidenced by at least a 50% reduction in disease burden in some patients and long-term disease stabilization in others ( WO 2019 / 186273 , incorporated herein by reference in its entirety). However, the feasibility and efficacy of administering TAK-079 in treating patients with SLE, particularly those with moderate or severe SLE, remains unclear.

[0059] The methods and unit dosages of the present disclosure provide, for the first time, subcutaneous administration of a therapeutically effective dose of an anti-CD38 antibody in treating patients with moderate or severe SLE.

[0060] 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 patients with moderate or severe SLE. In some embodiments, the antibody or antigen-binding fragment for subcutaneous administration comprises a variable heavy chain (VH) region comprising or consisting of SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto), and a variable light chain (VL) region comprising or consisting of SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto). 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 antigen-binding fragment thereof is administered subcutaneously at a dose of 40 milligrams to 140 milligrams.

[0061] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those skilled in the art. The meaning and scope of such terms will be clear. However, in the event of any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. Furthermore, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. The term "or" includes "and / or" unless otherwise specified. Furthermore, the use of the terms "including," "includes," or "comprised" is not limiting. Terms such as "element" and "component" encompass both elements and components that constitute a single unit and elements and components that constitute two or more subunits, unless otherwise specified.

[0062] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the specification, unless otherwise indicated. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients. Commercial enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein.

[0063] All heading and section names are used for clarity and reference purposes only and should not be construed as limiting in any way. For example, those skilled in the art will understand the utility 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 as described herein.

[0064] In order that the present invention may be more readily understood, selected terms are defined below.

[0065] The terms "human CD38" and "human CD38 antigen," as defined herein, refer to the amino acid sequence of SEQ ID NO: 1, or a functional fragment thereof, such as an epitope (Table 1). Generally, CD38 retains 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-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, 2'-phospho-cyclic ADP-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, and T10.

[0066] [Table 1]

[0067] The terms "therapeutically effective amount" and "therapeutically effective dosage" refer to an amount of a therapeutic agent sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof, prevent progression of a disorder, cause regression of a disorder, prevent the recurrence, occurrence, onset, or progression of one or more symptoms associated with a disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., a prophylactic or therapeutic agent) at dosages and for periods of time necessary to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the pharmaceutical agent to elicit a desired response in the individual. A therapeutically effective amount of an antibody or antigen-binding fragment thereof is one in which any toxic or adverse effects of the antibody or antigen-binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0068] The terms "patient" and "subject" include both humans and other animals. Thus, the compositions, dosages, and methods disclosed herein are applicable to both human and veterinary therapy. In one embodiment, the patient is a mammal, e.g., a human.

[0069] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities. For example, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind to antigens other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform, or variant of human CD38 or cynomolgus monkey CD38 may have cross-reactivity to other related antigens from other species (such as CD38 species homologs), for example. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0070] The term "about" refers to a number, degree, volume, or time that is approximately equal to a small variation of up to 10%.

[0071] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering a compound of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the compound of interest from one organ or body part to another. 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.

[0072] The term "pharmaceutical composition" refers to a preparation suitable for administration to a subject and treatment of a disease. When the anti-CD38 antibodies of the present invention are administered as pharmaceuticals to a mammal, e.g., a human, they can be administered "as is" or as a pharmaceutical composition comprising the anti-CD38 antibody in combination with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The pharmaceutical composition can be in the form of a unit dosage form for administering a specific dosage of the anti-CD38 antibody at a specific concentration, amount, or volume. Pharmaceutical compositions comprising an anti-CD38 antibody, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier, are provided. Preferably, the pharmaceutical composition can comprise a unit dosage form according to the present invention, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition can comprise a human anti-CD38 antibody as described herein, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier.

[0073] Traditional antibody structural units typically comprise a tetramer. Each tetramer typically consists of two identical pairs of polypeptide chains, each pair having one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). Human light chains (LC) are classified as kappa and lambda light chains. Heavy chains (HC) are classified as mu, delta, gamma, alpha, or epsilon, defining the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has multiple subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. Thus, "isotype" refers to any of the immunoglobulin subclasses defined by the chemical and antigenic characteristics of their constant regions. The 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.

[0074] The VH and VL regions (approximately 100-110 amino acids in length) each consist of three hypervariable regions called "complementarity-determining regions" (CDRs) and four framework regions (FRs) (approximately 15-30 amino acids in length), arranged from amino terminus to carboxy terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. "Variable" refers to the fact that the CDRs vary extensively in sequence among antibodies, thereby defining unique antigen-binding sites.

[0075] The hypervariable regions generally comprise amino acid residues approximately 24-34 (LCDR1, "L" refers to the light chain), 50-56 (LCDR2), and 89-97 (LCDR3) within the VL region, and amino acid residues approximately 31-35B (HCDR1, "H" refers to the heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) within the VL region (Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (incorporated herein by reference in its entirety)), and / or residues forming the hypervariable loops (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the VL region, and 26-32 (HCDR1), 53-55 (HCDR2), and 96-101 (HCDR3) in the VH region (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917 (incorporated herein by reference in its entirety)).

[0076] When referring to residues within the variable domains (approximately residues 1-107 for the VL region and residues 1-113 for the VH region), the Kabat numbering system is generally used (e.g., Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, incorporated herein by reference in its entirety), with the EU numbering system being used for the Fc region.

[0077] The term "immunoglobulin (Ig) domain" refers to a region of an immunoglobulin having a distinct tertiary structure. Ig domains include VH and VL regions, CDRs, framework regions, constant region domains, and hinge regions. The HC and LC each have constant region domains called the constant heavy (CH) domain and the constant light (CL) domain. In the context of IgG antibodies, each IgG isotype has a constant region containing three CH domains. The carboxy-terminal portion of each HC and LC defines a constant region primarily responsible for effector function. Thus, "CH" domains in the context of IgG are as follows: "CH1" refers to positions 118-220 according to the EU index of Kabat; "CH2" refers to positions 237-340 according to the EU index of Kabat; and "CH3" refers to positions 341-447 according to the EU index of Kabat.

[0078] Another type of Ig domain of the HC is the hinge region. The term "hinge region" refers to a flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain begins at EU position 237. Thus, with respect to IgG, the antibody hinge is defined herein to include positions 221 (D221 in IgG1) to 236 (G236 in IgG1), where the numbering is according to the EU index as in Kabat. For example, in some embodiments relating to the Fc region, the lower hinge is included, and "lower hinge" generally refers to positions 226 or 230.

[0079] "Fc region" refers to a polypeptide comprising the constant region of an antibody excluding the CH1 domain and, in some cases, a portion 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 N-terminal to these domains. For IgA and IgM, Fc may include the J chain. For IgG, the Fc domain includes 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 usually defined to include residues C226 or P230 at its carboxy terminus, with numbering here according to the EU index as in Kabat. In some embodiments, as described more fully below, amino acid modifications are made to the Fc region to, for example, alter binding to one or more FcγR or FcRn receptors.

[0080] CD38 antibody Thus, the present invention provides isolated anti-CD38 antibodies that specifically bind to human and primate CD38 protein, which find use in subcutaneous administration methods and unit dosage forms in treating patients with moderate or severe SLE. The antibodies or antigen-binding fragments thereof used in the present invention bind to both human CD38 protein and primate CD38 protein (particularly primates such as cynomolgus monkeys (Macaca fascicularis, Crab-eating macaques, also referred to herein as "cynos") used in clinical trials).

[0081] "TAK-079" or "mezagitamab," also referred to herein as AB79, is a therapeutic protein comprising a fully human immunoglobulin IgG1 monoclonal antibody that specifically binds to CD38 with high affinity (Kd=3.5 nM) (U.S. Patent No. 8,362,211, the contents of which are incorporated herein by reference in their entirety). The amino acid sequence of mezagitamab is shown in Table 2.

[0082] [Table 2]

[0083] TAK-079 inhibits the growth of CD38-expressing tumor cells by cell depletion via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). TAK-079 also reduces the levels of plasma cells and plasmablasts in blood isolated from healthy subjects and patients with systemic lupus erythematosus (SLE). In SLE, plasma cell populations, including short-lived and long-lived plasma cells, were reduced by 80%. Additionally, the number of cells producing pathogenic autoantibodies, including VH4-34 9G4+ antibodies (70% reduction), anti-Ro antibodies (70% reduction), and anti-dsDNA antibodies (80% reduction), was also reduced. The anti-human CD38 mAb daratumumab also dose-dependently depletes CD38-expressing plasmablasts and plasma cells in samples from patients with SLE and RA in vitro. In contrast to 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 models of autoimmune disease. In healthy cynomolgus monkeys, the efficiency of depletion of lymphocytes, B cells, T cells, and NK cells positively correlated with CD38 expression levels and AB79 dose levels (PCT Application No. PCT / US2017 / 042128; U.S. Patent No. US8,362,211, which are incorporated by reference in their entireties).

[0084] In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof of the present invention interact with CD38 at multiple amino acid residues, including, based on human sequence numbering, K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294. Preferably, the anti-CD38 antibodies or antigen-binding fragments thereof of the present invention interact with CD38 at multiple amino acid residues, which, based on human sequence numbering, may include K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 1. Preferably, the anti-CD38 antibodies or antigen-binding fragments thereof of the present invention interact with CD38 at multiple 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. Note that these residues are identical in both humans and cynomolgus monkeys, with the exception that S274 is actually F274 in cynomolgus monkeys. These residues may represent immunodominant epitopes and / or residues within the footprint of a specific antigen-binding peptide.

[0085] In some embodiments, an anti-CD38 antibody for use according to the 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 a variant of the sequence with up to three amino acid changes. In some embodiments, an antibody for use according to the 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 a variant of the sequence with up to three amino acid changes. In some embodiments, an antibody for use according to the 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), ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 TAK-079), or a variant of the sequence with 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 a variant of the sequence with 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 ARGSLFHDSSGFYFGH (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), ISWNGGKT (SEQ ID NO: 4, HCDR2 TAK-079), 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 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 the CDR sequences 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 to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 85% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 90% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 95% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 97% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 99% sequence identity with SEQ ID NO:9.

[0086] In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO:9.

[0087] 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 the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 85% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 90% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 95% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, with the remainder of the VL region sequence having at least 97% sequence identity to SEQ ID NO:10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, with the remainder of the VL region sequence having at least 99% sequence identity to SEQ ID NO:10.

[0088] In some embodiments, the antibody comprises a LC comprising the VL region amino acid sequence of SEQ ID NO:10.

[0089] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9, or a variant thereof described herein, and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10, or a variant thereof described herein.

[0090] As will be appreciated by one of skill in the art, the VH and VL regions can be linked to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4.

[0091] 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 defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 80% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 85% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 90% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 95% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences 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 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.

[0092] 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 defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 85% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 90% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 95% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise the CDR sequences 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 the CDR sequences 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.

[0093] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO:12.

[0094] In some embodiments, the antibody comprises or consists of an HC amino acid sequence of SEQ ID NO: 11, or a variant thereof described herein, and an LC amino acid sequence of SEQ ID NO: 12, or a variant thereof described herein.

[0095] The present 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. Preferably, the antibody can interact with at least 90% of these amino acid residues. Preferably, the antibody can interact with at least 95% of these amino acid residues. Preferably, the antibody can interact with at least 97% of these amino acid residues. Preferably, the antibody can interact with at least 98% of these amino acid residues. Preferably, the antibody can interact with at least 99% of these amino acid residues. Preferably, the antibody can interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids of SEQ ID NO:1 and SEQ ID NO:2 based on human numbering: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294.

[0096] In some embodiments, the antibody is full length. By "full length antibody" herein is meant the structure that constitutes the natural biological form of an antibody, including variable and constant regions, including one or more modifications as outlined herein.

[0097] Alternatively, antibodies may be of various structures, including, but not limited to, antibody fragments, antigen-binding fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as "antibody conjugates"), and fragments of each of the above. Specific antibody fragments include (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) an Fd fragment consisting of the VH and CH1 domains, (iii) an 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) an isolated CDR region, (vi) an F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, and (vii) a single-chain Fv molecule (scFv) in which the VH and VL domains are linked by a peptide linker that allows these 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 Fvs (WO03 / 11161), and (ix) "diabodies" or "triabodies," which are multivalent or multispecific fragments constructed by gene fusion (Tomlinson et al. (2000) Methods Enzymol. 326:461-479, WO94 / 13804; Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448).

[0098] Preferably, the antibody may be a Fab fragment. Preferably, the antibody may be an Fv fragment. Preferably, the antibody may be an Fd fragment. Preferably, the antibody structure may be an isolated CDR region. Preferably, the antibody may be a F(ab')2 fragment. Preferably, the antibody may be an scFv fragment.

[0099] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention further comprise one or more engineered glycoforms. In some embodiments, the engineered glycoforms comprise one or more glycosylation of the polypeptide. 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.

[0100] In some embodiments, the isolated antibody of the invention is mezagitamab.

[0101] antibody modification The present invention further provides variant anti-CD38 antibodies. There are several modifications that can be made to the antibodies of the present invention, including, but not limited to, amino acid modifications in the CDRs (affinity maturation), amino acid modifications in the VH and / or VL regions, amino acid modifications in the HC and / or LC, amino acid modifications in the Fc region, glycosylation variants, other types of covalent modifications, etc.

[0102] The term "variant" refers to a polypeptide that differs from a parent polypeptide. Amino acid variants can include amino acid substitutions, insertions, and deletions. Generally, as described herein, variants can include any number of modifications, so long as the protein's function remains intact. That is, for example, in the case of amino acid variants generated in the CDRs of TAK-079, the antibody should still specifically bind to both human CD38 and cynomolgus monkey CD38. The term "variant Fc region" refers to an Fc sequence that differs from that of the wild-type or parent Fc sequence by at least one amino acid modification. An Fc variant can refer to the Fc polypeptide itself, a composition comprising the Fc variant polypeptide, or an amino acid sequence. If amino acid variants are generated in the Fc region, for example, the variant antibody should maintain the functionality required for the antibody's particular application or indication. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, e.g., 1-10, 1-5, 1-4, 1-3, and 1-2 substitutions, can be utilized. Suitable modifications can be made at one or more positions, particularly for specific amino acid substitutions that increase binding to Fc receptors, as generally outlined in, for example, U.S. Patent Application 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 patents are expressly incorporated by reference in their entirety).

[0103] Variants can be considered in terms of similarity (ie, amino acid residues having similar chemical properties / functions), and preferably, variants are expressed in terms of sequence identity.

[0104] Sequence comparison can be accomplished with the aid of readily available sequence comparison programs, or usually by eye. These publicly and commercially available computer programs can calculate the percent sequence identity between two or more sequences.

[0105] For example, it may be desirable to have one to five modifications in the Fc region and one to five modifications in the Fv region of a wild-type or engineered protein. The variant polypeptide sequence preferably has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the parent sequence (e.g., the VH or VL region, constant region, and / or HC and LC sequences of TAK-079). Preferably, the variant may have at least 80% sequence identity to the parent sequence. Preferably, the variant may have at least 85% sequence identity to the parent sequence. Preferably, the variant may have at least 90% sequence identity to the parent sequence. Preferably, the variant may have at least 92% sequence identity to the parent sequence. Preferably, the variant may have at least 95% sequence identity to the parent sequence. Preferably, the variant may have at least 97% sequence identity to the parent sequence. Preferably, the variant may have at least 98% sequence identity to the parent sequence. Preferably, the variant may have at least 99% sequence identity to the parent sequence.

[0106] In one embodiment, sequence identity is determined across the entire sequence. In one embodiment, sequence identity is determined across the entire candidate sequence being compared to a sequence listed herein.

[0107] The term "amino acid substitution" refers to the replacement of an amino acid with another amino acid at a specific position in a parent polypeptide sequence. For example, the substitution S100A refers to a variant polypeptide in which the serine at position 100 is replaced with alanine. Preferably, the amino acid substitution can be a conservative amino acid substitution. Preferably, the variant can contain one or more, for example, two or three, conservative amino acid substitutions. Amino acids with similar biochemical properties can be defined as amino acids that can be substituted through conservative substitution.

[0108] Unless otherwise expressly defined herein by reference to specific individual amino acids, amino acids may be substituted using conservative substitutions as listed below. An aliphatic polar uncharged amino acid may be a cysteine, serine, threonine, methionine, asparagine, or glutamine residue. An aliphatic polar charged amino acid may be an aspartic acid, glutamic acid, lysine, or arginine residue. An 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, preferably in the same line in the third column, may be substituted for each other.

[0109] [Table 3]

[0110] The term "amino acid insertion" refers to the addition of an amino acid at a particular position within a parent polypeptide sequence.

[0111] The term "amino acid deletion" refers to the removal of an amino acid at a particular position in the parent polypeptide sequence.

[0112] The terms "parent antibody" and "precursor antibody" refer to an unmodified antibody that is subsequently modified to create a variant. In one embodiment, the parent antibody herein is TAK-079. In one embodiment, the parent antibody herein comprises a VH region having the amino acid sequence of SEQ ID NO: 9 and a VL region having the amino acid sequence of SEQ ID NO: 10. In some embodiments, 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 the amino acid sequence encoding it. Thus, the term "parent Fc polypeptide" refers to an Fc polypeptide that is modified to create a variant.

[0113] The terms "wild type," "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.

[0114] In some embodiments, one or more amino acid modifications are made to one or more CDRs of an anti-CD38 antibody. Generally, no more than 1, 2, or 3 amino acid substitutions are made in any single CDR, and generally no more than 4, 5, 6, 7, 8, 9, or 10 amino acid changes are made within a set of CDRs. However, it should be understood that any combination of none, 1, 2, or 3 substitutions in any CDR can be independently and optionally combined with any other substitution.

[0115] In some instances, amino acid modifications in the CDRs are referred to as "affinity maturation." An "affinity matured" antibody is one with one or more alterations in one or more CDRs that result in improved affinity of the antibody for the antigen, compared to a parent antibody that does not have those alterations. In some instances, it may be desirable to decrease the affinity of an antibody for its antigen.

[0116] Affinity maturation can be performed to increase the binding affinity of an antibody for an antigen by at least about 10%, 50%, 100%, 150%, or more, or 1-5 fold, compared to the "parent" antibody. Preferred affinity-matured antibodies will 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).

[0117] Alternatively, "silent" amino acid modifications, e.g., which do not significantly alter the affinity of the antibody for antigen, can be made to, e.g., one or more CDRs of an antibody of the invention. These can be made for several reasons, including optimization of expression (as can be made to nucleic acids encoding antibodies of the invention).

[0118] Thus, variant CDRs and antibodies are included within the definition of the CDRs and antibodies of the invention, i.e., antibodies of the invention can comprise amino acid modifications in one or more of the CDRs set forth in SEQ ID NOS: 3 to 8. In addition, as outlined below, amino acid modifications can be made independently and optionally in any region other than the CDRs, including the framework and constant regions.

[0119] In some embodiments, a variant antibody of TAK-079 is described that is specific for human CD38 (SEQ ID NO: 1) and cynomolgus monkey CD38 (SEQ ID NO: 2). This antibody is composed of six CDRs, and 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.

[0120] Glycosylation Another type of modification is altered glycosylation. In one embodiment, the antibodies disclosed herein can be modified to contain one or more engineered glycoforms. As used herein, "engineered glycoform" refers to a carbohydrate composition covalently attached to an antibody that is chemically distinct from the carbohydrate composition of the parent antibody. Engineered glycoforms can be useful for a variety of purposes, including, but not limited to, enhancing or reducing effector function. A preferred form of engineered glycoform is afucosylation, which has been shown to correlate with increased ADCC function, likely due to tighter binding to the FcγRIIIa receptor. In this context, "afucosylation" means that the majority of antibodies produced in host cells are substantially devoid of fucose; for example, 90-95-98% of produced antibodies lack appreciable fucose as a component of the antibody's carbohydrate moiety (typically attached to N297 within the Fc region). When defined functionally, afucosylated antibodies generally exhibit at least 50% or greater affinity for the FcγRIIIa receptor.

[0121] Engineered glycoforms can be produced by a variety of methods known in the art (U.S. Pat. No. 8,362,211, incorporated herein by reference in its entirety). Engineered glycoforms typically refer to different carbohydrates or oligosaccharides, and therefore, antibodies can include engineered glycoforms.

[0122] Alternatively, engineered glycoforms can refer to IgG variants that contain different carbohydrates or oligosaccharides. As is known in the art, glycosylation patterns can depend on both the protein sequence (e.g., the presence or absence of specific glycosylated amino acid residues, discussed below) or the host cell or organism in which the protein is produced. Specific expression systems are discussed below.

[0123] Glycosylation of polypeptides is typically 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 recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either 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, although 5-hydroxyproline or 5-hydroxylysine can also be used.

[0124] Addition of glycosylation sites to an antibody is conveniently accomplished by altering the amino acid sequence to include one or more of the above tripeptide sequences (for N-linked glycosylation sites). Alterations may also be made by adding or substituting one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). To facilitate this, the antibody amino acid sequence is preferably altered by changes at the DNA level, specifically by mutating the DNA encoding the target polypeptide at preselected bases to generate codons that translate into the desired amino acids.

[0125] Another means of increasing the number of carbohydrate moieties on an antibody is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling mode used, sugar(s) 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 WO 87 / 05330 and Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp. 259-306, both of which are incorporated by reference in their entireties.

[0126] Removal of carbohydrate moieties present on the starting antibody (e.g., post-translationally) can be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the polypeptide intact. 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 entireties. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved through the use of various endo- and exoglycosidases, as described by Thotakura et al., 1987, Meth. Enzymol. 138:350, incorporated by reference in their entireties. Glycosylation at potential glycosylation sites can be prevented by the use of 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.

[0127] Another type of covalent modification of antibodies involves conjugating the antibody to various nonproteinaceous polymers, including, but not limited to, various polyols such as polyethylene glycol, polypropylene glycol, or polyoxyalkylene, for example, in the manner described in Nektar Therapeutics' 2005-2006 PEG Catalog (available on the Nektar website), U.S. Patent Nos. 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 entireties). 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. Patent Publication No. 2005 / 0114037 A1 (incorporated by reference in their entireties).

[0128] In addition to the modifications outlined above, other modifications can be made. For example, the molecule can be stabilized by the incorporation of disulfide bridges linking the VH and VL domains (Reiter et al. (1996) Nature Biotech. 14:1239-1245, incorporated herein by reference in its entirety). Additionally, there are a variety of covalent modifications of antibodies that can be made, as outlined below.

[0129] Covalent modifications of antibodies are included within the scope of the present invention and are generally, but not always, carried out post-translationally. For example, some types of covalent modifications of antibodies are introduced into the molecule by reacting specific amino acid residues of the antibody with organic derivatizing agents capable of reacting with selected side chains or N- or C-terminal residues.

[0130] In some embodiments, the anti-CD38 antibodies of the invention specifically bind to one or more residues or regions of CD38 but 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.

[0131] Typically, lack of cross-reactivity means less than about 5% competitive inhibition between the molecules as assessed by ELISA and / or FACS analysis using sufficient amounts of the molecules under suitable assay conditions.

[0132] Reduced side effects An adverse event (AE) was defined as any untoward medical occurrence occurring in a clinical investigational subject receiving an investigational drug, which did not necessarily have a causal relationship to this treatment. A treatment-emergent adverse event (TEAE) was defined as an AE that occurred after the first dose of investigational drug administered during the treatment period and continued through the end of safety follow-up. The terms "serious TEAE" and "treatment-emergent SAE" can be considered interchangeable herein. PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0. TEAEs are typically referred to as grades 1, 2, 3, 4, and 5, with grade 1 being the least severe TEAE and grade 5 being the most severe. Based on FDA and other guidelines regarding the Common Terminology Criteria for Adverse Events for Oncology Agents (CTCAE) (see, e.g., https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, and https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / ctc.htm, and Nilsson and Koke (2001) Drug Inform. J. 35:1289-1299, which are incorporated herein by reference in their entireties), the following is how such grades are generally determined: Grade 1 is mild, with no or mild symptoms; clinical or diagnostic findings only; no intervention indicated. Grade 2 is moderate, with minimal, local, or non-invasive intervention indicated; and age-appropriate limitations in activities of daily living ("ADLs"). Grade 3 is severe or medically significant but not immediately life-threatening and indicates hospitalization or prolonged hospitalization; inactivity / incapacity; limiting self-care activities of daily living; Grade 4 is a life-threatening outcome and indicates urgent intervention; Grade 5 is death related to the AE.

[0133] The anti-CD38 antibodies of the present invention allow for reduced side effects compared to prior art anti-CD38 antibodies. In some embodiments, antibodies for use according to the present invention, e.g., TAK-079, do not induce TEAEs. In some embodiments, antibodies for use according to the present invention, e.g., TAK-079, allow for a reduced incidence of TEAEs in a patient population compared to other anti-CD38 antibodies, such as MOR202. In some embodiments, antibodies for use according to the present invention, e.g., TAK-079, allow for a reduction in the grade of TEAEs in a patient population compared to other anti-CD38 antibodies, such as MOR202. In some embodiments, antibodies for use according to the present invention, e.g., TAK-079, allow for a reduction in the grade of TEAEs from Grade 5 to Grade 4 compared to other anti-CD38 antibodies. In some embodiments, antibodies for use according to the present invention, e.g., TAK-079, allow for a reduction in the grade of TEAEs from Grade 4 to Grade 3 compared to other anti-CD38 antibodies. In some embodiments, an antibody for use according to the invention, e.g., TAK-079, compared to other anti-CD38 antibodies, enables a reduction in the grade of TEAEs from Grade 3 to Grade 2. In some embodiments, an antibody for use according to the invention, e.g., TAK-079, compared to other anti-CD38 antibodies, enables a reduction in the grade of TEAEs from Grade 2 to Grade 1.

[0134] In some embodiments, an antibody for use according to the invention, e.g., TAK-079, allows for a reduction in the grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRR), leukopenia, lymphopenia, and nausea. In some embodiments, an antibody for use according to the invention, e.g., TAK-079, allows for a reduction in the occurrence 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.

[0135] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the invention results in less than a 10% incidence of one or more Grade 3 or 4 TRAEs or TEAEs, optionally the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infestation, pyrexia, shingles, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0136] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the invention results in one or more TRAEs or TEAEs having a maximal intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0137] Signs of disease The antibodies or antigen-binding fragments thereof, methods, and dosage units of the invention find use in treating patients with systemic lupus erythematosus (SLE), particularly in treating patients with moderate or severe SLE.

[0138] Systemic lupus erythematosus (SLE) 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 that lead to multiple organ damage and variable clinical symptoms. SLE is defined by either the 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria (https: / / sliccgroup.org / research / sle-criteria / ) or the American College of Rheumatology diagnostic criteria.

[0139] The 2012 SLICC criteria for SLE classification require 1) the fulfillment of at least four criteria, with at least one clinical and one immunological criterion, or 2) lupus nephritis as the only clinical criterion in the presence of ANA or anti-dsDNA antibodies.

[0140] Clinical criteria: (1) acute cutaneous lupus, (2) chronic cutaneous lupus, (3) oral ulcers: palate, (4) non-cicatricial alopecia (diffuse thinning or brittle hair with visible breakage), (5) synovitis involving two or more joints characterized by swelling or effusion or tenderness in two or more joints and morning stiffness for 30 minutes or more, (6) serositis, (7) renal, (8) neurological, (9) hemolytic anemia, (10) leukopenia (at least once, ≥ 4000 / mm 3 or (11) microcytopenia (at least once, ≥ 100,000 / mm 3 less than).

[0141] Immunologic criteria: (1) antinuclear antibodies (ANA) above the laboratory reference range, (2) anti-dsDNA (anti-Sm or anti-Smith) above the laboratory reference range excluding ELISA, (3) antiphospholipid antibodies, (4) low complement, or (5) direct Coombs test in the absence of hemolytic anemia.

[0142] Moderate to severe SLE A subject diagnosed with "moderate SLE" is defined as a subject with a SLEDAI-2K score of 6-8.

[0143] A subject diagnosed with "severe SLE" is defined as a subject with a SLEDAI-2K score of 9-12.

[0144] The SLEDAI-2K disease assessment tool uses 24 items, 16 of which are clinical and 8 of which are based solely on laboratory findings (urinary 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.

[0145] Treating SLE and identifying novel therapies for it is challenging due to its genetic and phenotypic heterogeneity, and there remains a significant unmet medical need, particularly for patients with moderate to severe SLE (Kiriakidou and Ching (2020) Ann. Intern. Med. 172(11):ITC81-ITC96, incorporated herein by reference in its entirety).

[0146] Studies have shown an increase in the number of PBs in the blood of patients with active SLE (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 (incorporated by reference in their entirety)). CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PBs and plasma cells (Sullivan et al. (2017) Blood 129(22): 3033-7 (incorporated by reference in their entirety)) and may be a target for the treatment of SLE. In an ex vivo study of CD38 expression on various immune cells in peripheral blood mononuclear cells (PBs) from patients with SLE, the highest CD38 expression was observed on plasma cells and PBs, followed by natural killer (NK) cells, plasmacytoid dendritic cells, regulatory T cell subpopulations, and naive T cells (Ramaschi et al. (1996) Blood 87(6):2308-13, incorporated herein by reference in its entirety). The significantly higher CD38 expression on plasma cells and PBs compared with other immune cells suggests the possibility of selectively depleting these cells with anti-CD38 antibodies.

[0147] The therapeutic anti-CD38 antibodies of the present invention bind to CD38-positive cells and result in the depletion of these cells through multiple mechanisms of action, including both CDC and ADCC pathways.

[0148] In some embodiments, the 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 antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises (a) a VH 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 SEQ ID NO: 5, and (b) a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 milligrams to 140 milligrams.

[0149] In some embodiments, the invention provides a method for reducing levels 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 antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises (a) a VH 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 SEQ ID NO: 5, and (b) a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 milligrams to 140 milligrams.

[0150] In some embodiments, the invention provides a method of reducing levels of immunoglobulin(s) 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, wherein the antibody or antigen-binding fragment thereof comprises a VH region comprising 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 VL region comprising 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, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 milligrams to 140 milligrams.

[0151] In some embodiments, the invention provides a method 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.

[0152] In some embodiments, the 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 antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises (a) a VH 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 SEQ ID NO: 5, and (b) a VL 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 SEQ ID NO: 8, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 40 milligrams to 140 milligrams.

[0153] In some embodiments, the 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, Sjogren's SS-A, and Sjogren's SS-B.

[0154] In some embodiments, the present invention provides a method as disclosed herein, wherein the subject is diagnosed with severe SLE.

[0155] In some embodiments, the invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms.

[0156] In some embodiments, the present invention provides a method as disclosed herein, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, and the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0157] In some embodiments, the present invention provides a method as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0158] In some embodiments, the present invention provides a method as disclosed herein, wherein the glycosylation is O-linked glycosylation.

[0159] In some embodiments, the invention provides a method 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 to 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 to SEQ ID NO: 10.

[0160] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9.

[0161] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10.

[0162] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9.

[0163] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10.

[0164] In some embodiments, the invention provides a method as disclosed herein, wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:11.

[0165] In some embodiments, the invention provides a method as disclosed herein, wherein the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 12.

[0166] In some embodiments, the present invention provides a method 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.

[0167] In some embodiments, the present invention relates to the methods disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is-8 The present invention provides a method for the preparation of a medicament for the treatment of rhesus malabsorption, wherein the medicament binds to human CD38 (SEQ ID NO: 1) with an affinity at or above the KD of M, wherein the affinity is measured by a standard Biacore assay.

[0168] 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.

[0169] In some embodiments, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0170] In some embodiments, the invention provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain.

[0171] 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.

[0172] 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.

[0173] In some embodiments, the present invention provides a method as disclosed herein, wherein the subject receives background SLE medication(s).

[0174] In some embodiments, the invention provides a method as disclosed herein, wherein the background SLE medication(s) is selected from the group consisting of an immunosuppressant, a steroid, and an immunoglobulin.

[0175] In some embodiments, the invention provides methods as disclosed herein, wherein the background SLE drug(s) is selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil, and / or mycophenolic acid.

[0176] In some embodiments, the present invention provides a method as disclosed herein, wherein a background SLE drug(s) is administered in combination with the antibody or antigen-binding fragment thereof.

[0177] In some embodiments, the invention provides a method 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. 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.

[0178] In some embodiments, the present invention provides a method as disclosed herein, wherein the dosage is administered once per week, once every two weeks, once every three weeks, or once every four weeks.

[0179] In some embodiments, the invention provides a method disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0180] In some embodiments, the present invention provides a method as disclosed herein, wherein the pharmaceutically acceptable composition comprises an isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0181] In some embodiments, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12, and the antibody or antigen-binding fragment thereof is administered subcutaneously once every three weeks for 12 weeks. In some embodiments, the 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 one or more glycosylation of the polypeptide, and wherein the glycosylation is N-linked glycosylation.

[0182] In some embodiments, the present invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

[0183] In some embodiments, the invention provides a method disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in a less than 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4. In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infestation, pyrexia, shingles, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0184] 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 having a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0185] Antibody Compositions for In Vivo Administration Formulations of antibodies or antigen-binding fragments thereof used in accordance with the present invention are prepared for storage by mixing antibodies of the desired purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions (Remington's Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed., incorporated herein by reference in its entirety).

[0186] The formulations herein may optionally contain two or more active compounds for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide an antibody or antigen-binding fragment thereof with additional specificity. Alternatively or in addition, the composition may include a cytotoxic agent, cytokine, growth inhibitory agent, and / or small molecule antagonist. Such molecules are preferably present in combination in amounts effective for the intended purpose.

[0187] In some embodiments, two mezagitamab drug products are developed, designated Process A and Process B, as disclosed herein.

[0188] In one embodiment, the Process A mezagitamab drug product is a clear to opalescent, colorless solution comprising arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and TAK-079 (20 mg / mL) in water for injection (approximate pH 6.5). The Process A placebo is a clear, colorless solution comprising arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection (approximate pH 6.5). The Process A mezagitamab drug product and placebo are supplied in sterile-filled, clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0189] In another embodiment, Process B mezagitamab drug product is made in two strengths: 5 mg / mL or 100 mg / mL. Each strength is a clear to opalescent, colorless to brownish-yellow solution containing mezagitamab in an aqueous solution (approximate pH 5.9) of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection. Process B placebo is a clear, colorless solution containing histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection in an aqueous solution (approximate pH 5.9). Process B mezagitamab drug product and placebo are supplied in aseptically filled, clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0190] Subcutaneous administration The anti-CD38 antibodies described herein, such as TAK-079, can be administered at a sufficient dose to be therapeutically effective, thereby allowing for subcutaneous administration. Subcutaneous administration is the least invasive method of administration and is considered the most versatile and therefore desirable method of administration, which can be used for short-term and long-term treatment. In some embodiments, subcutaneous administration can be accomplished by injection. In some embodiments, if multiple injections or devices are required, the site of injection or device can be rotated.

[0191] Thus, subcutaneous formulations are much easier for patients to self-administer, especially since the formulation may have to be taken periodically throughout the patient's life. Furthermore, the ease and speed of subcutaneous delivery allows for increased patient compliance and faster access to medication when needed. Thus, the subcutaneous formulations of anti-CD38 antibodies provided herein offer substantial advantages over the prior art and address certain unmet needs.

[0192] In some embodiments, the antibodies of the present invention are administered to a subject via a subcutaneous route according to known methods. In some embodiments, the antibodies of the present invention can be administered by subcutaneous injection. In certain embodiments, the subcutaneous formulation is subcutaneously injected into the same site on the patient for repeated or sequential injections (e.g., into the upper arm, anterior thigh, lower abdomen, or upper back). In other embodiments, the subcutaneous formulation is subcutaneously injected into different or rotating sites on the patient. Single or multiple administrations of the formulation can be used.

[0193] 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.

[0194] In some embodiments, antibodies or antigen-binding fragments thereof of the present invention, after subcutaneous administration to a subject, result in depletion of plasmablasts, plasma cells, NK cells, B cells, and / or T cells. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention result in depletion of plasmablasts. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention result in depletion of plasma cells. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention allow increased depletion of NK cells compared to depletion of B cells or T cells. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention allow increased depletion of NK cells compared to B cells, and increased depletion of NK cells compared to T cells. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention allow increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. In some embodiments, antibodies or antigen-binding fragments thereof of the present invention allow increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. Suitably, antibodies or antigen-binding fragments thereof of the present invention bind to CD38 - Compared with cells, CD38 + This may allow for increased cell depletion.

[0195] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention result in a reduction in the level of immunoglobulin(s) 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.

[0196] In some embodiments, the antibodies or antigen-binding fragments thereof of the invention result in a reduction of 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, Sjogren's SS-A, and Sjogren's SS-B.

[0197] In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 50% to at least 80% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 60% to at least 80% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 50% to 70% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 65% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 70% compared to intravenous administration normalized to the same dose.

[0198] In certain embodiments, the bioavailability of an anti-CD38 antibody described herein following 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. Preferably, the bioavailability may be at least 50% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 60% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 70% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 80% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 90% compared to intravenous administration normalized to the same dose.

[0199] In some embodiments, the present disclosure provides methods in which the bioavailability of an antibody of the invention following subcutaneous administration is 50% to 80% compared to intravenous administration normalized to the same dose.

[0200] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 50% compared to intravenous administration normalized to the same dose.

[0201] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 55% compared to intravenous administration normalized to the same dose.

[0202] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 60% compared to intravenous administration normalized to the same dose.

[0203] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 65% compared to intravenous administration normalized to the same dose.

[0204] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 70% compared to intravenous administration normalized to the same dose.

[0205] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 75% compared to intravenous administration normalized to the same dose.

[0206] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the invention after subcutaneous administration is at least 80% compared to intravenous administration normalized to the same dose.

[0207] In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously in a single bolus injection. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously monthly. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every week. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously twice a week. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously daily. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 6 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every 4 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every 2 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every hour. In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is subcutaneously administered once every 3 weeks for 12 weeks.

[0208] In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof disclosed herein are administered subcutaneously at a dose of about 40 milligrams to about 140 milligrams. In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof disclosed herein are 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 antibodies or antigen-binding fragments thereof are administered at a dose of about 45 mg, about 90 mg, or about 135 mg. In some embodiments, the antibodies or antigen-binding fragments thereof are 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.

[0209] Unit dosage form 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: 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 these 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, LCDR1 TAK-079), RDS (SEQ ID NO: 7, LCDR2 TAK-079), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 TAK-079), or variants of these 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, HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4, HCDR2 TAK-079), ARGSLFHDSSGFYFGH (SEQ ID NO: 5, HCDR3 TAK-079), or variants of these sequences with 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 these 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, HCDR1 TAK-079), ISWNGGKT (SEQ ID NO: 4, HCDR2 TAK-079), and ARGSLFHDSSGFYFGH (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), ISWNGGKT (SEQ ID NO: 4, HCDR2 TAK-079), 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: 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), and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO: 9. In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0210] In some embodiments, the antibody comprises an 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 an LC comprising the VL region amino acid sequence of SEQ ID NO: 10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (SEQ ID NO: 10).

[0211] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9, or a variant thereof described herein, and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10, or a variant thereof described herein.

[0212] As will be appreciated by those skilled in the art, the VH and VL regions can be linked to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4. In some embodiments, the antibody comprises an HC having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, with the remainder of the HC having at least 80% sequence identity to SEQ ID NO: 11. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0213] In some embodiments, the antibody comprises an LC having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 80% sequence identity to SEQ ID NO: 12. In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 12).

[0214] 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.

[0215] In some embodiments, the formulation comprising the anti-CD38 antibody is in a unit dosage form. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 40 mg to about 140 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 45 mg to about 135 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 45 mg to about 140 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 40 mg to about 135 mg. In some embodiments, the unit dosage form contains 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.

[0216] In some embodiments, the unit dosage form contains an amount sufficient to administer about a 40 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 45 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 50 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 55 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 60 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 65 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 70 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 75 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about an 80 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about an 85 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 90 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 95 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 100 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 105 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 110 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 115 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 120 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 125 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 130 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 135 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 140 mg dose.

[0217] In some embodiments, unit dosage forms of anti-CD38 antibodies provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents. In some embodiments, the anti-CD38 antibodies are provided as pharmaceutical compositions comprising unit dosage forms according to the invention. Suitably, the pharmaceutical compositions may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents.

[0218] Dosage regimens are adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased in accordance with the exigencies of the therapeutic situation. Compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers, in some embodiments, to physically discrete units suitable as unitary dosages for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0219] The specifications for the unit dosage forms of the present 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 active compounds for the treatment of individuals.

[0220] The effective dosage and administration regimen of the anti-CD38 antibody or antigen-binding fragment thereof used in the present invention depends on the disease or condition to be treated and can be determined by one skilled in the art.

[0221] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg once a week. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg once every two weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg once every three weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 40 mg to about 140 mg once every four weeks.

[0222] Preferably, the dose every three weeks may be about 40 mg. Preferably, the dose every three weeks may be about 45 mg. Preferably, the dose every three weeks may be about 50 mg. Preferably, the dose every three weeks may be about 55 mg. Preferably, the dose every three weeks may be about 60 mg. Preferably, the dose every three weeks may be about 65 mg. Preferably, the dose every three weeks may be about 70 mg. Preferably, the dose every three weeks may be about 75 mg. Preferably, the dose every three weeks may be about 80 mg. Preferably, the dose every three weeks may be about 85 mg. Preferably, the dose every three weeks may be about 90 mg. Preferably, the dose every three weeks may be about 95 mg. Preferably, the dose every three weeks may be about 100 mg. Preferably, the dose every three weeks may be about 105 mg. Preferably, the dose every three weeks may be about 110 mg. Preferably, the dose every three weeks may be about 115 mg. Preferably, the dose every three weeks may be about 120 mg. Preferably, the dose every three weeks may be about 125 mg. Preferably, the dose every three weeks may be about 130 mg. Preferably, the dose every three weeks may be about 135 mg. Preferably, the dose every three weeks may be about 140 mg. Such administrations disclosed herein may be repeated, for example, three to five times. In some embodiments, such administrations disclosed herein may be repeated three times, i.e., every three weeks for a total of nine weeks. In some embodiments, such administrations disclosed herein may be repeated four times, i.e., every three weeks for a total of 12 weeks. In some embodiments, such administrations disclosed herein may be repeated five times, i.e., every three weeks for a total of 15 weeks.

[0223] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered at a 3-week dose of about 40 mg to about 140 mg. Preferably, the 3-week dose can be about 45 mg to about 135 mg. Preferably, the 3-week dose can be about 45 mg. Preferably, the 3-week dose can be about 90 mg. Preferably, the 3-week dose can be about 135 mg. The dosage may be determined or adjusted by measuring the amount of the compound of the present invention in the blood immediately after administration, for example, by collecting a biological sample and using an anti-idiotypic antibody that targets the antigen-binding region of the anti-CD38 antibody.

[0224] In one embodiment, the therapeutic antibody is formulated at a concentration of about 5 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 20 mg / ml. In another embodiment, the therapeutic antibody is formulated 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 into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated 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 into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated 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 into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated 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 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered every two weeks. In some embodiments, the dose is administered every three weeks. In some embodiments, the dose is administered every four weeks.

[0225] In some embodiments, the invention provides a unit dosage form comprising an isolated antibody or antigen-binding fragment thereof, wherein the unit dosage form comprises a VH 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 VL 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, 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 milligrams to 140 milligrams in the treatment of moderate or severe SLE.

[0226] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the unit dosage form is formulated for subcutaneous administration of an antibody or antigen-binding fragment thereof in the treatment of severe SLE.

[0227] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms. In some embodiments, the engineered glycoforms comprise one or more polypeptide glycosylation, wherein 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.

[0228] In some embodiments, the 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 to 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 to SEQ ID NO: 10.

[0229] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9.

[0230] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10.

[0231] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9.

[0232] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10.

[0233] In some embodiments, the 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 having at least 95% identity to SEQ ID NO:11.

[0234] In some embodiments, the 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 having at least 95% identity to SEQ ID NO: 12.

[0235] 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.

[0236] In some embodiments, the present invention provides a unit dosage form of the isolated antibody or antigen-binding fragment thereof disclosed herein, comprising 10 -8 A unit dosage form is provided that binds to human CD38 (SEQ ID NO: 1) with an affinity at or above the KD of M, as measured by a standard Biacore assay.

[0237] 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.

[0238] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0239] In some embodiments, the present invention provides a unit dosage form 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.

[0240] 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.

[0241] In some embodiments, the present invention provides a unit dosage form as disclosed herein, further comprising a background SLE medication(s).

[0242] In some embodiments, the invention provides a unit dosage form disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is used in combination with one or more background SLE medications. In some embodiments, the background SLE medication(s) is / are selected from the group consisting of an immunosuppressant, a steroid, and an immunoglobulin. In some embodiments, the background SLE medication(s) is / 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 medications.

[0243] In some embodiments, the invention provides a unit dosage form disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in a dosage amount 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 antigen-binding fragment thereof is administered in a 40 mg dosage amount. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a 45 mg dosage amount. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a 50 mg dosage amount. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a 55 mg dosage amount. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a 60 mg dosage amount. In some embodiments, the antibody or antigen-binding fragment thereof 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.

[0244] In some embodiments, the present invention provides a unit dosage form as disclosed herein, wherein the dosage is a dose administered once per week, once every two weeks, once every three weeks, or once every four weeks.

[0245] 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.

[0246] In some embodiments, the invention provides a unit dosage form disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than a 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4. In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infestation, pyrexia, shingles, urinary tract infection, skin and skin tissue disorders, headache, fever, chills / chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea. In some embodiments, administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs having a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0247] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12, and the antibody or antigen-binding fragment thereof is administered subcutaneously once every three weeks for 12 weeks. In some embodiments, the 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, and the engineered glycoforms comprise one or more glycosylation of the polypeptide, and the glycosylation is N-linked glycosylation.

[0248] treatment In the methods of the invention, treatment is used to provide a positive therapeutic response with respect to a disease or condition. The term "positive therapeutic response" refers to an improvement in the disease or condition and / or an improvement in symptoms associated with the disease or condition.

[0249] A positive therapeutic response in any given disease or condition can be determined by standardized response criteria specific to that disease or condition. In addition to a positive therapeutic response, the subject receiving treatment may experience the beneficial effect of improving symptoms associated with the disease.

[0250] Measurement of efficacy in treating SLE can be assessed based on SLE disease activity scales according to the SOE study activity tables (Tables 4 and 5, Example 1). SLE disease assessment is based on assessment tools disclosed in Example 1, including, but not limited to, the SLEDAI-2K disease assessment tool, Cutaneous Lupus Erythematosus Disease Area and Severity Index, 44-joint assessment, and Physician Global Assessment of Disease (visual analog scale).

[0251] Treatment according to the invention involves the use of a "therapeutically effective amount" of a pharmaceutical agent. The terms "therapeutically effective amount" and "therapeutically effective dosage" refer to an amount of a therapeutic agent that is sufficient, at dosages and for periods of time necessary to achieve the desired therapeutic result, to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof, to prevent progression of a disorder, to cause regression of a disorder, to prevent the recurrence, occurrence, onset, or progression of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., a prophylactic or therapeutic agent). A therapeutically effective amount may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the pharmaceutical agent to elicit a desired response in an individual. A therapeutically effective amount is also one in which any toxic or adverse effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

[0252] Anti-CD38 antibody kit In another aspect of the present invention, kits for treating SLE are provided. In some embodiments, kits for treating moderate or severe SLE are provided. In some embodiments, kits for treating severe SLE are provided. In one embodiment, the kit includes a dose of an anti-CD38 antibody described herein, such as TAK-079. In one embodiment, the kit includes a dose of an anti-CD38 antibody described herein, such as mezagitamab. In some embodiments, the kits provided herein may include one or more doses of a liquid or lyophilized formulation provided herein. When the kit includes a lyophilized formulation of an anti-CD38 antibody described herein, such as TAK-079, the kit generally also includes a liquid suitable for reconstitution of the liquid formulation, such as sterile water or a pharmaceutically acceptable buffer. In some embodiments, the kit may include an anti-CD38 antibody formulation described herein pre-filled into a syringe for subcutaneous administration by a healthcare professional or for home use.

[0253] In certain embodiments, the kit is for a single administration or dose of an anti-CD38 antibody described herein, such as TAK-079. In other embodiments, the kit may include multiple doses of an anti-CD38 antibody described herein, such as TAK-079, for subcutaneous administration. In one embodiment, the kit may include an anti-CD38 antibody formulation described herein pre-filled into a syringe for subcutaneous administration by a healthcare professional or for home use.

[0254] manufactured goods In other embodiments, an article of manufacture containing materials useful for treating the above-mentioned disorders is provided. The article of manufacture includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed from a variety of materials, such as glass or plastic. The container holds a composition effective for treating a condition and can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agent in the composition is an antibody. A label on or associated with the container indicates that the composition is used for treating the condition of choice. The article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. [Example]

[0255] 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 Study objectives and research plan This phase 1b, double-blind, placebo-controlled, multicenter study evaluated the safety, pharmacokinetics, and pharmacodynamics of mezagitamab in a study population receiving investigator-initiated standard background therapy for moderate to severe SLE.

[0256] The primary objective of this study was to evaluate the safety and tolerability of TAK-079 compared with matching placebo administered once every 3 weeks over a 12-week treatment period in subjects with active SLE receiving stable background therapy for SLE.

[0257] Secondary objectives of this study were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of TAK-079 administered over a 12-week treatment period.

[0258] Exploratory objectives were to assess the effect of repeated doses of TAK-079 on SLE disease activity using clinical assessment scales and biomarkers.

[0259] This Phase 1b trial was designed to evaluate the safety, PK, PD, and immunogenicity of TAK-079. Additionally, the study was designed to better understand the mechanism and evidence of potential biological activity of TAK-079 in a patient population with specific and measurable clinical symptoms of SLE. This study design allowed subjects to continue their supervised SLE background therapy under medical supervision while evaluating the benefit / risk of TAK-079 as an investigational add-on therapy.

[0260] This study compared active TAK-079 in combination with background SLE standard of care versus a matching placebo across three sequentially enrolled cohorts in a double-blind design (Figures 1 and 2). Subjects were randomized 3:1 within each cohort to receive either (1) TAK-079 administered as a subcutaneous (SC) injection every 3 weeks for 12 weeks (four total doses) or (2) a matching placebo administered by the same route and schedule. With the goal of enrolling eight subjects per cohort, six subjects were randomized to receive TAK-079 and two subjects were randomized to receive TAK-079-matching placebo. On each dosing day, subjects returned for post-dose assessments as outlined in Tables 4 and 5.

[0261] After the 12-week treatment period, subjects were evaluated for an additional 12-week safety follow-up period, completing safety visits every 4 weeks, with this post-treatment study period concluding with a safety visit at Week 24. Based on clinical evaluation at this visit, subjects could have completed the study or (based on the study exit criteria outlined in Table 13) progressed to a long-term safety follow-up period for an additional 12-week on-study safety monitoring period, during which end-of-study parameters that were not met and deemed study-relevant by the principal investigator continued to be evaluated and followed as outlined in the "End-of-Study Evaluations" section.

[0262] Sequential enrollment of double-blind cohorts allowed for evaluation of TAK-079 dosing in a stepwise double-blind design. Additionally, the double-blind design supported unbiased safety and tolerability assessments of active TAK-079 and matching placebo for PK, PD, immunogenicity, and efficacy endpoints, as well as within- and cross-cohort analyses. (See Figure 2.)

[0263] Selection of study population The study population was restricted to subjects with SLE who exhibited moderate to severe disease with persistent disease activity and had not responded adequately to standard SLE background therapy treatment, but who had not recently had a moderate to severe acute flare. All subjects had to be positive for anti-dsDNA antibodies and / or anti-extractable nuclear antigen (ENA) antibodies.

[0264] Based on findings from the first-in-human (FIH) study (TAK-079-101), most subjects will have detectable CD38 expression. CD38 expression levels (quantified by molecular equivalent soluble fluorochrome [MESF]) on PB cells were assessed in samples obtained from healthy subjects at screening in the TAK-079-101 study. A total of 129 evaluable subjects were analyzed for CD38 expression, of which 100% had detectable levels of CD38. CD38 expression levels in these healthy subjects ranged approximately fivefold from 693,474 MESF units to 3,531,222 MESF units, with a mean of 1,747,840 MESF units. The lowest CD38 expression was approximately seven-fold higher than background, indicating that healthy subjects express high levels of CD38 on the surface of peripheral blood PB.

[0265] Inclusion criteria Subjects eligible for enrollment in this study had to meet the following criteria: (a) the subject understood and consented to study participation by providing a signed and dated written ICF and any necessary privacy authorizations prior to the start of any study procedures (if applicable, the subject's legally acceptable representative may provide the written ICF in accordance with local and regional regulatory requirements) and, in the investigator's opinion, was able to comply with the protocol requirements; (b) the subject was between 18 and 75 years of age at the time of signing the study ICF; (c) the subject was diagnosed with systemic lupus erythematosus according to either the 2012 International Collaborating Clinic Criteria for Systemic Lupus Erythematosus or the American College of Rheumatology diagnostic criteria; (d) the subject had a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 6 or greater; (e) the subject was positive for anti-dsDNA and / or anti-ENA antibodies; (f) the subject was receiving current concomitant medications consistent with the medication restrictions and limits outlined in Tables 7 and 8, and in the investigator's best medical judgment, the subject was deemed likely to be able to maintain dosages consistent with protocol restrictions throughout the study drug administration period unless excluded by toxicity or the need for protocol-defined rescue therapy; (g) the subject met and / or agreed to the following contraceptive requirements:

[0266] Male contraception requirements: (i) if male infertile, or (ii) if not male infertile, agreed to (1) remain abstinent or (2) use appropriate contraception, including condoms with spermicide, from the first day of study drug administration until 90 days or 5 half-lives (whichever is longer) after the last dose of study drug. No restrictions were required for male subjects who had undergone vasectomy, provided that they had undergone at least 1 year of bilateral post-vasectomy treatment before the first day of study drug administration. Male subjects who had undergone vasectomy less than 4 months before the first day of study drug administration must adhere to the same restrictions as non-vasectomized men. Appropriate documentation of surgical procedures was provided. Subjects agreed not to donate sperm from the first day of study drug administration until 90 days or 5 half-lives (whichever is longer) after the last dose of study drug.

[0267] Contraception Requirements for Women: (i) Women of Childbearing Potential: (1) Female subjects of childbearing potential had to agree to remain abstinent or use double-barrier contraception consisting of a medically acceptable method (e.g., implant, injectable, oral contraceptive, intrauterine device) as defined by the study protocol, and had to use contraception from the time of signing the ICF until 90 days or 5 half-lives (whichever was longer) after the last dose of study drug; or (ii) non-childbearing women were defined as meeting at least one of the following criteria: (1) postmenopausal (defined as 12 months of spontaneous amenorrhea in women with serum follicle-stimulating hormone levels greater than 40 mIU / mL) and required adequate documentation of follicle-stimulating hormone levels; (2) surgically sterilized by hysterectomy and / or bilateral oophorectomy with adequate documentation of surgical procedure; (3) underwent tubal ligation with adequate documentation of surgical procedure; or (4) have a congenital condition that results in the absence of a uterus.

[0268] Exclusion criteria Subjects meeting any of the following criteria were ineligible for study enrollment: (a) The subject had participated in another clinical trial within 4 weeks or 5 half-lives (whichever was longer) of study drug administration prior to the screening visit (this 4-week time frame was derived from the date of the last study procedure and / or the date of an adverse event (AE) related to a study procedure in the previous study to the screening visit for the current study). (b) The subject had a positive pregnancy test. (c) The subject was currently lactating / breastfeeding or planned to breastfeed during the study (including during the 12-week safety follow-up period of the study). (d) The subject had a history of chronic alcohol or drug abuse within 12 months prior to the screening visit. (e) The subject had a history of malignancy (excluding successfully treated basal cell carcinoma, squamous cell carcinoma, or cervical intraepithelial neoplasia) within 5 years prior to the screening visit. (f) Subject had chronic obstructive pulmonary disease (COPD) or asthma with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal. Note: FEV1 testing was required for subjects suspected of having COPD or asthma. (g) Subject had major surgery and / or donated or lost one or more units of blood (approximately 500 mL) within 4 weeks prior to the screening visit. (h) Subject had had an opportunistic infection within 12 weeks prior to first study drug administration or was currently receiving treatment for a chronic opportunistic infection such as tuberculosis (TB), cystic pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria. (i) Subject currently or recently had an acute or chronic infection requiring one or more of the following interventions: (1) Hospitalization within 30 days prior to the screening visit, or (2) administration of parenteral (IV or intramuscular) antibacterial, antiviral, antifungal, or antiparasitic medication within 30 days prior to the screening visit.(j) Subjects had a positive T-cell interferon-gamma release assay (TIGRA) (obtained by QuantiFERON TB Gold test or T-Spot / Elispot) (analyzed by local laboratory) at the time of the screening visit, noting that: (1) if the TIGRA test was unavailable, the purified protein derivative skin test could be used as an alternative, or (2) subjects with an indeterminate TIGRA result had to meet the following criteria: (i) a negative purified protein derivative skin test (defined as an induration less than 5 mm), or (ii) a chest x-ray within 6 months prior to the screening visit consistent with low risk of contracting TB (e.g., avoided close contact with TB-positive individual(s)) and / or no evidence of latent or active TB. (k) Subjects had drug-induced SLE or any other rheumatic or autoimmune disease (excluding secondary Sjögren's syndrome or mixed connective tissue disease). (l) The subject required therapeutic intervention for active neuropsychiatric SLE within 60 days prior to the first study drug administration, as indicated by, but not limited to, the following: (1) new or worsening impaired level of consciousness, (2) psychosis, (3) delirium or confusion, (4) grand mal epilepsy (including status epilepticus), (5) aseptic meningitis, (6) ascending or transverse myelitis, or (7) chorea, cerebellar ataxia, or demyelinating syndrome. (m) The subject had active glomerulonephritis (i.e., concurrent acute renal flare or documented acute renal flare that required lupus nephritis induction therapy within the past 3 months) that met at least one of the following criteria: (1) proteinuria (greater than 3000 mg protein / 24 hours), (2) a urine protein-to-creatinine ratio of greater than 300 mg / mmol, or (3) a urine protein-to-creatinine ratio of 30 mL / min / 1.73 m. 2(n) Subjects had at least one of the following laboratory values: (1) alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal, (2) total bilirubin greater than 1.5 times the upper limit of normal (Note: Subjects with a confirmed diagnosis of Gilbert's syndrome documented in the subject's medical record were not excluded based on this criterion), (3) platelets 75,000 / mm 3 (4) neutrophil count is less than 1500 / mm 3 (5) hemoglobin less than 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 had an intercurrent medical condition that, in the investigator's opinion, could confound the interpretation of the results or affect the subject's ability to fully participate in the study. (q) The subject had a history of a severe allergic or anaphylactic reaction to recombinant proteins or excipients used in the TAK-079 formulation.

[0269] Exclusion of subject from treatment or evaluation Laboratory findings that resulted in the temporary withholding or permanent discontinuation of TAK-079 administration are outlined in Table 11. Subjects with these or other clinical findings, and in the opinion of the principal investigator that continued TAK-079 administration might expose the subject to undue risk, were immediately withheld from further TAK-079 administration and continued to be followed for safety. In such cases, TAK-079 could be resumed in consultation with the study medical monitor (MM) and in accordance with the dosing criteria defined by the protocol.

[0270] Treatment with the investigational product could be permanently discontinued for any of the following reasons: (a) AEs and / or serious adverse events (SAEs), (b) subject withdrawal, (c) protocol violation, (d) sponsor-initiated study withdrawal, (e) loss to follow-up, or (f) other.

[0271] At the time of study drug discontinuation, all study procedures outlined for follow-up were completed as specified in the Schedule of Events (SOE) (Tables 4 and 5). Subjects who discontinued study drug were asked whether they would like to allow follow-up assessments. If a subject completely withdrew consent, no further follow-up assessments were completed. The primary reason for study drug discontinuation was recorded on the electronic case report form (eCRF).

[0272] [Table 4-1]

[0273] [Table 4-2]

[0274] [Table 5]

[0275] Collection of demographic and medical history data A complete medical history was compiled for each subject during the screening period (i.e., within 28 days prior to Study Day 1), including assessment and documentation of prior medical history, comorbidities, and concurrent therapies. This included assessment of current SLE signs, symptoms, and morbidities as assessed and scored by disease activity tools and previous and current SLE therapies (see "Efficacy Measures" section). Demographics included the subject's date of birth, race, ethnicity, and sex during screening.

[0276] treatment Administration of treatment TAK-079 or matching placebo was administered as a single SC injection every 21 days (i.e., 3 weeks) for 12 weeks as part of each study cohort for a total of four doses. Subjects in Cohorts A, B, and C received 45, 90, and 135 mg of TAK-079 or matching placebo, respectively.

[0277] The selection of the dose and dosing frequency of TAK-079 was based on a comprehensive review and analysis of data obtained from: (1) administration of TAK-079 to healthy subjects (Study TAK-079-101), (2) non-clinical repeat-dose TAK-079 studies in cynomolgus monkeys (TAK-079-10015, TAK-079-1018, and TAK-079-10019), and (3) repeat-dose administration of daratumab (Daralex®), a related anti-CD38 cytolytic antibody approved for the treatment of multiple myeloma.

[0278] Based on the favorable safety profile and PD target effect (i.e., sustained reduction in PB) observed after administration of the 0.6 mg / kg dose to healthy subjects, a starting dose of 45 mg was selected for the first dosing cohort (i.e., Cohort A) (Study TAK-079-101). A single SC dose of the 0.6 mg / kg dose resulted in a greater than 90% reduction in PB levels and a greater than 80% reduction in NK cell levels in peripheral blood, with no comparable reduction in monocytes or B and T cells. PB and NK cell levels, on average, recovered to 50% of baseline levels 21 days after dosing. At this dose, no SAEs, on-study deaths, or AEs leading to study discontinuation were reported. No notable findings on clinical laboratory tests, electrocardiograms (ECGs), vital signs, or physical examinations related to TAK-079 administration were reported. Two subsequent dosing cohorts were planned at a 90 mg dose (a 2-fold increase from the first dose cohort) and a 135 mg dose (a 50% increase from the previous cohort). Because patients with lupus typically exhibit PBs that express higher levels of CD38 than those seen in healthy study subjects, higher doses may be required to achieve comparable PD efficacy, and subjects were closely monitored to maintain the benefit / risk balance.

[0279] Identification of investigational drug The study drug was provided as 100 mg of TAK-079 in 1 mL of an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and pH 5.9 buffer (100 mg / mL) and administered as a single SC injection (Table 6).

[0280] [Table 6]

[0281] Packaging, Labeling, and Storage TAK-079 drug product and matching placebo were supplied in aseptically filled clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0282] Supplies of TAK-079 and matching placebo were labeled according to current ICH guidelines for GCP and good manufacturing practice and included local required statements.

[0283] TAK-079 and matching placebo were stored according to manufacturer's instructions as specified on the label and kept in the original container until dispensing. A temperature log of the drug storage area was kept daily.

[0284] Test Reference Product Composition The matching placebo product consisted of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and pH 5.9 buffer administered by SC injection according to the same procedure as the TAK-079 drug product. Process B mezagitamab drug product is produced in two strengths: 5 mg / mL or 100 mg / mL. Each strength is a clear to opalescent, colorless to brownish-yellow solution containing mezagitamab in an aqueous solution (approximate pH 5.9) of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection. Process B placebo is a clear, colorless solution containing histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection in water (approximate pH 5.9). Process B Mezagitamab drug product and placebo will be supplied in aseptically filled clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0285] How subjects were assigned to treatments The allocation of study subjects to one of two study arms within each sequentially enrolled cohort was maintained by a blinded randomization schedule generated and maintained by an interactive voice / web response system (IXRS).

[0286] Selection and timing of dose for each subject Because infusion reactions and other antibody-mediated hypersensitivity reactions have been reported with other biologic agents, it was possible that similar AEs could occur after treatment with TAK-079. Premedication was mandatory for all patients before each study drug administration to prevent potential infusion-related reactions (IRRs). If deemed clinically necessary, post-administration medication should have been administered at the investigator's discretion to further minimize delayed IRRs.

[0287] Premedication On each dosing day, 1-3 hours prior to TAK-079 administration, subjects were premedicated with a regimen consistent with, but not limited to, (1) antipyretic: oral acetaminophen (650-1000 mg) and (2) antihistamine: oral or IV diphenhydramine (25-50 mg, or equivalent). The clinical site was responsible for procuring premedication as outlined in the protocol.

[0288] Administration of investigational drug After subjects were premedicated, TAK-079 doses or matching placebo were administered as SC injections via syringe up to a volume of 2 mL to ensure the full scheduled dose was administered. The time and anatomical site of SC injection were recorded for each dose, and injection sites were rotated for each dose (abdomen, thigh, arm, and upper buttock injection sites were acceptable).

[0289] Medication after administration If deemed clinically necessary and at the discretion of the principal investigator, subjects could receive low-dose methylprednisolone (less than 20 mg) to prevent delayed infusion-related reactions.

[0290] Subjects at higher risk of respiratory complications (e.g., subjects with a history of COPD and subjects with asthma) may be administered (at the investigator's discretion) the following after each study drug administration to further prevent IRR: (a) an antihistamine (diphenhydramine or equivalent) on days 1 and 2 after study drug administration, (b) a short-acting beta-2 adrenergic receptor agonist such as salbutamol (albuterol) aerosol, or (c) a control medication for pulmonary disease, e.g., (i) for subjects with asthma, an inhaled corticosteroid with or without a long-acting beta-2 adrenergic receptor agonist, or (ii) for subjects with COPD, a long-acting bronchodilator such as tiotropium or salmeterol with or without an inhaled corticosteroid. Based on the new data, Takeda's physicians / investigators were able to intensify treatments administered before or after TAK-079 injection to ensure subject safety.

[0291] Blinding Randomization and dosing schedules were generated and maintained by IXRS. All randomization information was stored in a secure location accessible only to authorized personnel.

[0292] To maintain the integrity of the study, all study personnel, including the principal investigator, site personnel, contract research organization MM, clinical trial clinicians, and sponsor, were blinded to treatment assignment during the treatment period. Treatment assignment was captured by IXRS according to procedures outlined in the study manual. Information regarding treatment assignment was securely stored at Takeda or the trial sponsor's location according to their standard operating procedures.

[0293] Records of subject number, date of study drug administration, and treatment assignment were maintained by the study site.

[0294] Emergency unblinding was performed by IXRS when necessary. No emergency unblinding occurred during this study.

[0295] After all subjects in Cohort A and Cohort B completed the study and all data were source-data verified, the treatment assignments of Cohort A and Cohort B were unblinded. At the time of unblinding, this was deemed appropriate because (1) all subjects in Cohort A and Cohort B had terminated their participation in the study (i.e., completed the study or discontinued it early), (2) the ongoing Cohort C followed a separate randomization schedule and was therefore unaffected, (3) information gathered in this interim analysis was unlikely to introduce bias into the ongoing Cohort C due to the small size of this early-phase study, and (4) the initial statistical analysis plan (SAP) was finalized and approved.

[0296] Prior and concomitant therapy Background SLE therapy Eligible subjects received background SLE therapy for ≥12 weeks (≥8 weeks of stable dosing) prior to screening. At enrollment in the study, subjects remained on background therapy throughout study participation, managed by the principal investigator in accordance with local institutional practice and consistent with the clinical trial protocol. Ongoing background SLE therapy at the time of screening was recorded on the eCRF, and any changes to this therapy were also recorded.

[0297] Rescue therapy Rescue therapy was defined as the additional administration of concomitant medications according to institutional practice standards or physician's best medical judgment to control and manage the underlying SLE condition.

[0298] Subjects continued to receive stable doses of immunosuppressive and corticosteroid therapy throughout the study. Reductions in immunosuppressant doses due to toxicity were permitted at the investigator's discretion. Increases, additions, or changes in background immunosuppressive therapy, if deemed necessary by the principal investigator to treat SLE symptoms, or the addition of medications not otherwise within the protocol limits, would result in the discontinuation of study drug administration to subjects and progression to safety follow-up, classifying these subjects as study non-responders.

[0299] Note: Subjects who required an increase in corticosteroid dose above 0.5 mg / kg / day (or 40 mg / day prednisone) or equivalent for control of SLE activity or management of a new SLE flare during the study were discontinued from study drug. Prednisone dose or equivalent could be increased to a dose of 0.5 mg / kg / day or 40 mg / day (whichever was lower). However, the dose was to be tapered to the pre-flare level or 20 mg / day (whichever was higher) within 4 weeks. If tapering was not possible and a higher dose was required to treat SLE symptoms, the subject was discontinued from study drug, progressed to safety follow-up, and designated a study non-responder.

[0300] Excluded drugs and drugs with dosage restrictions Excluded medications and dose-limiting concomitant medications are provided in Tables 7 and 8.

[0301] [Table 7]

[0302] [Table 8]

[0303] Documentation of concomitant medications 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., end of the Week 24 safety follow-up visit or, if applicable, end of the Week 36 long-term safety follow-up visit). Medications' brand names and international nonproprietary names (if available), indications, and start and end dates were recorded.

[0304] Treatment compliance The study drug will be administered in the clinic. Treatment compliance will be calculated as outlined in the "Exposure and Compliance" section.

[0305] Efficacy, PK, PD, biomarkers, and safety variables Evaluation of measurement values ​​and flow chart The study procedural schedule for the dosing period is presented in Table 4 and for the safety / long-term safety follow-up period is presented in Table 5. Additional information regarding PK, CD38, T lymphocyte, B lymphocyte, and NK cell samples, and ECG times is provided in Table 9.

[0306] [Table 9-1]

[0307] [Table 9-2]

[0308] Measuring effectiveness The principal investigator or appropriately trained delegated site personnel assessed each subject for disease activity based on the SLE Disease Activity Scale according to the SOE Study Activity Tables (Tables 4 and 5).

[0309] SLEDAI-2K The SLEDAI-2K disease assessment tool uses 24 items, 16 of which are clinical and 8 of which are based solely on laboratory findings (urinary casts, hematuria, proteinuria, pyuria, low complement levels, increased DNA binding, thrombocytopenia, and leukopenia). Symptoms were recorded if they occurred within 10 days of assessment, regardless of severity, whether they improved or worsened. Individual item scores range from 1 to 8, and the total score ranges from 0 to 105. See, e.g., Gladman et al. (2002). The Journal of Rheumatology, 29(2):288-291.

[0310] For the purposes of this study, items for which test results were unavailable were scored as negative or normal.

[0311] Cutaneous Lupus Erythematosus Disease Area and Severity Index The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) consists of two scores, the first summarizing disease activity and the second a measure of disease damage. Activity is scored based on erythema, scaling / hyperkeratosis, mucosal lesions, acute alopecia, and non-scarring. Damage is scored in terms of pigmentation abnormalities and scarring (including cicatricial alopecia). Pigmentation abnormalities associated with SLE lesions that remained visible for more than 12 months were classified as permanent and scored twice as high.

[0312] 44 joint evaluation The 44-joint assessment assesses the number and location of tender and swollen joints as outlined in the disease assessment tool.

[0313] Physician's global assessment of disease (visual analogue scale) The Physician 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 or more since the previous visit indicating a flare.

[0314] PK measurement To measure serum concentrations of TAK-079, blood samples were collected by venipuncture or an indwelling catheter at the time points detailed in the SOE (Table 4). Samples were tested in a central laboratory.

[0315] The timing of samples could be modified during the study based on new PK data if changes in the sampling scheme were deemed necessary to better characterize the PK profile of TAK-079. Additional PK samples could be requested if MM deemed necessary for specific events or AEs of clinical interest.

[0316] immunogenic sample Serum samples for measuring anti-TAK-079 antibodies (i.e., anti-drug antibodies [ADA]) will be collected at multiple time points as specified in the SOE (Table 4).

[0317] Samples were taken before each dose. Immunogenic samples were screened for potential ADA-positive samples and then further verified for true positives and titers in a bioanalytical laboratory. The relationship between immunogenic response and efficacy and safety may be explored.

[0318] Biomarker measurements The study evaluated several biomarkers to test for correlation with safety, PK, and, where possible, efficacy. Biomarkers of disease activity included anti-dsDNA, anti-ENA antibodies, complement C3, C4, urinary protein-to-creatinine ratio, and / or CD38 pathway modulation markers. These biomarkers are intended to be used to identify subjects more likely to respond or have an adverse reaction to TAK-079.

[0319] To measure biomarkers, blood samples were collected by venipuncture or indwelling catheter at the time points detailed in the SOE (Table 4). Samples were tested in a central laboratory.

[0320] PK, IgG, and autoantibody quantification TAK-079 serum concentrations were quantified by a clinically validated electrochemiluminescence immunoassay. The lower limit of quantification (LLOQ) of this assay was 5 ng / mL. IgG measurements were obtained centrally on a Roche Cobas 8000 analyzer. SLE-associated autoantibodies were quantified centrally on a Thermo Scientific Phadia 250 using a clinically validated enzyme-linked immunosorbent assay.

[0321] CyTOF analysis CyTOF analysis was performed on a CellCarta (Fremont, CA). Samples were run in approximately 10 batches. Each sample was thawed, washed, stained with a cell viability dye, and then hybridized with a defined antibody panel. After washing, the samples were fixed and incubated with a DNA intercalating agent 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 per sample. In addition to viability assessment, we performed an immuno-oncology panel containing 39 metal ion-binding antibodies. This panel was modified to include TSF-19 as a non-competitive antibody against CD38. Samples were obtained at baseline (during screening, up to 28 days before initiating mezagitamab), as well as on days 15, 36, 57, and 85. Data were collected as FCS plots and evaluated based on the analysis of 100,000 cells per randomly selected patient sample.

[0322] Cluster identification and analysis were performed using the R package CyTofWorkflow (Nowicka et al. (2017) F1000Res 6:748). FlowSOM (Van Gassen et al. (2015) Cytometry A 87(7):636-45) and ConsensusClusterPlus (Wilkerson, MD and DN Hayes (2010) Bioinformatics 26(12):1572-3) were utilized to identify distinct cell populations based on their expression profiles, and results were visualized using TSNE plots (Amir el et al. (2013) Nat. Biotechnol, 31(6):545-52). FlowSOM clustered cells into metaclusters using a self-organizing map algorithm, while ConsensusClusterPlus identified stable clusters using a consensus clustering approach. Additional analyses were performed in-house. Data were expressed as median CD38 expression and % of the parent population (± standard error of the mean, where applicable). Statistical analysis and plot generation were performed in Excel, GraphPad Prism 9, and R code. Flow cytometry panels were generated using FlowJo 10.

[0323] Safety Measurement Safety measurements were performed at the times specified in the SOE (Tables 4 and 5).

[0324] Takeda clinicians reviewed AEs, SAEs, and related clinical parameters to ensure consistency with an acceptable benefit / risk ratio throughout the study. At the subject level, safety and tolerability were closely monitored for each subject at the completion of each dose and before each subsequent dose to ensure that clinical dosing criteria were met before each subsequent dose of TAK-079 or matching placebo. Additionally, comprehensive safety assessments were conducted for each cohort at the end of treatment to enable decisions regarding enrollment in subsequent cohorts. A 12-week post-dose safety follow-up period allowed for continued observation and evaluation of safety and persistence of biological activity. Subjects whose safety parameters did not return to appropriate protocol-defined recovery levels by the end of the safety follow-up period progressed to the long-term follow-up period for continued monitoring (Tables 5 and 11). Continuation of these safety observation periods provided optimal monitoring and evaluation of ongoing study-related events.

[0325] Physical examination A symptom-directed physical examination with assessment of signs and symptoms of SLE was completed according to standard of care.

[0326] Vital signs Vital signs included temperature, pulse, respiratory rate (RR), and blood pressure (BP). Vital signs were assessed before and 4 hours after each study drug administration as part of the post-dose assessment. Pulse and BP were assessed in similar locations at each study evaluation.

[0327] In addition to the SOE scheduled assessments, vital signs were also assessed at any time clinically warranted, either in the clinic or house call setting (i.e., when subjects exhibited signs or symptoms of an injection reaction, CRS, or hypersensitivity reaction).

[0328] Clinically significant events as determined by the principal investigator were documented as AEs and closely monitored for follow-up.

[0329] NOTE: Additional vital signs, including BP measurements, were assessed at any time the subject reported symptoms consistent with an infusion reaction. If the subject experienced hypotension (with or without symptoms), intensive BP monitoring was initiated according to local practice standards. Subjects were not released from the study site until BP values ​​had returned to Grade 1 or baseline for at least 1 hour.

[0330] Laboratory evaluation Unless otherwise stated in the study protocol, all laboratory samples were sent to the study central laboratory for analysis, except for the Coombs test, which was performed on-site.

[0331] Clinical chemistry and hematology assays are outlined in Table 10, and urinalysis assays are outlined in Table 12. The timing of these assessments is outlined in the SOE (Tables 4 and 5).

[0332] [Table 10]

[0333] GFR was calculated using the MDRD formula: GFR = 175 × (serum creatinine) -1.154 ×(age) -0.023 For female subjects, multiply the product by 0.742. For African American subjects, multiply the product by 1.212.

[0334] Complete urinalysis and urine protein-creatinine ratios were performed at the study central laboratory (Table 12) as part of the pre-dose assessment one week prior to each dosing day and at each follow-up safety visit. Thereafter, prior to dosing on each dosing day and at each follow-up safety visit, urine was assessed for the presence of protein and nitrates as analyzed by the local laboratory (i.e., dipstick analysis).

[0335] Abnormal findings from the local laboratory urine protein-creatinine ratio assessment were followed by confirmation from the central study laboratory. If the urinalysis was abnormal, a urine microscopy was performed at the central laboratory. Microscopy consisted of red blood cells / high-power field, white blood cells / high-power field, and casts.

[0336] Prior to each study drug administration, the principal investigator provided a summary of assessment results related to dosing criteria to the MM for review and approval. If clinical parameters did not meet the dosing criteria, study drug administration was temporarily withheld or discontinued until the parameters met the dosing levels, as outlined in Table 11. Subjects returned for dosing criteria reassessment every 3 weeks until the 12-week treatment period was completed, at which time subjects began the safety follow-up period.

[0337] [Table 11-1]

[0338] [Table 11-2]

[0339] [Table 12]

[0340] ECG Each ECG recording was performed according to standard institutional practice. All study ECGs, including triplicate ECGs, were interpreted (i.e., read on-site) by qualified personnel. Additionally, triplicate 12-lead ECGs were electronically recorded and submitted to a central vendor for archiving and future analysis.

[0341] ECGs with clinically significant findings as judged by the investigator were considered treatment-emergent adverse events (TEAEs) (excluding ECGs obtained as part of the screening visit, which were considered part of the medical history). Clinically significant findings were recorded on source documents and eCRFs and monitored continuously.

[0342] AE An AE was defined as any adverse medical occurrence occurring to a clinical investigation subject who signed an ICF to participate in the study, which did not necessarily have to be causally related to treatment. Thus, an AE could be any untoward and unintended sign (e.g., clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not considered drug-related.

[0343] Collection of AEs (i.e., AEs, SAEs, AEs of clinical interest, and abnormal liver function tests) began when the subject signed the ICF. Ongoing AEs at the end of treatment were monitored until they resolved, returned to baseline, were clearly determined to be attributable to the subject's stable or chronic condition or intercurrent illness(ies), or 6 months after treatment ended (whichever occurred first). For subjects who discontinued before study drug administration, AEs were tracked until the subject discontinued study participation.

[0344] All AEs were documented on the AE page of the eCRF.

[0345] pregnancy Urine or serum pregnancy tests were performed as outlined in Tables 4 and 5. Study pregnancy tests could be performed at designated local laboratories determined and confirmed by the sponsor and were accompanied by appropriate laboratory documentation prior to the study test.

[0346] End-of-exam evaluation End-of-study clinical parameters, outlined in Table 13, were assessed at Week 24 (the end of the safety follow-up period). If clinical findings and parameters did not meet the end-of-study criteria and were deemed study-related by the principal investigator, the subject had to remain on study and complete a 12-week long-term safety follow-up period, during which study-related parameters not meeting the end-of-study criteria continued to be assessed.

[0347] [Table 13]

[0348] Measurement appropriateness All assessments used in this study were appropriate for the study population and are widely used in studies of subjects with SLE.

[0349] Evaluation items Primary endpoint The primary endpoint assessed the safety and tolerability of TAK-079, including the incidence, type, and grade of AEs, and the proportion of subjects with one or more AEs leading to study drug discontinuation.

[0350] Secondary endpoints Secondary endpoints included (a) PK evaluation of TAK-079, (b) PD evaluation of TAK-079, and (c) immunogenicity evaluation of TAK-079.

[0351] Exploratory endpoints Exploratory objectives were to evaluate the effect of repeated administration of TAK-079 on disease activity using the following clinical assessment scales: (a) CLASI, (b) SLEDAI-2K, (c) PGA of Disease (VAS), and (d) 44-joint assessment.

[0352] Additionally, biomarkers of disease activity (e.g., anti-dsDNA, anti-ENA antibodies), complement C3 and C4, urinary protein-creatinine ratio, and / or specific CD38 pathway modulation markers were also assessed.

[0353] Measurement of drug concentrations For drug concentration measurements, see the PK Measurements section.

[0354] Management of events of clinical interest Hypersensitivity reactions: infusion reactions and injection site reactions Infusion reactions and other antibody-mediated hypersensitivity reactions have been reported with other biologic agents, so it is possible that similar AEs may have been seen with TAK-079. Infusion reactions are potentially dose-limiting AEs, but are not typically associated with IV administration of biologic agents and are less frequently associated with SC injection of these therapies.

[0355] Symptoms of hypersensitivity range from mild skin rash to more severe reactions, including wheezing, hypotension, poor perfusion, respiratory arrest, and, rarely, death. Non-anaphylactic clinical hypersensitivity typically occurs within the first hour, although delayed responses have been reported in the literature. Symptoms of anaphylaxis, a potentially life-threatening condition, range from swelling, angioedema, bronchospasm, dyspnea, and shock. Hypersensitivity reactions in the literature often occur within hours of drug ingestion. Based on the results of studies with daratumumab, patients with preexisting COPD or asthma may be at particular risk for respiratory complications, such as bronchospasm, if an infusion-reaction event occurs. Therefore, patients with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal were excluded from the study. Eligible patients with a history of COPD may have required additional post-administration medications to manage respiratory complications.

[0356] To date, no subjects administered TAK-079 have experienced anaphylactic reactions. In a clinical trial in healthy subjects (TAK-079-101), an infusion-related reaction (IRR) was defined as a treatment-emergent adverse event (TEAE) occurring within two hours of the start of the infusion; no allergic or cytokine-releasing reactions were observed within this time period, and therefore there were no IRRs in this study.

[0357] Cytokine release syndrome (CRS) CRS represents an important infusion reaction that is often associated with the use of monoclonal antibodies used in anti-inflammatory and anti-tumor therapy. The onset of CRS can occur early in treatment, often after the first infusion of the drug, due to high levels of activation of the immune system and also due to the involvement and proliferation of T cells, which can lead to increased cytokine release.

[0358] Nonclinical studies have demonstrated that TAK-079 lacks agonist activity, suggesting that it is unlikely to cause cytokine release due to cell activation. At 0.1 mg / kg, no TAK-079-associated increases in cytokines were observed. At doses above 0.3 mg / kg, dose-related increases in tumor necrosis factor (TNF-α) (up to 29.5-fold in any individual monkey) were observed 30 minutes after the first dose of TAK-079. These increases were considered small compared to those observed during cytokine storm events, were not accompanied by changes in other cytokines, and did not result in clinical symptoms of IRR. The increase in serum TNF-α may be related to TAK-079-mediated lysis of CD38+ lymphocytes.

[0359] In FIH studies conducted in healthy subjects, infrequent symptoms consistent with mild CRS were reported, especially at higher doses, and no dose adjustment or interruption was required.

[0360] CRS is characterized by fever. It may also present with rash, hives, headache, chills, fatigue, nausea, and / or vomiting. Severe CRS is characterized by fever, chills, hives, and angioedema, as well as severe dyspnea, often accompanied by bronchospasm and hypoxia. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltrates or edema visible on chest radiography. This syndrome frequently manifests within one or two hours after the start of the initial infusion. Patients with a history of pulmonary dysfunction or pulmonary tumor infiltration may be at higher risk for poor outcomes and should be treated more carefully. Based on the results of trials of the anti-CD38 mAb daratumumab, patients with preexisting COPD or asthma may be at particularly high risk for respiratory complications, such as bronchospasm, if an infusion reaction or CRS event occurs.

[0361] Therefore, patients were excluded from the study if their FEV1 was less than 50% of the predicted normal value. Eligible patients with a history of COPD may require additional post-infusion medications to manage respiratory complications.

[0362] Hematological effects Decreases in platelets, lymphocytes, and red blood cells (RBCs) occurred in some nonclinical animal studies administered TAK-079 at doses higher than the no-observed-adverse-effect level (NOAEL) of 0.3 mg / kg. After repeated administration at higher dose levels (≥1 mg / kg), no RBC or platelet reductions were observed in FIH studies, despite RBC or platelet cell count reductions observed in monkey toxicity studies.

[0363] Patients were closely monitored throughout the clinical trial, including hematological parameter testing. If clinical parameters did not meet the treatment criteria, study drug administration was temporarily or permanently withheld. Medical interventions were administered according to institutional guidelines.

[0364] infection In a 13-week GLP-compliant toxicity study, bacterial and / or viral infections secondary to immunosuppression were observed in cynomolgus monkeys receiving IV doses of 3, 30, and 80 mg / kg once every 2 weeks. The NOAEL dose of 0.3 mg / kg once weekly IV was not associated with any infections. In the FIH study, minor infections, particularly nasopharyngitis, were reported.

[0365] Patients were monitored for any signs and symptoms of infection throughout the clinical trial. If clinical parameters did not meet the dosing criteria, study drug administration was temporarily or permanently withheld. Management of infection according to standard of care was recommended.

[0366] Anti-drug antibody interactions Antidrug antibody (ADA) responses were detected in most monkeys in the single-dose PK study and the 4-week (non-GLP) and 13-week (GLP) toxicity studies. Stronger positive ADA responses were generally associated with lower serum concentrations of TAK-09, which was particularly evident in the 13-week repeat-dose toxicity study and at lower doses. In the single-dose healthy subjects study (TAK-079-1001), five of 54 TAK-079-treated subjects were ADA-positive (three subjects had transient ADA and two subjects had persistent ADA). Of these, one subject was treated with the 0.06 mg IV cohort, and the remaining four subjects were treated with SC TAK-079 at 0.03 mg / kg (two subjects), 0.1 mg / kg (one subject), or 0.6 mg / kg (one subject). Immunogenicity was not associated with clinically significant AEs, even in the two subjects with persistent immunogenicity.

[0367] Overdose Overdose is defined as the known intentional or accidental administration of an investigational drug to or by an individual subject at a dose that exceeds the dose assigned to that subject according to the protocol.

[0368] To date, there have been no cases of overdose. If an overdose occurs, close monitoring and supportive care, if medically indicated, is recommended.

[0369] Statistical methods and determination of case size Analysis Set Safety Analysis Set: The safety analysis set included all subjects who were enrolled and received at least one dose of study drug. This analysis set was used to summarize demographics, baseline characteristics, efficacy, and safety.

[0370] PK Analysis Set: The PK analysis set included all subjects who received study drug and had at least one measurable serum concentration.

[0371] PD Analysis Set: The PD analysis set included all subjects who received study drug and had at least one post-dose PD measurement.

[0372] Immunogenicity Analysis Set: The immunogenicity analysis set included all subjects from the safety population who had a baseline immunogenicity sample and underwent at least one post-dose immunogenicity sample assessment.

[0373] General Considerations Continuous data were summarized using the following descriptive statistics, as appropriate: number of subjects, mean, SD, median, minimum, and maximum. Percent coefficient of variation (CV%) and geometric mean were included in the continuous data summaries, as indicated. Arithmetic means, geometric means, and medians were presented rounded to one decimal place beyond the recorded data, and SDs were presented rounded to two decimal places beyond the recorded data, as appropriate.

[0374] In the PK-related tables, the mean, SD, median, minimum, and maximum values ​​were rounded to four significant figures, and the CV% was rounded to two decimal places.

[0375] Where appropriate, categorical data were summarized using the number and percentage of subjects per category. Percentages were reported rounded to two decimal places.

[0376] Unless otherwise stated, baseline values ​​were defined as the last observed value before the first dose of study drug.

[0377] There were no visit time frames for the dosing visit, the safety follow-up period, and the long-term safety follow-up period. All non-dosing visits during the dosing period had a time frame of ±1 day.

[0378] For some non-missing measurements, eg, triplicate ECGs, the mean value of the triplicate assessments was used.

[0379] Subjects who received placebo in each cohort were pooled across cohorts. All summaries are presented separately by pooled placebo group, TAK-079 dose, and total TAK-079 subjects in the study.

[0380] For analyses based on safety, PK, PD, or immunogenicity analysis sets, subjects were analyzed as treated, i.e., as their actual treatment. For analyses based on all randomized subjects, subjects were analyzed as randomized, i.e., as their planned treatment.

[0381] Breakdown of targets Summary and listing of subject disposition was based on all randomized subjects. Number of subjects in the safety analysis set was presented. Disposition was tabulated in terms of subjects who discontinued study drug early, subjects who completed study drug, subjects who discontinued the study early, and subjects who completed the study. Primary reasons for early discontinuation of the study or study drug as entered on the eCRF were tabulated. Percentages were based on number of subjects in the safety analysis set.

[0382] In addition, the number of subjects randomized was summarized by country and center.

[0383] Major protocol deviations were summarized and listed based on all randomized subjects. Protocol deviations related to coronavirus disease 2019 (COVID-19) were summarized.

[0384] Date of first dose, date of last dose, duration of treatment, and reason for early discontinuation of study drug / study visit were provided for each subject in the list.

[0385] Demographics and other baseline characteristics demographics Summary statistics were presented for continuous variables (e.g., age and weight). Numbers and percentages of subjects in each category were presented for categorical variables (e.g., race and sex). Demographic and baseline characteristic data for individual subjects were listed. Placebo data were pooled across cohorts.

[0386] Demographic variables and reasons for screening ineligibility were summarized for subjects who were screened but did not enroll in the study.

[0387] Individual demographic characteristics, ICF dates, and reasons for screening ineligibility were listed.

[0388] Analysis and listing of demographic and baseline characteristics was based on the safety analysis set.

[0389] Medical history Medical history refers to any significant condition or disease that ceased at or before the time of informed consent, or that was ongoing at the time of informed consent.

[0390] 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 contains the number and percentage of subjects and is arranged alphabetically by SOC. Within an SOC, PTs were arranged by decreasing frequency based on the total number of subjects. Subjects were counted only once within a particular class, even if they had multiple conditions / symptoms. The summary was based on the safety analysis set.

[0391] All medical history data was presented in a list based on the safety analysis set.

[0392] Prior therapy and concomitant medications 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 Week 24 safety follow-up visit or the end of the Week 36 long-term safety follow-up visit, if applicable). Medications' proprietary and international nonproprietary names (if available), indications, and start and end dates were recorded. Medications were coded using the World Health Organization Drug Dictionary (B3 Global version September 2018 or later). The number and percentage of subjects taking prior therapies and concomitant medications were tabulated by World Health Organization Drug Dictionary nonproprietary name based on the safety analysis set.

[0393] All prior therapy and concomitant medication data were presented in a list based on the safety analysis set. Missing concomitant medication dates were not imputed.

[0394] Efficacy analysis Exploratory efficacy endpoints were summarized by descriptive statistics. Additionally, where applicable, analyses of treatment effects were presented in terms of estimates and two-sided 95% CIs. The safety analysis set was used for all efficacy analyses.

[0395] Rating scales were also analyzed using longitudinal modeling and responder analysis.

[0396] Longitudinal Modeling Changes from baseline at each scheduled visit were calculated for the CLASI, SLEDAI-2K, PGA of Disease (VAS), and 44-joint assessment assessments.

[0397] Analysis of change from baseline in rating scales by visit was performed using a repeated measures mixed model (MMRM) analysis, including treatment, visit, and the (treatment × visit) interaction term as factors, with baseline values ​​as covariates and further adjusted for baseline-by-visit interaction. Unstructured covariance was used as the default structure for this model. Alternative covariance structures were evaluated when convergence issues arose. Comparisons of mean change from baseline between different doses of TAK-079 and placebo were performed at all scheduled post-baseline assessments. CIs based on least-squares means of the between-group differences are presented. Based on the "missing at random" hypothesis, this analysis was performed using only observed case data.

[0398] Observed scale values ​​and changes from baseline by visit were summarized descriptively. The observed mean change from baseline based on the MMRM model for each treatment group was plotted. Scales were provided in a per-subject list. Where appropriate, individual subject profiles over time for selected scales or subscales could be plotted.

[0399] Responder analysis The proportion of subjects meeting the following clinical response criteria for each clinical rating scale was calculated for each scheduled assessment.

[0400] CLASI total activity score: score reduced by 4 points or 20% or more from baseline (only subjects with a baseline score >0 were analyzed).

[0401] SLEDAI-2K total score: A score reduction of 4 or more points from baseline.

[0402] PGA of the disease (VAS): score reduced by 0.3 points or more from baseline.

[0403] Subjects who met the clinical response criteria for each clinical assessment scale were considered responders for that clinical assessment scale. Comparisons of responder rates between different doses of TAK-079 and placebo were performed at all scheduled post-baseline assessment time points. CIs for the difference in rates are presented. This analysis was based only on observed data at each time point (i.e., complete case analysis). Missing data were not imputed.

[0404] Observed responder proportions were summarized descriptively by visit. 95% CIs for responder proportions by treatment group could be generated. Observed responder proportions over time could be plotted.

[0405] Safety analysis AE A TEAE was defined as an AE that occurred after the first dose of study drug administered during the treatment period and that occurred through the end of safety follow-up.

[0406] TEAEs were presented by intensity. Treatment-emergent SAEs, TEAEs leading to study drug discontinuation, TEAEs leading to dose modification (e.g., described as dose delays, dose skips), and TEAEs leading to death were also summarized using SOC and PT.

[0407] When calculating frequencies and percentages of subjects reporting TEAEs, if multiple TEAEs were coded to the same SOC or PT, the subject was counted only once for each SOC or PT. For intensity or association summaries, if a subject reported multiple TEAEs coded to the same SOC or PT, the TEAE with the greatest intensity or strongest association was included.

[0408] Adverse events with missing intensities were listed as such in the adverse event list but summarized as severe in the summary tables. Similarly, if the relationship between events was missing, the event was considered related but presented as missing in the list.

[0409] Missing AE dates were not imputed.

[0410] Clinical laboratory evaluation If a subject had a repeat laboratory value at a given time point, the value from the last assessment was used.

[0411] All clinical laboratory parameters were presented in individual subject data listings in both International Standard (SI) and conventional (CV) units. For test results not in SI units, known conversion factors were used to convert to SI units. Where necessary, SI units from the central laboratory could be converted to Takeda's preferred SI units. All summaries and analyses were based on values ​​using the preferred SI units, and data were presented in both SI and conventional units in data listings.

[0412] Common Terminology Criteria for Adverse Events (CTCAE) grading (version 4.03) of laboratory values ​​was summarized by creating a shift table of baseline toxicity grade to the worst post-baseline toxicity grade.

[0413] Vital signs The investigator captured as an adverse event any individual vital sign finding that met the abnormal criteria and was clinically significant according to the PI.

[0414] 12 lead ECG Overall ECG interpretation categories (normal, clinically insignificant abnormal, clinically significant abnormal, unevaluable) were collected via eCRF at baseline and each scheduled post-baseline visit. Shifts in ECG interpretation are presented as cross-tabulations (baseline vs. each post-baseline visit) of the number of subjects with normal interpretations, clinically insignificant abnormal interpretations, and clinically significant abnormal interpretations, with unevaluable, missing, if applicable, and an overall total category. The rate-corrected QT interval (milliseconds) of the electrocardiogram (corrected QT [QTc]) was calculated using the Bazett and Fridericia corrections, as appropriate. The formula is: QTc(Bazett)=QT / (RR^0.5) QTc(Fridericia)=QT / (RR^0.33) Where RR is 60 / heart rate (beats / min). All ECG parameters are listed in the data list.

[0415] Exposure level and compliance The total number of doses taken and the total amount of doses taken were summarized narratively in the pooled placebo and TAK-079 groups.

[0416] Treatment compliance was summarized in terms of the percentage of scheduled doses received by the pooled placebo and TAK-079 groups. The percentage of scheduled doses received per subject was defined as [(actual total number of doses taken) / (number of planned doses)] × 100.

[0417] The date and time of each dose for each subject was reported in the data listing.

[0418] PK, PD, and biomarker analysis PD and biomarker analysis Individual values, changes from baseline, and mean changes from baseline and / or percent changes from baseline at different time points for placebo and each TAK-079 dose level were calculated for various immune cell subsets, including plasma cells, PBs, NK cells, B cells, T cells, monocytes, and total lymphocytes. CD38 expression and receptor occupancy for plasma cells, PBs, NK cells, B cells, T cells, and monocytes were also assessed. Cytokine measurements and changes from baseline at different time points for placebo and each TAK-079 dose level were calculated for each subject. Individual values ​​and changes in autoantibody, immunoglobulin, and complement protein levels were summarized.

[0419] Descriptive summaries included geometric means and CV% where appropriate.

[0420] Plots of mean values ​​and mean percent change from baseline were generated. Mean percent change from baseline was not plotted against measures related to receptor occupancy; instead, mean change from baseline was generated. Individual subject profiles over time for selected parameters could have been plotted, if desired.

[0421] PK analysis PK analysis types and methods: Serum and whole blood concentrations of TAK-079 summarized by TAK-079 dose level at each scheduled sampling time point using descriptive statistics (N, arithmetic mean, SD, median, maximum, and percent coefficient of variation [CV%]). Individual plasma concentration data versus time presented in the data listing. PK parameters of TAK-079 summarized by dose level using descriptive statistics. Maximum observed concentration (C max ) and the geometric mean calculated for the area under the concentration-time curve (AUC). Dose proportionality was assessed graphically using a power model. max and AUC, and dose-normalized C max and AUC plots. Other analyses or methods are contemplated where appropriate.

[0422] Non-compartmental analysis was not performed due to sparse PK sampling. TAK-079 concentration-time profiles were summarized using descriptive statistics. Individual TAK-079 concentration-time data, the final concentration reached before the next dose (C trough ) and the individual maximum observed concentrations (C max ) were presented in a list and tabulated by treatment group using summary statistics. Individual and mean concentration-time profiles were plotted by treatment group. The PK analysis set was used for summarizing and analyzing PK parameters.

[0423] Population PK models may be developed and, if so, will be reported separately. Analytical plans for population PK analyses will be defined separately, and the results of these analyses will be reported separately.

[0424] PK-PD relationships may be explored graphically. PK / PD models may 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, results will be reported in a separate report. PD parameters will also be listed in the data listing. Additional PD analyses to assess dose effect may be performed, if appropriate.

[0425] Immunogenicity analysis Where applicable, immunogenicity analyses (ADA transient, persistent, negative, and titer) were summarized using descriptive statistics. The relationship between immunogenic response and efficacy and safety may be explored.

[0426] A transient positive ADA response was defined as a subject with confirmed positive ADA status at one or two post-baseline assessment(s) in SAP.

[0427] A persistent positive ADA response was defined as a subject with confirmed positive ADA status at more than two post-baseline assessments in SAP.

[0428] A positive ADA assessment at each post-baseline visit was defined in the SAP as having either (1) a negative assessment and a positive assessment value at baseline, or (2) a positive assessment value at baseline and a assessment value that met criteria for a treatment-enhanced ADA response (≥4-fold the baseline value).

[0429] During the actual analysis of the study data, modifications and additions were made to the ADA responses defined by the SAP outlined above, and these modifications are described in detail in the "Modifications to Immunogenicity Analysis" section.

[0430] Interim analysis The sponsor may have conducted an unblinded review or analysis of data from one or more dose cohorts after all subjects enrolled in those dose cohorts completed the safety follow-up period or discontinued the study early. The sponsor received treatment assignment only for individual subjects within the relevant cohort but remained blinded to the treatment assignment of other subjects.

[0431] Determining the number of cases The study did not have high statistical power for any hypothesis testing. A sample size of 6 active subjects and 2 placebo subjects in each of the 3 cohorts (resulting in 6 subjects treated with placebo or 45 mg, 90 mg, or 135 mg of TAK-079) was considered sufficient to achieve the study objectives of evaluating safety, tolerability, and PK in each cohort.

[0432] Example 2: Test Subjects Breakdown of targets In total, 35 subjects were screened but did not participate in the study. Reasons for screening ineligibility included not meeting inclusion criteria (28 subjects), subject withdrawal (5 subjects), and other (2 subjects).

[0433] The trial planned to randomize 24 subjects, but accrual was terminated early due to a high study screening failure rate and logistical difficulties in recruiting subjects.

[0434] Twenty-three subjects were randomized at 13 study sites across the U.S. One randomized subject discontinued the study before receiving study drug, and 22 randomized subjects received at least one dose of study drug and were included in the safety analysis set (Table 14).

[0435] The mean age was lower in the placebo group (36.4 years) than in the mezagitamab group (pooled mezagitamab group: 49.1 years). Mean baseline body weight was higher in the placebo group (87.3 kg) and the mezagitamab 90 mg group (85.6 kg) and lower in the mezagitamab 45 mg group (75.0 kg) and the mezagitamab 135 mg group (64.6 kg). Other demographic variables were similar across treatment groups. Most study subjects were female, and the proportions of African American and Caucasian study subjects were similar.

[0436] [Table 14]

[0437] Protocol deviations In total, three subjects reported significant protocol deviations, one in the informed consent category and two in the study drug administration / dispensing category.

[0438] Impact of the COVID-19 pandemic on study subjects In total, two subjects reported protocol deviations related to COVID-19: a subject in the TAK-079 90 mg group reported deviations in two categories: study procedures / assessments and visit schedule, and a subject in the TAK-079 135 mg group reported deviations in two categories: study drug compliance and visit schedule.

[0439] Example 3: PK, PD, immunology, and efficacy evaluation Dataset analyzed The number of subjects in each analysis set is shown in Table 15. The safety analysis set was used to summarize demographics, baseline characteristics, efficacy, and safety.

[0440] [Table 15]

[0441] Demographic characteristics Demographic characteristics are summarized in Table 16.

[0442] The mean age was lower in the placebo group (36.4 years) than in the TAK-079 group (pooled TAK-079 group: 49.1 years). Other demographic variables were similar across treatment groups. Most study subjects were female, and there were similar proportions of African-American and Caucasian study subjects.

[0443] [Table 16-1]

[0444] [Table 16-2]

[0445] Medical history and other baseline characteristics All 22 subjects (100%) had a reported medical history. Common medical histories (≥25% of all subjects) excluding SLE included gastroesophageal reflux disease (13 subjects [59.1%]), hypertension (11 subjects [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).

[0446] Medication history and concomitant medications Medication history All 22 (100%) subjects had at least one medication history. Common medication histories (abnormal in 25% of all subjects) included hydroxychloroquine (13 subjects, 59.1%), prednisone (9 subjects, 40.9%), gabapentin (8 subjects, 36.4%), and hydroxychloroquine sulfate (6 subjects, 27.3%).

[0447] Concomitant medications All 22 (100%) subjects had at least one concomitant medication, reflecting the fact that all subjects were required to receive stable background SLE therapy throughout the study period. The most common background SLE medications in this study included:

[0448] 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%).

[0449] 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.

[0450] 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%).

[0451] Mycophenolate: 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%).

[0452] 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.

[0453] Overall, background medications were balanced across treatment groups and did not change during the treatment period. Among subjects receiving corticosteroids (prednisone and methylprednisolone), slightly higher mean daily doses were observed in the placebo group (8.3 mg) and the TAK-079 45 mg group (10.0 mg) compared with the TAK-079 90 mg group (7.0 mg) and the TAK-079 135 mg group (4.7 mg) during the treatment period.

[0454] Measuring Treatment Compliance Investigational drug compliance data are provided in Table 17.

[0455] [Table 17]

[0456] Analysis of PK, PD, immunology, and efficacy results PK Results - Serum Concentration of TAK-079 Serum concentrations of TAK-079 were detectable in all subjects at all dose levels. However, TAK-079 concentrations were below the lower limit of quantitation after dosing in some subjects, particularly in the 45 mg dose group. Serum PK data excluded from PK analysis and / or reporting were due to dose holds and early discontinuations (see "Magnitude of Exposure" section), as well as other reasons related to sample availability and condition.

[0457] Log-linear plots of mean / SD serum concentrations of TAK-079 versus time after multiple doses of TAK-079 administered by SC injection at 45, 90, and 135 mg are presented in Figures 3A and 3B. maxThe number of participants with maximum observed plasma concentrations and changes from baseline in CD38 expression levels and receptor occupancy on plasma cells, plasmablasts, NK cells, B cells, T cells, and monocytes are presented in Table 18 and Table 19, respectively.

[0458] [Table 18]

[0459] [Table 19-1]

[0460] [Table 19-2]

[0461] TAK-079 peak exposure was greater than dose-proportional across the dose range tested, from 45 mg to 135 mg. After the initial dose, a three-fold increase in dose resulted in a mean C max increased approximately 100-fold, from 57.5 ng / mL to 6130 ng / mL. This greater than dose-proportional increase in exposure was largely maintained at subsequent dosing intervals.

[0462] C max Time to reach (t max Individual values ​​for t (t) ranged from 33 to 168 hours post-injection at each dosing interval in subjects with available and measurable concentration data. The majority of subjects, across all dose groups, reached maximum drug concentrations 108 hours after the first and second doses of TAK-079. No PK collections were identified between 5 and 168 hours after the third and fourth doses, and the apparent t max The interval between these doses was 168 hours in all but two subjects.

[0463] Biomarker validation Pre-validation characterization and technical validation was completed for a flow cytometry assay to assess CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, PB, and plasma cells in whole blood. Additionally, the assay was validated to quantitatively determine CD38 receptor occupancy and receptor density across each cell type. The number of participants with changes from baseline in immune cells (i.e., plasma cells, plasmablasts, NK cells, B cells, T cells, monocytes, and lymphocytes) is presented in Table 20.

[0464] [Table 20-1]

[0465] [Table 20-2]

[0466] Target binding based on receptor occupancy flow cytometry analysis A CD38 receptor occupancy assay was developed to assess changes in CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, PB, and plasma cells in whole blood. Additionally, CD38 expression and TAK-079 receptor occupancy were assessed for every individual cell type by comparing the CD38 fluorescence signal of two independent flow cytometry samples containing either labeled TAK-079 (for quantification of "free" CD38 receptor) or labeled TSF-19 (a non-competitive CD38 antibody for quantification of "total" CD38 receptor).

[0467] Trends in the PD profile were most pronounced after the first dose. Data at subsequent dosing intervals were confounded by dose withholding and early discontinuation (see "Range of Exposure" section), as well as other reasons related to sample availability and condition.

[0468] NK cell populations are the most abundant CD38-expressing cell population in peripheral blood, and receptor occupancy of this cell type can be used as a surrogate marker of CD38 binding on target cells. TAK-079 dose-dependently bound to the CD38 target on CD38+ NK cells, with median receptor occupancy increasing from 43.8% to 88.4% within the tested dose range of 45 mg to 135 mg one day after the first dose. This dose-dependent target binding trend was less evident with subsequent doses, with the 90 mg dose achieving similar or even higher mean receptor occupancy compared to the 135 mg dose. Maximum receptor occupancy was achieved approximately 4–7 days after study drug administration in all dose groups, and returned to near baseline before the next dosing interval, except for the 90 mg dose group, where receptor occupancy did not fully return to baseline from the second dosing interval.

[0469] Target engagement was accompanied by changes in absolute CD38+ NK cell counts. The corresponding decline in CD38+ NK cells was largely similar across all TAK-079 dose groups, with mean changes from baseline of -71.5%, -65.5%, and -90.0% observed at 45 mg, 90 mg, and 135 mg, respectively (Figure 4A). These declines occurred on day 2 after the first dose and did not demonstrate a full return to baseline by the time of the next dose. Similar trends were observed during subsequent dosing intervals. CD38+ NK cells were depleted by a 33.7% change from baseline at the end of treatment (day 85) across the pooled TAK-079 groups. Placebo-treated subjects did not demonstrate a decline in CD38+ NK cells from baseline throughout the study period.

[0470] Because PBs represent target cells for TAK-079 that can be quantified in peripheral blood, we examined changes in absolute PB counts. The reduction in absolute PB counts was similar across TAK-079 dose groups. The maximal effect was observed on day 1 after the first dose, with mean changes from baseline of -87.0%, -69.4%, and -75.8% observed at 45 mg, 90 mg, and 135 mg, respectively (Figure 4B). PB counts returned to baseline before the second dose administration. Similar trends were observed during subsequent dose intervals, although PB depletion was less pronounced.

[0471] Downstream pharmacology of targeting CD38 Because plasma cells reside primarily in tissues (e.g., bone marrow) and are rarely present in peripheral blood, we indirectly assessed the potential effects on plasma cells. Therefore, we evaluated serum total IgA, IgG, and IgM concentrations as surrogate biomarkers for the effects of TAK-079 on plasma cells in tissues.

[0472] Multiple doses of TAK-079 at either the 45 mg or 90 mg dose resulted in only modest reductions of less than 10% mean decrease from baseline at any given time point, demonstrating no substantial difference compared to the placebo group, which had a maximum mean decrease from baseline of approximately 5% during the treatment period (Figures 4C and 4D). The 135 mg dose of TAK-079 resulted in a maximum mean decrease from baseline of 18.8% in IgG. IgA depletion tended to be dose-dependent, with maximum mean decreases from baseline of 11.3%, 17.1%, and 32.6% achieved at 45 mg, 90 mg, and 135 mg, respectively (Figure 5). The decrease in IgM concentrations was similar across all treatment groups, with the mean decrease from baseline across pooled TAK-079 groups during the treatment period ranging from approximately 11.3% to 16.7%. The decline in immunoglobulins generally had not returned to baseline levels by day 85, the final time point examined in the study.

[0473] In addition to changes in total immunoglobulin concentrations, the effect of TAK-079 was evaluated on changes in serum concentrations of autoantibodies in subjects who tested positive for a given autoantibody at baseline. There were six main autoantibodies for which subjects tested positive: anti-dsDNA, anti-SmD p , beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjogren's SS-A, and Sjogren's SS-B. Many subjects were positive for anti-dsDNA (9 of 22 subjects total) or Sjogren's SS-A (14 of 22 subjects total). Changes in autoantibody concentrations did not appear to be dose-dependent and generally did not show strong agreement with changes in total immunoglobulins (Figures 6A and 6B). The maximum decrease in autoantibody concentrations was a mean decrease of approximately 20% from baseline for all autoantibodies evaluated.

[0474] CyTOF To gain further insight into the broad immune landscape changes induced by mezagitamab, we performed CyTOF analysis on PBMC samples collected during the study. These results showed a generalized trend in which CD38 expression correlated with the degree of cell depletion (Figure 7A). Plasma cells, Brems, NK cells, and plasmablasts were the most affected populations, consistent with the receptor occupancy data for these cell subsets. Additionally, unsorted CyTOF data were subjected to FlowSOM clustering and tSNE visualization (Figures 7B, 7C, 8A, and 8B). These data showed changes in cluster size, particularly around clusters expressing high levels of CD38. To gain more information about specific clusters undergoing substantial changes, the number of clusters was increased from 20 to 50 (Figure 9A). This more detailed analysis revealed two clusters of CD8+ and CD4+ cells (32 and 34, Figures 9B and 9C) that expressed granzymes, were CCR7-, and CD45RAlo / -. Evaluation of the therapeutic effect on this population revealed an increase in the prevalence of these cells, which appeared to be dependent on the time of treatment and / or administration. Collectively, the data indicated that mezagitamab targeted high CD38-expressing cells, resulting in their depletion and an overall reduction in CD38 signaling in immune cells.

[0475] IFN gene signature Whole blood RNA samples were collected at separate time points throughout the course of mezagitamab treatment and subjected to the nanostring autoimmune profile panel. Genes associated with type 1 IFN response were identified as downregulated in patients in the 135 mg cohort compared to placebo (Figure 10). This response was most pronounced in patients with a strong cutaneous response based on CLASI score.

[0476] Immunogenicity results Changes made to the immunogenicity analysis after the final SAP are described in the "Changes to the Immunogenicity Analysis" section.

[0477] Baseline and at least one post-baseline ADA assessment was performed for 21 subjects in the immunogenicity set. One subject's assessment was missing at baseline, so this subject was not included in the immunogenicity set.

[0478] Subjects with a baseline positive ADA result were considered to have pre-existing ADA. Three subjects in the placebo group, zero subjects in the TAK-079 45 mg group, and one subject each in the TAK-079 90 mg and 135 mg groups had pre-existing ADA, for an overall pre-existing ADA incidence of 23.8% (Table 21). The high proportion of subjects with pre-existing ADA is likely the result of active autoimmune disease in these subjects with SLE (Faustini et al. (2021) Arthritis Res. Ther. 23(1):211-23).

[0479] Subjects with a baseline positive ADA result and a post-baseline titer increase of 4-fold or greater compared to the baseline titer were considered to have treatment-emergent ADA; however, no subjects in this study met these criteria. Subjects with a baseline negative ADA result and any post-dose positive ADA result were considered to have treatment-emergent ADA. Zero subjects in the placebo group, two subjects each in the TAK-079 45 mg and 135 mg groups, and one subject in the TAK-079 90 mg group had treatment-emergent ADA, for an overall treatment-emergent ADA incidence of 23.8% (Table 21). Of the subjects with treatment-emergent ADA, four (19% of all subjects) were transiently ADA-positive, and only one (4.8% of all subjects) was persistently ADA-positive.

[0480] The overall ADA positivity rate, including both pre-existing ADAs and treatment-emergent ADAs at any time point, was 47.6% (10 of 21 subjects) (Table 21). This rate was similar across treatment groups, including the placebo group.

[0481] The minimum required dilution or minimum titer in this study was 20, and titers were assessed only in ADA-positive samples. Among all subjects with treatment-emergent ADA, the moderate titer was 200, with a range of 20 to 327,680 (Table 21). No correlation was observed between ADA titer and medication dose.

[0482] Even in subjects with persistently positive ADA responses, immunogenicity was not associated with clinically significant AEs or hypersensitivity reactions. AEs and efficacy outcomes were carefully evaluated in two subjects with ADA titers greater than 40,000 (one subject in the TAK-079 45 mg group and one subject in the TAK-079 135 mg group). Both subjects were ADA-negative at baseline, but based on their medical history, they exhibited immune dysregulation at study initiation, which may partially explain the occurrence of high ADA titers. No clinically relevant adverse events or hypersensitivity reactions were observed in these subjects, and efficacy outcomes were consistent with study group responses. Due to the limited number of subjects, we were unable to assess the drug dose-dependence of immunogenicity, but no clear differences in ADA-positive responses were observed between the different treatment groups (Table 21).

[0483] Individual subject values ​​for serum TAK-079 concentrations over time, along with ADA results, were max At the individual level, the C of subjects with a treatment-emergent positive (transient or persistent) ADA response was not revealed. max was generally lower after a positive ADA assessment. However, a similar decrease in drug concentration with continued administration was observed in subjects with negative ADA responses. In addition, C was significantly higher among subjects regardless of ADA. max For example, in the TAK-079 45 mg group, where all subjects were ADA-negative, a geometric CV% of 186.3% was reported at Dose 1. Overall, data were too limited and variable to determine the impact of immunogenicity on the PK of TAK-079, but there was no clear trend for differences in exposure between ADA-positive and ADA-negative subjects.

[0484] [Table 21]

[0485] [Table 22]

[0486] Efficacy analysis Exploratory objectives included assessing the effect of repeated doses of TAK-079 on disease activity using clinical rating scales.

[0487] CLASI There was a moderate improvement in the CLASI Total Activity Score from baseline to the end of treatment, with no clear change in the CLASI Total Injury Score, and no observable differences between treatment groups. At baseline, the mean CLASI Total Activity Score was lower in the placebo group (4.8), TAK-079 45 mg group (7.2), and TAK-079 90 mg group (5.2) compared with the TAK-079 135 mg group (11.8) (Table 23). At the end of treatment on Day 85, the change from baseline in the Total Activity Score (LS mean) was similar in the placebo group (-3.7) compared with the TAK-079 treatment groups (TAK-079 45 mg: -4.3, TAK-079 90 mg: -3.9, TAK-079 135 mg: -3.6) (Table 23 and Figure 11). The number of responders, defined as subjects whose score decreased by at least 4 points or at least 20% from baseline, was also similar across treatment groups at this time point (Table 23). When individual total activity scores were assessed, all subjects with a baseline CLASI score greater than 10 met responder criteria at the end of treatment (Figure 12, Table 24). At the end of treatment on Day 85, there was little change from baseline (LS mean) in total injury scores in both the placebo group (0.0) and the TAK-079 treatment groups (TAK-079 45 mg: -1.3, TAK-079 90 mg: 0.0, TAK-079 135 mg: 0.4).

[0488] [Table 23]

[0489] [Table 24]

[0490] SLEDAI-2K In this study, mild to moderate improvements in SLEDAI-2K total scores from baseline to the end of treatment were observed. There were no observable differences across treatment groups. At baseline, mean SLEDAI-2K total scores were similar in 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 (LS mean) in total score was similar in the placebo group (-5.2) compared to the TAK-079 treatment groups (TAK-079 45 mg: -3.1, TAK-079 90 mg: -2.5, TAK-079 135 mg: -4.2) (Table 25 and Figure 13). The number of responders, defined as subjects who experienced a reduction in score of at least 4 points from baseline, was similar across treatment groups at this time point (Table 25). No trends were observed in individual SLEDAI-2K total scores (Figure 14).

[0491] [Table 25]

[0492] PGA of the disease (VAS) Mild to moderate improvements in PGA scores from baseline to the end of treatment were detected, with no observable differences between treatment groups.

[0493] At baseline, mean PGA scores for disease, presented as disease severity on a 3-point scale, were similar in the placebo group (1.48), TAK-079 45 mg group (1.70), TAK-079 90 mg group (2.02), and TAK-079 135 mg group (1.84) (Table 25).

[0494] At the end of treatment on Day 85, the change from baseline in score (LS Mean) was similar in the placebo group (-0.58) compared to 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 whose score decreased by at least 0.3 points from baseline, was similar across treatment groups at this time point (Table 26).

[0495] No trends in PGA scores for individual diseases were observed.

[0496] Similar results were observed when the PGA of the disease was presented as disease severity on a VAS scale.

[0497] [Table 26]

[0498] 44 joint evaluation Overall, there was a moderate improvement in total tender joint counts, total swollen joint counts, and total active joint counts from baseline to the end of treatment, with no observable differences between treatment groups.

[0499] 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) compared with the TAK-079 treatment groups (TAK-079 45 mg: -7.9, TAK-079 90 mg: -14.2, TAK-079 135 mg: -10.1).

[0500] At baseline, the 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) compared with the TAK-079 treatment groups (TAK-079 45 mg: -3.1, TAK-079 90 mg: -2.1, TAK-079 135 mg: -7.1).

[0501] At baseline, mean total active joint counts were similar across treatment groups. At end of treatment on Day 85, the change from baseline (LS mean) was similar in the placebo group (-6.1) compared with the TAK-079 treatment groups (TAK-079 45 mg: -4.0, TAK-079 90 mg: -6.4, TAK-079 135 mg: -6.7).

[0502] Statistical and analytical issues Handling dropouts or missing data Efficacy data were analyzed using only observed case data under the assumption of "missing at random."

[0503] Interim analysis and data monitoring There were no interim analyses in this study.

[0504] After all subjects in Cohort A and Cohort B completed the study and all data were source-validated, Cohort A and Cohort B treatment assignments were unblinded. The sponsor received treatment assignments only for individual subjects within the relevant cohort but remained blinded to the treatment assignments of subjects in other cohorts. Details of the unblinding process and steps to minimize bias are provided in the "Blinding" section.

[0505] Multicenter study This was a multicenter trial. There was no coordination of study sites.

[0506] Multiple comparisons / multiplicity No multiplicity adjustment was performed.

[0507] Use of target validity subsets The efficacy subset of subjects was not used in this study.

[0508] Active-controlled trials intended to show equivalence This was not an active-controlled study intended to show equivalence.

[0509] Subgroup Considerations No subgroup analyses were performed in this study.

[0510] PK, PD, immunogenicity, and efficacy conclusions Consistent with the literature and other SLE studies, most study subjects were women. The study was racially balanced, with approximately equal proportions of African-American and Caucasian study subjects.

[0511] TAK-079 exposure increased more than dose-proportionally across the dose range tested (45-135 mg). After the initial dose, a 3-fold increase in dose significantly increased mean C max was increased approximately 100-fold. This greater than dose-proportional increase in exposure was generally maintained at subsequent dosing intervals.

[0512] The majority of subjects across all dose groups reached maximum drug concentrations 108 hours after the first and second doses of TAK-079.

[0513] TAK-079 bound to the CD38 target on CD38+ NK cells in a dose-dependent manner after the first dose. Maximum receptor occupancy was achieved approximately 4-7 days after study drug administration for all dose groups. CD38+ NK cells were depleted by 33.7% change from baseline at the end of treatment (day 85) in the pooled TAK-079 group. Placebo-treated subjects did not demonstrate a decrease in CD38+ NK cells from baseline throughout the study period.

[0514] Reductions in absolute PB counts were similar across TAK-079 dose groups, with the maximal effect observed on day 2 after the first dose, reaching a mean change of -74.0% in the pooled TAK-079 groups.

[0515] The decrease in IgG was most pronounced in the TAK-079 135 mg group, with a maximum mean decrease from baseline of 18.8%. IgA depletion tended to be dose-dependent, with maximum mean decreases from baseline of IgA of 11.3%, 17.1%, and 32.6% achieved at TAK-079 doses of 45 mg, 90 mg, and 135 mg, respectively. The decrease in IgM concentrations was similar across all treatment groups, with mean decreases from baseline in pooled TAK-079 groups over the treatment period ranging from approximately 11.3% to 16.7%.

[0516] Changes in autoantibody concentrations did not appear to be dose-dependent and generally did not show strong agreement with changes in total immunoglobulins. The maximum reduction in autoantibody concentrations was a mean decrease from baseline of approximately 20% for all autoantibodies evaluated.

[0517] A total of five subjects in the placebo and TAK-079 treatment groups had pre-existing ADAs, for an overall average rate of 23.8%. An additional five subjects in the TAK-079 treatment group had treatment-emergent ADAs, for an incidence of 23.8%. Immunogenicity was not associated with clinically significant AEs or hypersensitivity reactions, and the limited number of subjects prevented assessment of the dose-dependence of immunogenicity.

[0518] Four clinical assessment scales were used to evaluate exploratory efficacy in this study: 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 in any of these clinical assessment scales across treatment groups. When individual CLASI total activity scores were assessed, all patients with a baseline CLASI score greater than 10 met responder criteria at the end of treatment, suggesting a trend toward more severe response among patients with higher CLASI scores at baseline.

[0519] Overall, responder analyses of the CLASI, SLEDAI-2K, and PGA did not reveal any observable differences across treatment groups.

[0520] Example 4: Evaluation of safety and safety biomarkers Degree of exposure A summary of study drug exposure and compliance is provided in Table 17. In total, 17 subjects were exposed to TAK-079. Mean compliance was 80.0% in the placebo group and 70.6% in the pooled (total) TAK-079 groups.

[0521] Many subjects did not receive all four doses of study drug due to several factors, including the COVID-19 pandemic (see "Impact of the COVID-19 Pandemic on Study Subjects" section) and dose holds (see "Dose Holds" section). A small number of subjects in each treatment group received all four 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.

[0522] Administration withheld Prior to administration of each study drug dose, subjects were assessed for dosing criteria based on laboratory assessments and events of clinical interest defined in Table 11.

[0523] Overall, the number of dose withholdings was balanced across treatment groups, with three subjects in the placebo group, two subjects each in the TAK-079 45 and 135 mg groups, and one subject in the TAK-079 90 mg group having dose withholdings based on laboratory evaluations, and one subject in the TAK-079 45 mg group having dose withholdings based on an event of clinical interest.

[0524] AE A pretreatment event (PTE) was defined as any adverse medical occurrence that occurred in a clinical trial subject who signed informed consent to participate in the study but before administration of the study drug, and which did not necessarily have a causal relationship to study participation.

[0525] An AE was defined as any adverse medical occurrence occurring in a clinical investigational subject receiving a drug, which did not necessarily have a causal relationship to this treatment. Thus, an AE could be any untoward and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally related to the use of a drug, regardless of whether it was considered drug-related. A TEAE was defined as an AE with onset occurring after receiving the investigational drug. An SAE was an adverse event resulting in any of the following outcomes or deemed significant for any other reason: death, first or prolonged hospitalization, life-threatening experience (imminent risk of death), persistent or significant disability / incapacity, congenital anomaly, or any event or symptom listed in Table 27. A TEAE was defined as an AE occurring after the first dose of investigational drug administered during the treatment period and occurring through the end of safety follow-up. The terms "serious TEAE" and "treatment-emergent SAE" can be considered interchangeable herein. The severity of TEAEs is graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 definitions of Grade 1 to Grade 5. Grade 1 is mild, with asymptomatic or mild symptoms, clinical or diagnostic observation only, and no intervention required. Grade 2 is moderate, requiring minimal, local, or noninvasive intervention and limiting age-appropriate instrumental activities of daily living. Grade 3 is severe or medically significant but not immediately life-threatening, requiring hospitalization or prolonged hospitalization, disabling status, and limiting self-care activities of daily living. Grade 4 is life-threatening and requires urgent intervention. Grade 5 is death related to the AE.

[0526] [Table 27]

[0527] PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0.

[0528] A summary of TEAEs is presented in Table 28.

[0529] [Table 28]

[0530] The most common TEAEs (occurring in ≥3 subjects across all TAK-079 groups) are presented in Table 29 by SOC and PT.

[0531] [Table 29]

[0532] Analysis of AEs TEAEs were uncommon in study participants. The two most common TEAEs, regardless of causality, were nausea and urinary tract infection. Zero subjects in the placebo group and four subjects (23.5%) in the pooled TAK-079 group reported the TEAE urinary tract infection, and one subject (20.0%) in the placebo group and three subjects (17.6%) in the pooled TAK-079 group reported the TEAE nausea (Table 31). All other TEAEs were reported by two or fewer subjects. All TEAEs had a maximum intensity of CTCAE grade 1 or grade 2.

[0533] Deaths, other SAEs, and other significant AEs List of deaths, other SAEs, and other significant AEs death No deaths occurred during the study.

[0534] Other SAEs Two treatment-emergent SAEs occurred during the study: palpitations reported by a subject in the TAK-079 45 mg group and dyspnea reported by a subject in the TAK-079 135 mg group (Table 30). Both of these treatment-emergent SAEs were CTCAE Grade 2, determined to be unrelated to study drug, and followed with an outcome of recovery / resolution. The palpitations event did not result in any change in study drug, and the dyspnea event resulted in discontinuation of study drug.

[0535] [Table 30]

[0536] Other significant AEs The most common non-serious adverse events (AEs) are presented in Table 31.

[0537] [Table 31-1]

[0538] [Table 31-2]

[0539] [Table 31-3]

[0540] Drug-related TEAEs In total, one subject (20.0%) in the placebo group and three subjects (one from each dose group) (17.6%) in the pooled TAK-079 group experienced a TEAE that was considered to be study drug-related by the investigator (Table 32).

[0541] [Table 32]

[0542] TEAEs leading to discontinuation of study drug One subject (20.0%) 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.

[0543] TEAEs leading to dose modification Dose modifications in this study consisted of either dose interruptions or study drug discontinuation. Zero subjects in the placebo group and two subjects (11.8%) in the pooled TAK-079 groups reported TEAEs that led to dose modifications (including diarrhea, a TEAE reported by one subject in the TAK-079 45 mg group, and dyspnea, a TEAE reported by one subject in the TAK-079 135 mg group). The dyspnea event was serious and also led to study drug discontinuation, as further described in the "Other SAEs" section.

[0544] Analysis and Discussion of Deaths, Other SAEs, and Other Significant AEs No subjects reported life-threatening or fatal AEs, and two subjects reported serious TEAEs. None of the serious TEAEs were considered to be study drug-related.

[0545] There were no cases of CRS or local injection site reactions in this study. From a systemic perspective, one CTCAE Grade 2 TEAE event, pyrexia, was observed in a subject in the TAK-079 135 mg group the day after Dose 1. This event was considered a hypersensitivity reaction. This was considered study drug-related, did not lead to a dose modification, and was treated with 1000 mg paracetamol with a resolution / resolution outcome.

[0546] serum chemistry No trends were observed in mean serum chemistry parameters or changes from baseline. The higher mean serum creatinine observed in the TAK-079 135 mg group compared with the other treatment groups was driven by one subject who had elevated serum creatinine at baseline, which did not worsen and persisted throughout the study. This subject had underlying chronic kidney disease at the start of the study.

[0547] There was no shift from baseline to post-baseline by more than 1 CTCAE grade in any serum chemistry parameter.

[0548] There were no adverse events related to serum chemistry parameters during the study.

[0549] hematology There were no trends observed in the mean values ​​or changes from baseline of hematological parameters.

[0550] Baseline to post-baseline shifts of >1 CTCAE grade in hematology parameters included a shift in blood neutrophils from baseline Grade 0 to worst post-baseline Grade 2 in one subject in the placebo group and one subject in the TAK-079 45 mg group, and a shift in blood lymphocytes from baseline Grade 0 to worst post-baseline Grade 2 in one subject in the TAK-079 45 mg group.

[0551] There were no adverse events related to hematological parameters during the study.

[0552] Urine tests There were no observed trends in the mean or change from baseline in urinalysis parameters other than a higher urinary protein-to-creatinine ratio (UPCR) in the TAK 135 mg group compared with the other treatment groups. The higher mean UPCR in this treatment group was driven by two subjects with elevated UPCR values ​​at baseline that persisted throughout the study. One of these two subjects had a diagnosis of chronic kidney disease at the start of the study.

[0553] Baseline to post-baseline shifts of >1 CTCAE grade in urinalysis parameters included a shift from baseline Grade 0 to worst post-baseline Grade 2 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.

[0554] There were no adverse events related to urinalysis parameters during the study.

[0555] Other test results No significant results were observed in other test results.

[0556] Vital signs There were no trends observed in the means or changes from baseline of vital sign parameters.

[0557] Physical examination Physical examination was focused on symptoms and SLE disease. Any significant clinical findings were recorded as AEs (see "AEs" section for AEs).

[0558] ECG No trends were observed in the means or changes from baseline of ECG parameters.

[0559] At baseline, all subjects reported normal or clinically insignificant abnormal ECG results, and no subjects reported a shift to clinically significant abnormal post-baseline results at any time point.

[0560] Safety Biomarkers Safety-related biomarkers were based on A167 QTBNK flow cytometry analysis. For safety assessment related to potential depletion of immune cell populations, CD3 + Total T cells, CD8 + cytotoxic T cells, CD4 + Helper T cells, B cells, and monocytes were examined.

[0561] The overall effect of TAK-079 on the cell counts of these cell types was modest and did not appear to differ across doses. + Total T cells and CD4 +Helper T cells, B cells, and monocytes showed a mean decrease of less than 20.0% from baseline across the pooled TAK-079 groups throughout the study period. CD8 + Cytotoxic T cells showed a maximum mean decrease of 32.8% from baseline, which was observed 2 days after the first dose and was transient as cell numbers returned to baseline by pre-dose on day 22. The placebo group did not show significant depletion in any of the aforementioned cell populations.

[0562] pregnancy No pregnancies were reported during the study.

[0563] Safety Conclusions Overall, TAK-079 was well tolerated, with no substantial imbalance in AEs between treatment arms, and no dose-dependent effects or safety concerns identified.

[0564] Seventeen subjects were exposed to TAK-079 during the study.

[0565] Reported AE events were balanced across placebo and treatment groups and are consistent with the reported safety profiles of the individual agents (hydroxychloroquine, prednisone, gabapentin, and mycophenolate). Infections and cytopenias did not pose clinical problems in this study.

[0566] The TEAEs of urinary tract infection and nausea were each reported by four subjects, and all other TEAEs were reported by two or fewer subjects.

[0567] All TEAEs had a maximum intensity of CTCAE Grade 1 or Grade 2. No AEs were life-threatening or fatal.

[0568] Two subjects reported treatment-emergent SAEs (including palpitations reported by a subject in the TAK-079 45 mg group and dyspnea reported by a subject in the TAK-079 135 mg group). Neither was study drug related. The dyspnea event led to study drug discontinuation. In total, four subjects (one from each treatment group) experienced TEAEs that were considered study drug related by the investigator.

[0569] There was one case of hypersensitivity reaction and no cases of cytokine release syndrome or injection site reactions.

[0570] There were no clinically significant findings related to laboratory evaluation, vital signs, or ECG.

[0571] The overall effects of TAK-079 on CD3+ total T cell, CD8+ cytotoxic T cell, CD4+ helper T cell, B cell, and monocyte cell counts were modest and did not appear to differ between doses.

[0572] Overall, TAK-079 was well tolerated. There were no substantial imbalances in AEs between treatment arms, and no dose-dependent effects or safety concerns were identified.

[0573] Discussion and Overall Conclusions Consideration The primary objective of this study was to evaluate the safety and tolerability of TAK-079 in subjects with SLE. To this end, TAK-079 was well tolerated, and no safety concerns were identified in this study. The TAK-079 safety profile was consistent with that observed in a first-in-human study (TAK-079_101) in healthy volunteers. There was no substantial imbalance in AEs between treatment groups. All TEAEs had a maximum intensity of CTCAE Grade 1 or Grade 2. Four subjects (one from each treatment group) experienced non-serious TEAEs that were deemed drug-related by the investigator. Neither of the two reported treatment-emergent SAEs was considered related. The most commonly reported AEs were urinary tract infection and nausea, each reported by a total of four subjects. There were no cases of CRS or local injection site reactions in this study, and one case of hypersensitivity reaction. Safety dose withholdings were balanced across treatment groups, and there was no dose-dependent trend for increased safety-related dose withholdings among TAK-079 treatment groups.

[0574] Secondary objectives of this study were to evaluate the PK, PD, and immunogenicity of TAK-079 in patients with SLE. TAK-079 exposure appeared to increase in a greater-than-dose-proportional manner across the dose range tested, consistent with observations from the first-in-human study (TAK-079-101) and nonclinical studies (TAK-079-10666). The apparent nonlinearity of TAK-079 PK is consistent with target-mediated drug elimination often observed with mAbs and arises from binding to abundant cellular receptors such as CD38. Peak concentrations were generally observed 108 hours (4.5 days) post-dose, consistent with expectations for SC drug administration. Due to limited data, other PK parameters were not evaluated in this study. Incomplete concentration-time profiles in most subjects also prevented adequate assessment of drug accumulation after multiple doses and determination of the impact of ADAs on exposure. Overall, there was substantial variability in serum TAK-079 concentrations, and interpretation of PK data was confounded by dose holds, early discontinuations, and excluded samples.

[0575] Target binding of TAK-079 on the CD38 antigen was assessed by receptor occupancy on CD38+ NK cells. Although NK cells are not the target cells involved in autoantibody production, they serve as a surrogate PD marker because they are abundant in peripheral blood and highly express the receptor. Target binding by TAK-079 on CD38+ NK cells was dose-dependent, with peak occupancy coinciding with maximal CD38+ NK cell depletion. Receptor occupancy did not saturate at the dose tested and was not sustained within the dosing interval. The return of receptor occupancy on CD38+ NK cells to baseline was paralleled by partial recovery of this cell population by the next dose, which likely benefits the cytotoxicity of TAK-079 against antibody-producing cells, given the importance of these effector cells in driving ADCC effects.

[0576] Limited decreases in immunoglobulins were observed, with the best response seen for IgA. The greatest change in IgG was observed with the 135 mg dose of TAK-079, with the other two dose levels showing minimal differences compared to the placebo group. The decrease in total immunoglobulins was generally not accompanied by changes in autoantibody concentrations at the individual level, which may be partially attributable to the overall modest immunoglobulin response. Furthermore, results were confounded by dose withholding and small case numbers.

[0577] The therapeutic hypothesis for investigating TAK-079 in SLE was based on targeting CD38-expressing cells, such as plasma cells and PBs, and therefore reducing the production of pathogenic autoantibodies. In this study, subjects were enrolled in a clinical trial with anti-dsDNA, anti-SmD, and pPatients were required to be positive for at least one of the following autoantibodies: ribonucleoprotein-70, Sjögren's syndrome-A, or Sjögren's syndrome-B. In addition, five other lupus-associated autoantibodies were evaluated. The reduction in autoantibodies for which patients were positive at baseline did not appear to correlate with efficacy measures assessed by clinical assessment scales such as the CLASI, SLEDAI-2K, and PGA, which appears consistent with literature reports (Marks and Tullus (2012) Pediatr. Nephrol. 27(10):1855-68; Pisetsky (2020) J. Autoimmun. 110:102356). The apparent lack of agreement may also be due to insufficient depletion of plasma cells, resulting in limited reduction of immunoglobulins. Additionally, given that each autoantibody may have a different pathogenic contribution to disease activity (Dema and Charles (2016) Antibodies (Basel) 5(1):2), and that some subjects tested positive for more than one autoantibody, more uniform suppression of all autoantibodies in a given patient may be required to observe a correlation between autoantibody reduction and clinical improvement. The clinical response in some subjects in the absence of PD effects warrants investigation of the potential contribution of additional mechanisms unrelated to antibody-producing target cells to gain better insight into the link between downstream pharmacology of CD38 targeting and clinical efficacy.

[0578] Overall, the PD results suggest that the dosing regimen of TAK-079 in SLE may be optimized, such that higher doses and / or more frequent dosing schedules may result in more potent PD effects. The degree of depletion observed for CD38-expressing cells (i.e., PB and NK cells) in peripheral blood was consistent with the results of the first-in-human study (TAK-079_101), which informed dose selection in this study. However, the magnitude of the decrease in total immunoglobulins in SLE was less substantial than in healthy subjects, which may be explained by changes in the immune landscape in the disease state.

[0579] The incidence of treatment-emergent and pre-existing ADAs was 23.8%, respectively, resulting in an overall ADA positivity rate of 47.6% in this study. No clear association was observed between immunogenicity and PK / PD, efficacy, or safety. The relatively high ADA positivity rate in this study may be due to the active immune status of patients with SLE autoimmune disease (Faustini et al. (2021) Arthritis Res. Ther. 23(1):211-23). ​​In addition, scheduled interruptions in study drug administration may have contributed to ADA occurrence; three of five subjects with treatment-emergent ADA reactions had detectable titers after TAK-079 administration was withheld. A high incidence of ADA formation in autoimmune patients has been observed in studies using biologics where treatment was intermittent or included long drug-free periods (Atiqi et al. (2020) Front. Immunol. 11:312). The immunogenicity results may also be due in part to the low dose investigated in this study, which is associated with a higher risk of ADA reactions (Mok et al. (2016) Expert Opin. Biol. Ther. 16(2):201-11).

[0580] The exploratory objective of this study was to evaluate the effect of repeated administration of TAK-079 on disease activity using various clinical assessment scales for SLE. The study's greatest limitation with respect to this objective was its inability to assess the significance of clinical scores across groups. Additionally, the COVID-19 pandemic led to numerous discontinuations and missed doses, further reducing the number of subjects available for efficacy evaluation within each cohort.

[0581] An additional limitation with regard to the exploratory efficacy endpoints was the relatively high placebo response observed in this study. This is not an uncommon phenomenon in SLE trials due to the allowance of concomitant background therapy, the administration of rescue medications, inadequate clinical assessment scales, reporter bias, and heterogeneity of patient populations (Mahieu et al. (2016) Lupus 25(10):1122-40). The use of rescue therapy may interfere with the measurement of the true effect of the investigational drug and may also incite placebo responses in SLE clinical trials (Mahieu et al. (2016) Lupus 25(10):1122-40). Although this study was designed to recruit subjects who had not adequately responded to standard SLE background therapy and who had not actually recently had a moderate to severe acute flare, all subjects recruited to this study were receiving stable background therapy for SLE throughout the study period. Although there were no additions to background medications or increases in ongoing background medication doses during the treatment period, patients in the study were receiving a variety of different SLE medications and doses, making it difficult to distinguish the true effect of the investigational drug from the effect of ongoing background medications. Therefore, it is plausible that stable background medication use contributed to the efficacy results of this study, and that mild to moderate improvements in SLE symptoms were observed in the placebo group regardless of the assessment tool. The positive results observed in the placebo group may be further supported by the use of slightly higher mean corticosteroid doses in this group compared with the TAK-079 90 mg and 135 mg groups.

[0582] There is no consensus among drug developers regarding the best way to conduct efficacy trials for SLE. Currently available, most commonly used outcome measures, such as the SLEDAI-2K, were primarily developed from observational datasets rather than prospective, randomized clinical trials. Therefore, they are not optimally designed to capture multiorgan clinical responses in heterogeneous SLE patient populations (Mahieu et al. (2016) Lupus 25(10):1122-40). The clinical assessment measures used in this study have various advantages and disadvantages. The SLEDAI-2K is an effective tool for measuring changes in global disease activity but does not respond to deterioration or improvement of individual organ systems (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 disease beyond the typical "rash," with 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 trial and the high number of patients with a CLASI below 5 limited the usefulness of this scale during the trial, leading to a floor effect. Evaluation of the 44-joint assessment scale aimed to more precisely characterize joint involvement and associated treatment benefit. 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 to be the most comprehensive disease activity index (Ohmura (2021) Mod. Rheumatol. 31(1):20-8), this study showed poor sensitivity, with only approximately 70% of study patients across treatment groups meeting responder criteria; of these, 100% of placebo study patients met PGA responder criteria at the end of treatment.

[0583] In future trials, utilizing a more severe SLE patient population with specific clinical findings may be more appropriate for evaluating efficacy and / or mechanistic evidence. Inclusion of patients with higher baseline SLEDAI-2K scores and lupus nephritis may facilitate validation of TAK-079's mechanism of action in reducing anti-dsDNA antibodies, as shown in another SLE study using an anti-CD38 antibody (Ostendorf et al. (2020) N. Engl. J. Med. 383(12):1149-55). Additionally, evaluation of more targeted disease biomarkers of cutaneous lupus, such as type I interferon gene signatures, would provide a better mechanistic understanding of the trends observed among patients with higher baseline CLASI scores. Requiring a minimum CLASI score in future trials may minimize the floor effect observed in this study and therefore help assess whether patients with more severe skin disease can effectively benefit from TAK-079 treatment.

[0584] Although a potential trend toward more severe CLASI responses was identified in patients with higher baseline scores, there was a lack of associated PD effects to support the observed clinically relevant improvement in skin symptoms. This warrants further investigation into the potential contribution of additional mechanisms of TAK-079 unrelated to antibody-producing target cells. More targeted in vitro and in vivo studies are needed to further evaluate whether TAK-079 may elicit clinical benefit in patients with severe SLE and / or moderate-to-severe cutaneous lupus.

[0585] The clinical responses (particularly in terms of CLASI scores) in the absence of immunoglobulin depletion in some subjects (Figure 6B) warranted investigation into consequences of CD38 blockade independent of antibody-producing target cells. CyTOF analysis identified changes in the immune landscape after treatment, including a decrease in Breg, pDC, and NK cells. Alterations in upstream regulatory populations may have significant effects on effector cells (e.g., pDC loss and altered type I IFN signaling) and, more broadly, on the immune landscape. To this end, unbiased cluster analysis identified two clusters representing populations with characteristics of effector CD4 and CD8 T cells (among others). Both of these populations appeared to have a therapeutic effect, although this was most pronounced only at the highest tested dose.

[0586] We evaluated more targeted cutaneous lupus biomarkers to gain a mechanistic understanding of the severe CLASI response. These results demonstrated a reduction in the type I IFN gene signature from whole blood RNA, suggesting a systemic reduction in the inflammatory response but potentially not directly linked to cutaneous findings. Skin biopsies were not performed in this study, precluding evaluation of tissue IFN expression and the immune cells involved in its production (e.g., plasmacytoid dendritic cells and keratinocytes).

[0587] conclusion Seventeen patients with moderate to severe SLE received TAK-079 in combination with background therapy. The study drug was well tolerated, and no safety concerns were identified. Study drug exposure was balanced across treatment groups, but exposure was low, with the majority of missed doses due to pre-specified sponsor-initiated safety holds and the COVID-19 pandemic.

[0588] TAK-079 exposure in patients with SLE was nonlinear at the doses tested, likely due to the antibody's high affinity binding to the CD38 target. Reductions in total immunoglobulins and autoantibodies were modest at the doses tested and did not appear to correlate with each other or with clinical response. PD results suggest that it may be possible to optimize the dosing regimen of TAK-079 in SLE, such that higher doses and / or more frequent dosing schedules may result in more sustained target binding and more substantial changes in downstream pharmacology.

[0589] The overall ADA positivity rate in this study was relatively high, with approximately 24% of patients ADA-positive at baseline, but no clear association was observed between immunogenicity and PK / PD, efficacy, or safety.

[0590] Clinical efficacy was an exploratory endpoint, and the study was unable to provide definitive efficacy conclusions. No observable differences from placebo were observed on any clinical assessment measure, longitudinally, or in the responder analysis.

[0591] Overall, data from this study suggest that mezagitamab has a favorable safety profile, promising pharmacodynamic effects, and favorable mechanistic data that support continued investigation in autoimmune diseases.

[0592] In conclusion, the study met its primary safety endpoint, and TAK-079 was well tolerated at all doses tested in subjects with moderate to severe SLE.

[0593] Example 5: TAK-079 antibody structure This example provides a summary of the structural characterization of the TAK-079 antibody. The TAK-079 amino acid sequence is detailed in Table 2. The locations of disulfide bridges are detailed in Table 33.

[0594] [Table 33] Glycosylation details (position and type of sugar residue): HC contains a consensus asparagine-linked (N-linked) glycosylation site at residue Asn303 (303 and 303''). The major species have been tentatively identified as G0F (asialo-, agalacto-, core-fucosylated biantennary glycan), G0 (asialo-, agalacto-, biantennary glycan), M5 (oligomannose 5), and G1F (asialo-, monogalacto-, core-fucosylated biantennary glycan).

[0595] LC N-terminal glutamine cyclization to Glp (5-oxoproline, pyroglutamic acid).

[0596] L VL Q1>Glp(1', 1''').

[0597] C terminal clipping: H CHS K2: 453, 453''.

[0598] The precursor nucleotide sequence is detailed in Table 34.

[0599] [Table 34]

[0600] Material Characterization molecular weight The predicted molecular weight of the unmodified antibody based on the DNA sequence is 144,421 daltons (Da). The molecular weight of the major species of the intact antibody determined by ESI-MS is approximately 147,280 Da.

[0601] The CDR-IMGT (closest V, J, and C genes and alleles) are detailed in Table 35.

[0602] IG class / subclass: IgG1.

[0603] Species / taxonomic related structures: Human.

[0604] Antigen target: CD38.

[0605] Expression system: CHO-K1SV.

[0606] Clone name(s): M3C6.

[0607] [Table 35]

[0608] Incorporation by Reference The contents of all cited references (including literature references, patents, patent applications, and websites) that may be cited throughout this application, as well as the references cited therein, are hereby expressly incorporated by reference in their entirety for all purposes to the same extent as if each respective reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0609] equivalent The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the above-described embodiments should be considered in all respects as illustrative and not limiting of the present disclosure. The scope of the present disclosure is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein. Modifications for carrying out the present invention that are obvious to those skilled in the art are intended to be within the scope of the appended claims.

Claims

1. A therapeutic agent for moderate or severe systemic lupus erythematosus (SLE) in a subject, comprising a human anti-CD38 antibody or its antigen-binding fragment, The antibody or its antigen-binding fragment A variable heavy chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, A variable light chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, A drug comprising the antibody or its antigen-binding fragment, administered subcutaneously to the subject in a dose of approximately 40 milligrams to approximately 140 milligrams.

2. An agent comprising a human anti-CD38 antibody or its antigen-binding fragment, for reducing the levels of plasmablasts and / or plasma cells in a subject diagnosed with moderate or severe SLE, The antibody or its antigen-binding fragment A variable heavy chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, A variable light chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, A drug comprising the antibody or its antigen-binding fragment, administered subcutaneously to the subject in a dose of approximately 40 milligrams to approximately 140 milligrams.

3. An agent comprising a human anti-CD38 antibody or its antigen-binding fragment, for reducing immunoglobulin levels in a subject diagnosed with moderate or severe SLE, The antibody or its antigen-binding fragment A variable heavy chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, A variable light chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, A drug comprising the antibody or its antigen-binding fragment, administered subcutaneously to the subject in a dose of approximately 40 milligrams to approximately 140 milligrams.

4. The agent according to claim 3, wherein the immunoglobulin is IgA, IgG, and / or IgM.

5. An agent comprising a human anti-CD38 antibody or its antigen-binding fragment, which reduces the level of one or more autoantibodies in a subject diagnosed with moderate or severe SLE, The antibody or its antigen-binding fragment A variable heavy chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, A variable light chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, A drug comprising the antibody or its antigen-binding fragment, administered subcutaneously to the subject in a dose of approximately 40 milligrams to approximately 140 milligrams.

6. The one or more autoantibodies mentioned above are anti-dsDNA and anti-SmD ｐ The agent according to claim 5, selected from the group consisting of beta-2 glycoprotein 1 IgM, ribonucleoprotein-70, Sjögren SS-A, and Sjögren SS-B.

7. The agent according to any one of claims 1 to 6, wherein the subject is diagnosed with severe SLE.

8. The agent according to any one of claims 1 to 6, wherein the antibody or antigen-binding fragment further comprises one or more manipulated glycoforms, the manipulated glycoform comprising glycosylation of one or more polypeptides, and optionally the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally the glycosylation is N-linked glycosylation.

9. The variable heavy chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 90% identity with SEQ ID NO: 9, and / or the variable light chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 90% identity with SEQ ID NO:

10. Optionally, the variable heavy chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO: 9, and / or the variable light chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO:

10. Optionally, the variable heavy chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 99% identity with SEQ ID NO: 9, and / or the variable light chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 99% identity with SEQ ID NO:

10. Optionally, the heavy chain of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO: 11, and / or the light chain of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO:

12. Optionally, the antibody or its antigen-binding fragment 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 SEQ ID NO number assignment, Optionally, the antibody or its antigen-binding fragment may be 10 －８ M binds to human CD38 (SEQ ID NO: 1) with a higher affinity than or equal to KD, and the affinity is measured by a standard Biacore assay. Optionally, the variable heavy chain region includes sequence number 9, and the variable light chain region includes sequence number 10. The agent according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment optionally comprises the heavy chain described in SEQ ID NO: 11 and the light chain described in SEQ ID NO:

12.

10. The antibody or its antigen-binding fragment further comprises an Fc domain, Optionally, the Fc domain may be a human Fc domain or a variant Fc domain. The agent according to any one of claims 1 to 6, wherein the antibody or antigen-binding fragment is optionally a human IgG antibody, and optionally the human IgG antibody is a human IgG1 antibody.

11. The agent according to any one of claims 1 to 6, wherein the subject receives a background SLE drug (or more), and optionally the background SLE drug (or more) is selected from the group consisting of immunosuppressants, steroids, and immunoglobulins, and optionally the background SLE drug (or more) is selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil, and / or mycophenolic acid.

12. The agent according to claim 11, wherein the background SLE agent(s) is administered in combination with the antibody or its antigen-binding fragment.

13. Administration of the antibody or its antigen-binding fragment reduces the incidence of one or more treatment-related adverse events (TRAEs) or treatment-induced adverse events (TEAEs) of grade 3 or 4 to less than 10%. Optionally, the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, parasitic invasion, fever (pyrexia), herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea. The agent according to any one of claims 1 to 6, wherein, optionally, administration of the antibody or its antigen-binding fragment causes one or more TRAEs or TEAEs to have the maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

14. The agent according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment is administered in 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, the antibody or its antigen-binding fragment is administered in a dose of about 45 mg, about 90 mg, or about 135 mg.

15. The agent according to any one of claims 1 to 6, wherein the dose is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

16. The agent according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment is administered in the form of a pharmaceutically acceptable composition, and optionally the pharmaceutically acceptable composition comprises the antibody or its antibody fragment and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

17. The agent according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment comprises a heavy chain as described in SEQ ID NO: 11 and a light chain as described in SEQ ID NO: 12, and the antibody or its antigen-binding fragment is administered subcutaneously once every three weeks for 12 weeks.

18. The agent according to any one of claims 1 to 6, wherein the antibody or its antigen-binding fragment is mezagitamab.

19. A variable heavy chain region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, A unit dosage form comprising an antibody or an antigen-binding fragment, comprising a variable light chain region including CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, The unit dosage form wherein the antibody or its antigen-binding fragment is bound to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the antibody or its antigen-binding fragment in doses of 40 milligrams to 140 milligrams for the treatment of moderate or severe systemic lupus erythematosus (SLE).

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

21. The unit dosage form according to claim 19, wherein the antibody or antigen-binding fragment further comprises one or more manipulated glycoforms, the manipulated glycoform comprising glycosylation of one or more polypeptides, optionally the glycosylation being N-linked glycosylation or O-linked glycosylation, and optionally the glycosylation being N-linked glycosylation.

22. The variable heavy chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 90% identity with SEQ ID NO: 9, and / or the variable light chain region of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 90% identity with SEQ ID NO:

10. Optionally, the variable heavy chain region includes an amino acid sequence having at least 95% identity with SEQ ID NO: 9, and / or the variable light chain region includes an amino acid sequence having at least 95% identity with SEQ ID NO:

10. Optionally, the variable heavy chain region includes an amino acid sequence having at least 99% identity with SEQ ID NO: 9, and / or the variable light chain region includes an amino acid sequence having at least 99% identity with SEQ ID NO:

10. Optionally, the heavy chain of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO: 11, and / or the light chain of the antibody or its antigen-binding fragment contains an amino acid sequence having at least 95% identity with SEQ ID NO:

12. Optionally, the antibody or its antigen-binding fragment 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 SEQ ID NO number assignment, Optionally, the antibody or its antigen-binding fragment may be 10 －８ M binds to human CD38 (SEQ ID NO: 1) with a higher affinity than or equal to KD, and the affinity is measured by a standard Biacore assay. Optionally, the variable heavy chain region includes sequence number 9, and the variable light chain region includes sequence number 10. The unit dosage form according to any one of claims 19 to 21, wherein the antibody or its antigen-binding fragment optionally comprises the heavy chain described in SEQ ID NO: 11 and the light chain described in SEQ ID NO:

12.

23. The antibody or its antigen-binding fragment further comprises an Fc domain, and optionally the Fc domain is a human Fc domain or a variant Fc domain. Optionally, the antibody or antigen-binding fragment is a human IgG antibody. The unit dosage form according to any one of claims 19 to 21, wherein the human IgG antibody is optionally a human IgG1 antibody.

24. The unit dosage form according to any one of claims 19 to 21, wherein the antibody or its antigen-binding fragment is used in combination with one or more background SLE drugs, optionally the background SLE drug(s) are selected from the group consisting of immunosuppressants, steroids, and immunoglobulins, optionally the background SLE drug(s) are selected from the group consisting of hydroxychloroquine, hydroxychloroquine sulfate, prednisone, methylprednisolone, gabapentin, mycophenolate mofetil, and / or mycophenolic acid, and optionally the unit dosage form further comprises the one or more background SLE drugs.

25. Administration of the antibody or its antigen-binding fragment reduces the incidence of one or more treatment-related adverse events (TRAEs) or treatment-induced adverse events (TEAEs) of grade 3 or 4 to less than 10%. Optionally, the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, parasitic invasion, fever (pyrexia), herpes zoster, urinary tract infection, skin and skin tissue disorders, headache, fever, chills, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, chest, and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea. The unit dosage form according to any one of claims 19 to 21, wherein, optionally, administration of the antibody or its antigen-binding fragment causes one or more TRAEs or TEAEs to have a maximum intensity of CTCAE grade 1 or grade 2.

26. The unit dosage form according to any one of claims 19 to 21, wherein the antibody or its antigen-binding fragment is administered in 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, the antibody or its antigen-binding fragment is administered in a dose of about 45 mg, about 90 mg, or about 135 mg.

27. The unit dosage form according to any one of claims 19 to 21, wherein the dose is a dose administered once a week, once every two weeks, once every three weeks, or once every four weeks.

28. A unit dosage form according to any one of claims 19 to 21, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

29. The unit dosage form according to any one of claims 19 to 21, wherein the antibody or its antigen-binding fragment comprises a heavy chain as described in SEQ ID NO: 11 and a light chain as described in SEQ ID NO: 12, and the antibody or its antigen-binding fragment is administered subcutaneously once every three weeks for 12 weeks.

30. The unit dosage form according to any one of claims 19 to 21, wherein the antibody or its antigen-binding fragment is mezagitamab.

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