Dosing regimens of Anti-CD38 antibodies for treatment of subjects with immune thrombocytopenia

Abstract

Methods for treating subjects with autoimmune diseases such as immune thrombocytopenia (ITP) by administering isolated anti-CD38 antibodies are disclosed. Also disclosed are unit dosage forms for the anti-CD38 antibodies used in treating subjects with autoimmune diseases such ITP.

Description

Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 DOSING REGIMENS OF ANTI-CD38 ANTIBODIES FOR TREATMENT OF SUBJECTS WITH IMMUNE THROMBOCYTOPENIA Cross Reference to Related Applications

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No.63 / 564,458 filed on March 12, 2024, U.S. Provisional Application Serial No. 63 / 647,966 filed on May 15, 2024, U.S. Provisional Application Serial No.63 / 661,008 filed on June 17, 2024, U.S. Provisional Application Serial No.63 / 713,022 filed on October 28, 2024, and U.S. Provisional Application Serial No.63 / 745,261 filed on January 14, 2025, the entire disclosures of which are incorporated herein by reference. Incorporation By Reference Of Material Submitted Electronically

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML file, created on March 10, 2025, is named 101588-5018-WO Sequence Listing.xml and is 14,814 bytes in size. Field

[0003] Methods for treating subjects with autoimmune diseases such as immune thrombocytopenia (ITP) by administering isolated anti-CD38 antibodies are disclosed. Also disclosed are unit dosage forms for the anti-CD38 antibodies used in treating subjects with autoimmune diseases such as ITP. Background

[0004] Immune thrombocytopenia (ITP), also known as immune thrombocytopenic purpura, is an autoimmune disorder that results in a decreased platelet count and may lead to bleeding events, some of which can be severe or life-threatening. Approximately 20% of subjects with ITP do not respond to currently available treatments, and an additional 20% to 30% of subjects who have an initial response experience relapse, resulting in increased bleeding-related morbidity and diminished quality of life. As such, there is an unmet need for a new safe and effective therapy for treating ITP, with a favorable safety profile, rapid onset of action, the 1DB2 / 47155346.6Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 potential to achieve disease remission and a new standard of long-term durable platelet response, off therapy. Summary

[0005] Provided herein are methods and unit dosage forms comprising anti-CD38 antibodies or antigen binding fragments thereof used in treating subjects with autoimmune diseases such as immune thrombocytopenia (ITP). AB79 (the drug substance component of mezagitamab) is a fully human recombinant monoclonal antibody (mAb) directed against CD38, an antigen that is highly expressed on plasma cells, plasmablasts, and natural killer (NK) cells and is induced on activated T cells and B cells. AB79 binds specifically to CD38 with high affinity (Kd = 3.5 nM) (US Patent No. US 8,362,211, the contents of which is hereby incorporated by reference in its entirety). AB79 administration results in depletion of cells expressing high levels of CD38 through a mechanism that involves apoptosis, antibody-dependent cell-mediated cytotoxicity, and complement-dependent cytotoxicity (Smithson et al. (2017) J. Immunol.198(1 Supplement): 224.20). AB79 depletes the cells that produce the pathogenic autoantibodies (plasmablasts, plasma cells, and especially long-lived plasma cells). A reduction in plasmablasts and long-lived plasma cells by mezagitamab is expected to result in a reduction in the levels of pathogenic autoantibodies, thereby improving the autoantibody-mediated pathology in ITP.

[0006] It is an objective of the present invention to provide methods of treating subjects with autoimmune diseases such as ITP by subcutaneous administration of an anti-CD38 antibody (e.g., mezagitamab).

[0007] The present disclosure provides methods and unit dosage forms for subcutaneous administration of a therapeutically effective amount of an isolated anti-CD38 antibody or antigen binding fragment to a subject with ITP. In some embodiments, the antibody or antigen binding fragment for subcutaneous administration comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody or DB2 / 47155346.6 2Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 antigen binding fragment for subcutaneous administration comprises a variable heavy chain (VH) region comprising or consisting of SEQ ID NO: 9 (or a sequence with 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 with at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity thereto). In some embodiments, the antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 mg to about 600 mg.

[0008] In some embodiments, the disclosure provides a method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0009] In some embodiments, the disclosure provides a method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0010] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg.

[0011] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered subcutaneously.

[0012] In some embodiments, the disclosure provides a method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ DB2 / 47155346.6 3Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0013] In some embodiments, the disclosure provides a method of reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0014] In some embodiments, the disclosure provides a method of reducing the level of immunoglobulin(s) in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0015] In some embodiments, the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in three weeks or DB2 / 47155346.6 4Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 less, two weeks or less, or one week or less. In some embodiments, the immunoglobulin(s) are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s).

[0016] In some embodiments, the disclosure provides a method of increasing platelet counts in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0017] In some embodiments, the disclosure provides a method of achieving platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0018] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0019] In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL and / or wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, the platelet response is further defined as a platelet count of ≥20,000 / μL above baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering. DB2 / 47155346.6 5Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0020] In some embodiments, the method achieves a platelet response in three weeks or less, two weeks or less, or one week or less.

[0021] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

[0022] In some embodiments, the disclosure provides method of achieving a durable platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0023] In some embodiments, the durable platelet response is defined as a sustained platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy, and wherein the platelet response is defined at a platelet count of ≥50,000 / μL. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from week 10 to week 24. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering.

[0024] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured DB2 / 47155346.6 6Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL).

[0025] In some embodiments, the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0026] In some embodiments, the disclosure provides a method of achieving complete platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0027] In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0028] In some embodiments, the disclosure provides a method of achieving a clinically meaningful platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a DB2 / 47155346.6 7Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0029] In some embodiments, the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL above baseline.

[0030] In some embodiments, the clinically meaningful platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0031] In some embodiments, the disclosure provides a method of achieving hemostatic platelet response in a subject in need thereof having a baseline platelet count of <15,000 / μL, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0032] In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline.

[0033] In some embodiments, the hemostatic platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0034] In some embodiments, the disclosure provides a method of reducing the level of anti- platelet autoantibodies in a subject diagnosed with immune thrombocytopenia (ITP), the method DB2 / 47155346.6 8Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:8 ; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0035] In some embodiments, the disclosure provides a method of reducing immune thrombocytopenia (ITP) disease activity and / or progression in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0036] In some embodiments, the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP- PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L). In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who DB2 / 47155346.6 9Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 had at least one menstrual period within 12 months before the receiving the isolated antibody. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering. In some embodiments, wherein the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

[0037] In some embodiments, the disclosure provides a method of reducing bleeding events in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0038] In some embodiments, the bleed events are measured by Immune Thrombocytopenia- specific Bleeding Assessment Tool (ITP-BAT). In some embodiments, the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

[0039] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in ITP remission. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

[0040] In some embodiments, the disclosure provides a method of treating immune thrombocytopenia (ITP) in a subject diagnosed with ITP, the method comprising administering DB2 / 47155346.6 10Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 to the subject an isolated human anti-CD38 antibody, wherein the isolated antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein: the ITP is chronic primary ITP or persistent primary ITP; the subject has had an insufficient response or intolerance to other therapy; the other therapy is a first-line ITP therapy and / or a second-line ITP therapy, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); the isolated antibody is subcutaneously administered in a dosage of about 600 mg in a course of once per week for 8 weeks; optionally wherein the isolated antibody is further administered in more than one course of once per week for 8 weeks; and / or optionally wherein the isolated antibody is not further administered for a period of 8 weeks.

[0041] In some embodiments, the subject in need thereof is diagnosed with immune thrombocytopenia (ITP). In some embodiments, the ITP is primary ITP. In some embodiments, the ITP is persistent ITP. In some embodiments, the ITP is chronic ITP. In some embodiments, the ITP is persistent primary ITP. In some embodiments, the ITP is chronic primary ITP. In some embodiments, the primary ITP has persisted for at least about 3 months.

[0042] In some embodiments, the subject has had a prior response to other therapy excluding a thrombopoietin receptor agonist (TPO-RA), wherein the prior response is defined as achieving a platelet count of ≥50,000 / mL.

[0043] In some embodiments, wherein the subject has a baseline mean platelet count of <30,000 / µL from at least 2 consecutive measurements taken at least about 5 days apart; optionally wherein the baseline mean platelet count comprises individual values ≤35,000 / µL. DB2 / 47155346.6 11Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0044] In some embodiments, the subject has had an insufficient response or intolerance to other therapy. In some embodiments, the other therapy is a first-line ITP therapy and / or a second-line ITP therapy. In some embodiments, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone). In some embodiments, the insufficient response to other treatment is defined as failure to achieve a sustained platelet count of at least 50,000 / µL or doubling of baseline platelet count after an appropriate course of the other therapy. In some embodiments, the intolerance to other therapy is defined as a documented side effect causing discontinuation of the therapy.

[0045] In some embodiments, the subject in need thereof has an ITP disease duration (e.g., mean ITP disease duration) of at least about 0.1 years, at least about 0.3 years, at least about 0.5 years, at least about 1 year, at least about 5 years, or at least about 10 years.

[0046] In some embodiments, the subject in need thereof has received a mean of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13 prior ITP treatments.

[0047] In some embodiments, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA), and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone).

[0048] In some embodiments, the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides. In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. DB2 / 47155346.6 12Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0049] In some embodiments, the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10.

[0050] In some embodiments, the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10.

[0051] In some embodiments, the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10.

[0052] In some embodiments, the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11; and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0053] In some embodiments, the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 14; and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0054] In some embodiments, 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.

[0055] In some embodiments, the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10-8M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay. DB2 / 47155346.6 13Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0056] In some embodiments, the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10.

[0057] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12.

[0058] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12.

[0059] In some embodiments, the isolated antibody or antigen binding fragment thereof further comprises an Fc domain. In some embodiments, the Fc domain is a human Fc domain or a variant Fc domain. In some embodiments, the isolated antibody or antigen binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0060] In some embodiments, the subject receives background ITP medication(s). In some embodiments, the background ITP medication(s) is one or more selected from the group consisting of a thrombopoietin receptor agonist (TPO-RA), a corticosteroid, an immunosuppressant, and an inhibitor. In some embodiments, the background ITP medication(s) is one or more selected from the group consisting of romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and dexamethasone. In some embodiments, the background ITP medication(s) is administered in combination with the isolated antibody or antigen binding fragment thereof.

[0061] In some embodiments, the subject in need thereof has a baseline mean platelet count of less than or equal to about 40×109 / L, less than or equal to about 35×109 / L, less than or equal to about 30×109 / L, less than or equal to about 25×109 / L, or less than or equal to about 20×109 / L.

[0062] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a length of platelet response of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, or at least about 25 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject DB2 / 47155346.6 14Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥50,000 / μL.

[0063] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL and / or wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering. In some embodiments, the platelet response is further defined as a platelet count of ≥20,000 / μL above baseline.

[0064] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response in three weeks or less, two weeks or less, or one week or less.

[0065] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

[0066] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a sustained platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy, and wherein the platelet response is defined at a platelet count of ≥50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable DB2 / 47155346.6 15Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering.

[0067] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL).

[0068] In some embodiments, the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0069] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering. In some embodiments, the subject has not received a rescue therapy in the previous four weeks. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering.

[0070] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0071] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. DB2 / 47155346.6 16Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0072] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL.

[0073] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than 75%, less than 50%, or less than 25% incidence of use of a rescue therapy. In some embodiments, the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the method does not include the use of a rescue therapy.

[0074] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP disease activity and / or progression in a subject diagnosed with ITP. In some embodiments, the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP- PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L); optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease DB2 / 47155346.6 17Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

[0075] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in bleeding events in the subject. In some embodiments, the bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP- BAT). In some embodiments, the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

[0076] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in ITP remission. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

[0077] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s). In some embodiments, the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in three weeks or less, two weeks or less, or one week or less. In some embodiments, the immunoglobulin(s) are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s).

[0078] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst. In some embodiments, a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2. In some embodiments, administering DB2 / 47155346.6 18Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 the isolated antibody or antigen binding fragment thereof results in a reduction in ITP-associated bleeding adverse events (AEs) relative to placebo.

[0079] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in dose and / or frequency of use of background ITP medication(s).

[0080] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, and about 600 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0081] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered once every week, once every two weeks, once every three weeks or once every four weeks.

[0082] In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered once per week for 8 weeks. In some embodiments, (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks. In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; and (d) the DB2 / 47155346.6 19Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 isolated antibody is not administered for a period of from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks.

[0083] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in the form of a pharmaceutically acceptable composition. In some embodiments, the pharmaceutically acceptable composition comprises the isolated antibody or antigen binding fragment thereof and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0084] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

[0085] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

[0086] In some embodiments, the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0087] In some embodiments, the isolated antibody or antigen binding fragment thereof is from about 2 times to about 4 times more efficacious than fostamatinib and / or efgartigimod. In some embodiments, the isolated antibody or antigen binding fragment thereof results in from about 2 times to about 4 times more durable platelet response as compared to fostamatinib and / or efgartigimod. DB2 / 47155346.6 20Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0088] In some embodiments, the disclosure provides a unit dosage form comprising an isolated antibody or antigen binding fragment thereof that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; 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 isolated antibody or antigen binding fragment thereof at a dosage of from about 100 mg to about 600 mg in the treatment of ITP.

[0089] In some embodiments, the disclosure provides a unit dosage form comprising an isolated human anti-CD38 antibody that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; 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 isolated antibody or antigen binding fragment thereof at a dosage of about 600 mg in a course of once per week for 8 weeks in the treatment of chronic primary ITP or persistent primary ITP in a subject that has had an insufficient response or intolerance to other therapy; wherein the other therapy is a first-line ITP therapy and / or a second- line ITP therapy, wherein the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); optionally wherein the isolated antibody is further administered in more than DB2 / 47155346.6 21Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 one course of once per week for 8 weeks, and / or optionally wherein the isolated antibody is not further administered for a period of 8 weeks.

[0090] In some embodiments, the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides. In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation.

[0091] In some embodiments, the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10.

[0092] In some embodiments, the variable heavy chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10.

[0093] In some embodiments, the variable heavy chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10.

[0094] In some embodiments, the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11, and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0095] In some embodiments, the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 14, and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12. DB2 / 47155346.6 22Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0096] In some embodiments, 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.

[0097] In some embodiments, the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10-8M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay.

[0098] In some embodiments, the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10.

[0099] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12.

[0100] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12.

[0101] In some embodiments, 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 or a variant Fc domain. In some embodiments, the isolated antibody or antigen binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0102] In some embodiments, wherein the isolated antibody or antigen binding fragment thereof is used in combination with one or more background ITP medication(s). In some embodiments, the background ITP medication(s) is one or more selected from the group consisting of a thrombopoietin receptor agonist (TPO-RA), a corticosteroid, an immunosuppressant, and an inhibitor. In some embodiments, the background ITP medication(s) is one or more selected from the group consisting of romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and dexamethasone. DB2 / 47155346.6 23Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0103] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a length of platelet response of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, or at least about 25 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥50,000 / μL.

[0104] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL and / or wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is further defined as a platelet count of ≥20,000 / μL above baseline. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering.

[0105] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is achieved in three weeks or less, two weeks or less, or one week or less. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

[0106] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a durable platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy, and wherein the platelet response is defined at a platelet count of ≥50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in DB2 / 47155346.6 24Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 a durable platelet response, wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering.

[0107] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL).

[0108] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0109] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering.

[0110] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful DB2 / 47155346.6 25Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0111] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL.

[0112] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL.

[0113] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than 75%, less than 50%, or less than 25% incidence of use of a rescue therapy. In some embodiments, the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the unit dosage form does not include the use of a rescue therapy.

[0114] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP disease activity and / or progression in a subject diagnosed with ITP. In some embodiments, the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP- PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L); optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, DB2 / 47155346.6 26Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

[0115] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in bleeding events in the subject. In some embodiments, the bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP- BAT). In some embodiments, the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

[0116] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in ITP remission. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

[0117] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s). In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s), wherein the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s), wherein the reduction in immunoglobulin(s) is achieved in three weeks or less, two weeks or less, or one week or less. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s), wherein the immunoglobulin(s) are DB2 / 47155346.6 27Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s).

[0118] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst. In some embodiments, a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results a reduction in ITP-associated bleeding adverse events (AEs) relative to placebo.

[0119] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in dose and / or frequency of use of background ITP medication(s).

[0120] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, and about 600 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg. In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0121] In some embodiments, the dosage is a dosage administered once every week, once every two weeks, once every three weeks or once every four weeks.

[0122] In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 DB2 / 47155346.6 28Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered once per week for 8 weeks. In some embodiments, (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks. In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; and (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks.

[0123] In some embodiments, the unit dosage form further comprises at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0124] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

[0125] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks. DB2 / 47155346.6 29Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0126] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered to a subject once a week for 8 weeks.

[0127] In some embodiments, the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of about 600 mg.

[0128] In some embodiments, the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0129] In some embodiments, the ITP is persistent or chronic ITP in an adult human.

[0130] In some embodiments, the subject is an adult.

[0131] In some embodiments, the subject has had an insufficient response or intolerance to other therapy.

[0132] In some embodiments, the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0133] In some embodiments, the ITP is primary ITP. In some embodiments, the ITP is persistent ITP. In some embodiments, the ITP is chronic ITP. In some embodiments, the ITP is persistent or chronic primary ITP. In some embodiments, the primary ITP has persisted for at least about 3 months. In some embodiments, wherein the subject has had a prior response to other therapy excluding a thrombopoietin receptor agonist (TPO-RA), wherein the prior response is defined as achieving a platelet count of ≥50,000 / mL. In some embodiments, the subject has a baseline mean platelet count of <30,000 / µL from at least 2 consecutive measurements taken at least about 5 days apart; optionally wherein the baseline mean platelet count comprises individual values ≤35,000 / µL.

[0134] In some embodiments, the unit dosage form is administered to a subject having an insufficient response or intolerance to other therapy. In some embodiments, wherein the other therapy is a first-line ITP therapy and / or a second-line ITP therapy. In some embodiments, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, DB2 / 47155346.6 30Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone). In some embodiments, the insufficient response to other treatment is defined as failure to achieve a sustained platelet count of at least 50,000 / µL or doubling of baseline platelet count after an appropriate course of the other therapy. In some embodiments, the intolerance to other therapy is defined as a documented side effect causing discontinuation of the therapy.

[0135] In some embodiments, the unit dosage form is administered to a subject having an ITP disease duration (e.g., mean ITP disease duration) of at least about 0.1 years, at least about 0.3 years, at least about 0.5 years, at least about 1 year, at least about 5 years, or at least about 10 years.

[0136] In some embodiments, the unit dosage form is administered to a subject having received a mean of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13 prior ITP treatments.

[0137] In some embodiments, the disclosure provides an isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of immune thrombocytopenia (ITP), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0138] In some embodiments, the disclosure provides a pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a DB2 / 47155346.6 31Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 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.

[0139] In some embodiments, the disclosure provides a medicament for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0140] In some embodiments, the disclosure provides a use of an isolated human anti-CD38 antibody or antigen binding fragment thereof in the manufacture of a medicament for treating immunoglobulin A nephropathy (IgAN), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8. Brief Description of the Drawings

[0141] The objects and features of the invention may be better understood by reference to the drawings described below.

[0142] Figure 1 shows the mechanism of action of various pharmacological agents in treating ITP.

[0143] Figure 2A shows the Phase 2 study design. The primary objective was to evaluate the safety and tolerability of mezagitamab in subjects with persistent / chronic primary ITP. The secondary objective was to assess the effects of mezagitamab administration on platelet counts in subjects with persistent / chronic primary ITP. DB2 / 47155346.6 32Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0144] Figure 2B shows the Phase 2 study schematic. LFP: long-term follow-up period; SFP: safety follow-up period.

[0145] Figure 2C shows the two part, Phase 2, randomized, double-blind, placebo-controlled study that evaluated the safety and efficacy of mezagitamab.

[0146] Figure 3A shows the subject disposition of the main study (enrolled set, i.e., all randomized subjects). Figure 3B shows the participant flow diagram from the phase 2 study. IP, investigational product. *Due to adverse event. **After completion of the main study but before enrolment in the open-label extension.†Due to withdrawal by participant or other reason. Due to withdrawal by participant.

[0147] Figure 4A shows platelet response (PR) by week 16. >60% PR was observed at all three dose levels; 600 mg mezagitamab reached to >90% PR. *Without a dosing period-permitted rescue treatment in the previous 4 weeks and without any other previous rescue therapy. For hemostatic platelet response, the percentages are based on all subjects in the full analysis set with baseline platelet count <15,000 / μL. n = number of subjects with the response; N = number of total subjects; BL = baseline; p-value based on Bernard’s test.

[0148] Figure 4B shows platelet responses at week 16 (secondary endpoints, efficacy). PR, platelet response; n, number of patients with the response; N, number of total patients. PR defined as PC ≥50,000 / µL and ≥20,000 / µL above BL on ≥2 visits*; Complete PR defined as PC ≥100,000 / µL on ≥2 visits*; Clinically meaningful PR defined as PC ≥20,000 / µL above BL on ≥2 visits*; Hemostatic PR defined as PC ≥30,000 / µL and ≥20,000 / µL above BL on ≥2 visits* (*without a dosing period–permitted rescue treatment in the previous 4 weeks and without other previous rescue therapy; for hemostatic platelet response, the percentages are based on all patients in the full analysis set with baseline platelet count <15,000 / µL; P-value based on Barnard’s test).

[0149] Figure 5 shows platelet count (109 / L) change from baseline over time through week 16: dose-dependent increase over time with mezagitamab treatment (Mixed Effects Model for Repeated Measures). LS: least squares; SEM: standard error of the mean. DB2 / 47155346.6 33Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0150] Figure 6 shows the change from baseline platelet counts (109 / L) in mezagitamab cohorts (combined) versus placebo cohort.

[0151] Figure 7 shows mezagitamab demonstrated favorable durable platelet (PLT) response off therapy in comparison with the platelet responses achieved in clinical trials of fostamatinib (Syk Inhibitor, approved in 2018 for ITP) and efgartigimod (anti-FcRn) on therapy. Durable platelet response: mezagitamab, subjects achieving PLT counts of at least 50x109 / L for at least 4 out of the last 6 visits between study week 10 and week 24 of the main study period for the mezagitamab group; placebo, subjects for at least 2 of the last 3 visits between week 12 and week 16 for the placebo group (the use of rescue therapy was considered for this ad hoc analysis). For the interim analysis, in the TAK-079600 mg cohort, 7 / 11 subjects completed week 20 and 4 / 11 subjects completed week 24.

[0152] Figure 8 shows the distribution of observed post dose serum concentrations (Ctrough) resulting from multiple SC administrations of mezagitamab (100 mg, 300 mg, and 600 mg) in subjects with ITP (Phase 2 Study; interim analysis). The figure shows a sustained dose-exposure relationship, less than moderate variability, and no impact of key intrinsic factors (age, sex, and race). Mezagitamab follows target-mediated drug disposition, and observed PK exposures were generally consistent with previously completed studies (i.e., RRMM, MG, and SLE).

[0153] Figure 9 shows dose dependent serum immunoglobulins reductions (observed mean change from baseline) resulting from multiple SC administrations of mezagitamab (100 mg, 300 mg, and 600 mg) in subjects with ITP (Phase 2 study, interim analysis). The figure shows rapid, profound, and sustained dose-dependent immunoglobulin reductions (including IgG) closely pertinent to ITP pathogenesis. At the highest dose of 600 mg, immunoglobulin reductions were generally consistent with other studies, and levels gradually returned to baseline starting from study week 20.

[0154] Figure 10 shows the exposure-response analysis. Exposure-dependent improvement in platelet count and extended duration of response were observed, and the effect appears to be saturated at the higher end of drug exposures. DB2 / 47155346.6 34Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0155] Figure 11 shows the trial schema for the Phase 3 study in Example 2. Subjects who meet all eligibility criteria during screening are randomly assigned in a 2:1 ratio to receive mezagitamab 600 mg or placebo QW for 8 weeks.

[0156] Figure 12 shows the trial schema for the Phase 3 study in Example 3.

[0157] Figure 13 shows the duration of platelet response through week 16. Data are presented as mean + SD. *Duration of platelet response is defined as the number of weeks with platelet count ≥50,000 / μL.

[0158] Figure 14 shows the change from baseline in ITP-PAQ scale scores at week 16. The data are presented as model-based mean and standard error of the mean.

[0159] Figure 15 shows the mean change from baseline in ITP-PAQ scale scores at week 16. The data are presented as model-based mean and standard error of the mean.

[0160] Figure 16A shows the observed mean percentage change from baseline in total plasmablasts.

[0161] Figure 16B shows the observed mean percentage change from baseline in total CD38+ B cells.

[0162] Figure 16C shows the observed mean percentage change from baseline in total NK cells.

[0163] Figure 16D shows the observed mean percentage change from baseline in total CD38+ NK cells.

[0164] Figure 16E shows the percentage change from baseline in IgG. Detailed Description

[0165] Increased expression of CD38 has been documented in a variety of diseases, including autoimmune diseases such as immune thrombocytopenia (ITP). CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing plasmablasts and plasma cells, making it a potential target for treatment of ITP. The significantly higher CD38 expression on plasma cells and plasmablasts compared with other immune cells suggests the potential for selectively depleting these cells with an anti-CD38 antibody. DB2 / 47155346.6 35Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0166] Mezagitamab is a full-length, human IgG1 monoclonal antibody (mAb) directed against human CD38. Mezagitamab selectively depletes cells expressing high levels of the CD38 target by antibody-dependent cell mediated cytotoxicity, complement-dependent cytotoxicity (CDC), antibody-dependent phagocytosis, and apoptosis. CD38 is uniformly and constitutively highly expressed on antibody-producing plasma cells and plasmablasts as well as on subsets of natural killer (NK) cells, B cells, and T cells. Sensitivity of cells to lysis by mezagitamab depends, in part, on the level of cell-surface CD38 expression such that cells having high levels of CD38 expression are depleted more effectively than cells with low levels of CD38 expression. The depletion of plasma cells and plasmablasts by mezagitamab in patients with ITP is expected to reduce the production of antiplatelet antibodies, thereby decreasing disease activity.

[0167] Daratumumab (DARZALEX®), a commercially available anti-CD38 antibody, showed encouraging preliminary data for the treatment of ITP in three patients (Tsykunova et al. HemaSphere, 2022 Jun; 6(Suppl ): 2182-2183). Two of the three patients responded to the study treatment at week 12, and one relapsed by week 24. The results demonstrated only a slight decrease in immunoglobulin G levels and no serious adverse events >grade 2 were reported. Daratumumab was also demonstrated to successfully treat thrombocytopenia in a patient after an allogenic transplant (Migdady, Y. et al., Blood Advances, 2020, 4(5): 815-818). Intravenous daratumumab has been approved for subjects with multiple myeloma (relapsed and newly diagnosed). However, the most frequent adverse reactions (≥20%) with daratumumab monotherapy or in combination with standard anti-myeloma regimens are infusion-related reactions (IRRs), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infections (DARZALEX® USPI). Daratumumab can cause severe and / or serious infusion reactions including anaphylactic reactions and have been reported in approximately half of all subjects (DARZALEX® USPI). Attention must also be paid to daratumumab interference with certain laboratory assays, which importantly may complicate blood compatibility testing.

[0168] Other 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 DB2 / 47155346.6 36Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 prior art antibodies are inferior to mezagitamab for a variety of reasons. MOR03080 binds to human CD38 and cynomolgus CD38 but with a low affinity to human CD38 (Biacore KD = 27.5 nm). OKT10 binds to human CD38 and cynomolgus CD38 but with a low / moderate affinity to human CD38 (Biacore KD = 8.28 nm). MOR03079 binds to human CD38 with a high affinity (Biacore KD = 2.4 nm) but does not bind to cynomolgus CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD = 10 nm and 56 nm, respectively). By comparison, mezagitamab binds to human and cynomolgus CD38 with a high affinity (to human CD38 with Biacore KD = 5.4 nm). Moreover, the prior art antibodies have poor antibody dependent cellular cytotoxicity (ADCC) as well as complement dependent cytotoxicity (CDC) activity.

[0169] An advantage of more efficient ADCC is the ability to deliver an anti-CD38 therapeutic as a low volume injection. A safety profile and pharmacodynamic (PD) target effect was observed after mezagitamab, at a dose up to 0.6 mg / kg dose was subcutaneously administered to healthy subjects. A single subcutaneous dose of 0.6 mg / kg mezagitamab reduced the level of plasmablasts (PBs) in peripheral blood >90% and natural killer (NK) cells >80% without comparable reductions in monocytes and B and T cells. Levels of PBs and NK cells recovered to 50% of baseline levels 21 days after administration, on average. At this dose, there were no Serious Adverse Events (SAEs), on-study deaths, or Adverse Events (AEs) that led to study discontinuation (WO 2019 / 140410, incorporated herein by reference in its entirety). In studies with subjects with relapsed and / or refractory multiple myeloma (RRMM), after mezagitamab was subcutaneously administered at a dosage of 45 mg, 135 mg, 300 mg, or 600 mg, no drug- related SAEs, on-study deaths, or AEs that led to study discontinuation were reported. Administration of mezagitamab was shown to achieve ~50% reduction of the plasma cells resident in the bone marrow and ~80% reduction of plasmablasts in the peripheral blood. In subjects with advanced RRMM, mezagitamab also showed early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in some subjects and prolonged disease stabilization in others (WO 2019 / 186273; incorporated herein by reference in its entirety). In studies with subjects with moderate to severe systemic lupus erythematosus (SLE), subcutaneously administered dosages of 45 mg, 90 mg, and 135 mg were found to be well tolerated, with no substantial imbalances in AEs between the placebo and treatments groups and DB2 / 47155346.6 37Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 no dose-dependent effects or safety concerns were identified (PCT Application No. PCT / US2023 / 073238, incorporated herein by reference in its entirety). In studies with subjects with myasthenia gravis (MG) receiving concomitant stable background therapy, weekly doses of mezagitamab up to 600 mg had a favorable safety profile and showed improvements in MG symptom severity and persistent and durable reductions in both IgG and autoantibody levels (PCT Application No. PCT / US2023 / 085225, incorporated herein by reference in its entirety). Moreover, at clinically achievable doses of mezagitamab, the depletion of plasma cells and plasmablasts has been associated with a substantial reduction in the levels of various immunoglobulins, specifically between 20%-40% and 40-60% reductions in levels of IgG and IgA, respectively, which have both been linked to the causation of various autoimmune diseases. However, the feasibility and efficacy of administering mezagitamab in treating subjects with immune thrombocytopenia (ITP) is unknown.

[0170] The methods and unit dosages of the present disclosure provide, for the first time, subcutaneous administration of therapeutically effective dosages of anti-CD38 antibodies in treating subjects with ITP.

[0171] The present disclosure provides methods and unit dosage forms for subcutaneous administration of a therapeutically effective amount of an isolated anti-CD38 antibody or antigen binding fragment to a subject with ITP. In some embodiments, the antibody or antigen binding fragment for subcutaneous administration comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8. 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 with 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 with at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity thereto). In some embodiments, the antibody or antigen binding DB2 / 47155346.6 38Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 fragment thereof is subcutaneously administered in a dosage of from about 100 mg to about 600 mg.

[0172] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear. However, in the event of any latent ambiguity, definitions provided herein take precedence over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The term “or” includes “and / or” unless stated otherwise. Furthermore, the use of the term “including,” “includes,” or “included” is not limiting. Terms such as “element” and “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

[0173] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of subjects. Commercial enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein.

[0174] All headings and section designations are used for clarity and reference purposes only and are not to be considered limiting in any way. For example, those of skill in the art will appreciate the usefulness of combining various aspects of the disclosure from different headings and sections as appropriate according to the spirit and scope of the disclosure described herein.

[0175] Select terms are defined below in order for the present disclosure to be more readily understood.

[0176] The terms “human CD38” and “human CD38 antigen” refer to the amino acid sequence of SEQ ID NO: 1, or a functional fraction thereof, such as an epitope, as defined herein (Table 1). In general, CD38 possesses a short intracytoplasmic tail, a transmembrane domain, and an extracellular domain. The terms “cynomolgus CD38” and “cynomolgus CD38 antigen” refer to DB2 / 47155346.6 39Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 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. Table 1. Amino Acid Sequence of Human and Cynomolgus Monkey CD38 Species Amino Acid Sequence SEQ ID NO 12345678901234567890123456789012345678901234567890

[0177] The terms “therapeutically effective amount” and “therapeutically effective dosage” refer to an amount of a therapy that is sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof; prevent the advancement of a disorder; cause regression of a disorder; prevent the recurrence, development, onset, or progression of one or DB2 / 47155346.6 40Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 more symptoms associated with a disorder; or enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., prophylactic or therapeutic agent), at dosages and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments 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 detrimental effects of the antibody or antigen binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0178] The terms “subject” and “subject” include both humans and other animals. Thus, the compositions, dosages, and methods disclosed herein are applicable to both human and veterinary therapies. In one embodiment, the subject is a mammal, for example, a human.

[0179] The term “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities. For instance, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind antigens other than CD38. An isolated antibody that specifically binds to an epitope, isoform, or variant of human CD38 or cynomolgus CD38 may, however, have cross-reactivity to other related antigens, for instance from other species, such as CD38 species homologs. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0180] The term “about” refers to an extent near in number, degree, volume, time, etc., with only minor variations in dimension of up to about 10%.

[0181] The term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle, suitable for administering compounds of the present disclosure to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration. DB2 / 47155346.6 41Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0182] The term “pharmaceutical composition” refers to preparations suitable for administration to a subject and treatment of disease. When the anti-CD38 antibodies of the present disclosure are administered as pharmaceuticals to mammals, e.g., humans, they can be administered “as is” or as a pharmaceutical composition containing 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 administration of a particular dosage of the anti-CD38 antibody at a particular concentration, a particular amount, or a particular volume. Pharmaceutical compositions comprising the anti-CD38 antibodies, either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers are provided. Suitably, the pharmaceutical composition may comprise a unit dosage form according to the present disclosure either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers. Suitably, the pharmaceutical composition may comprise a human anti-CD38 antibody as described herein either alone or in combination with prophylactic agents, therapeutic agents, and / or pharmaceutically acceptable carriers.

[0183] Traditional antibody structural units typically comprise a tetramer. Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one “light” chain (typically having a molecular weight of about 25 kDa) and one “heavy” chain (typically having a molecular weight of about 50-70 kDa). Human light chains (LC) are classified as kappa and lambda light chains. Heavy chains (HC) are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. Thus, “isotype” refers to any of the subclasses of immunoglobulins 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 can also comprise hybrids of isotypes and / or subclasses.

[0184] Each variable heavy (VH) chain and variable light (VL) chain region (about 100 to 110 amino acids in length) is composed of three hypervariable regions called “complementarity determining regions” (CDRs) and four framework regions (FRs) (about 15-30 amino acids in DB2 / 47155346.6 42Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 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 differ extensively in sequence among antibodies and thereby determines a unique antigen binding site.

[0185] The hypervariable region generally encompasses amino acid residues from about amino acid residues 24-34 (LCDR1; “L” denotes light chain), 50-56 (LCDR2) and 89-97 (LCDR3) in the VL region and around about 31-35B (HCDR1; “H” denotes heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in 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 those residues forming a hypervariable loop (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)

[0186] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately, residues 1-107 of the VL region and residues 1-113 of the VH region) (e.g., Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD; incorporated herein by reference in its entirety), with the EU number system used for the Fc region.

[0187] 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. Each HC and LC has constant region domains referred to as constant heavy (CH) domains and constant light (CL) domains. In the context of IgG antibodies, the IgG isotypes each have a constant region comprising three CH domains. The carboxy-terminal portion of each HC and LC defines a constant region primarily responsible for effector function. Accordingly, “CH” domains in the context of IgG are as follows: “CH1” refers to positions 118-220 according to the EU index as in Kabat. “CH2” refers to positions 237-340 according to the EU index as in Kabat, and “CH3” refers to positions 341-447 according to the EU index as in Kabat. DB2 / 47155346.6 43Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0188] Another type of Ig domain of the HC is the hinge region. The term “hinge region” refers to the 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 residue EU position 237. Thus, for IgG the antibody hinge is herein defined to include positions 221 (D221 in IgG1) to 236 (G236 in IgG1), wherein the numbering is according to the EU index as in Kabat. In some embodiments, for example in the context of an Fc region, the lower hinge is included, with the “lower hinge” generally referring to positions 226 or 230.

[0189] The term “Fc region” refers to the polypeptide comprising the constant region of an antibody excluding the CH1 domain and in some cases, part 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 comprises 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 to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcγR receptors or to the FcRn receptor. CD38 Antibodies

[0190] Accordingly, the present disclosure provides isolated anti-CD38 antibodies that specifically bind human and primate CD38 protein that find use in subcutaneous administration methods and unit dosage forms in treating subjects with ITP. The antibodies or antigen binding fragments thereof used in the present disclosure bind to both the human and primate CD38 proteins, particularly primates used in clinical testing, such as cynomolgus monkeys (Macaca fascicularis, Crab eating macaque, also referred to herein as “cyno”).

[0191] “Mezagitamab” or “TAK-079” is a therapeutic protein comprising a fully human IgG1 monoclonal antibody that binds specifically to human CD38 with high affinity (Kd = 3.5 nM) referred to herein as “AB79” (US Patent No.8,362,211, the contents of which is hereby DB2 / 47155346.6 44Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 incorporated by reference in its entirety) which binds to and depletes plasma cells / plasmablasts expressing the glycoprotein CD38, a specific biomarker, on their cell surface. CD38 is highly expressed on the cell surfaces of various components of the immune system including plasma cells and plasmablasts, which produce immunoglobulins. It is also expressed on subsets of natural killer (NK) cells, T-cells, and B-cells. The amino acid sequences of mezagitamab are shown in Table 2. Table 2: Amino Acid Sequences of Mezagitamab Sequence12345678901234567890123456789012345678901234567890SEQ ID NODB2 / 47155346.6 45Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0192] Mezagitamab inhibits the growth of tumor cells expressing CD38 by cell depletion via ADCC and CDC. Mezagitamab also reduces the level of plasma cells and plasmablasts in blood isolated from healthy subjects and subjects with autoimmune diseases. The anti-human CD38 mAb daratumumab also depletes CD38-expressing plasmablasts and plasma cells in samples from subjects with autoimmune diseases in a dose-dependent manner in vitro. For example, daratumumab provided a clinically relevant depletion of autoreactive long-lived plasma cells in subjects with treatment-refractory autoantibody-mediated neurological diseases such as myasthenia gravis (Scheibe et al. (2022) Eur. J. Neurol.29(6): 1847-1854).

[0193] In contrast to daratumumab, mezagitamab cross-reacts with CD38 expressed by cynomolgus monkeys providing a unique opportunity to determine if reducing the level of cells expressing CD38 would affect inflammation and tissue damage in a non-human primate model of autoimmune disease. In healthy cynomolgus monkeys, the efficiency of depletion for lymphocytes, and B, T and NK cells correlated positively with level of CD38 expression and AB79 dose level (PCT Application No. PCT / US2017 / 042128; US Patent No.8,362,211, incorporated herein by reference in their entirety).

[0194] In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure interact with CD38 at a number of amino acid residues including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 based on human sequence numbering. Suitably, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure may interact with CD38 at a number of amino acid residues including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1, based on human sequence numbering. Suitably, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure interact with CD38 at a number of amino acid residues including K121, F135, Q139, D141, M142, E239, W241, F274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 2. It should be noted that these residues are identical in both human and cynomolgus monkeys, with the exception that S274 is actually F274 in cynomolgus monkeys. These residues may represent the immunodominant epitope and / or residues within the footprint of the specific antigen binding peptide. DB2 / 47155346.6 46Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0195] In some embodiments, the anti-CD38 antibody for use according to the disclosure comprises a heavy chain (HC) comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the disclosure comprises a light chain (LC) comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the disclosure comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the anti-CD38 antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab). In some embodiments, the antibody comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody comprises an 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 as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at DB2 / 47155346.6 47Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 least 80% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least 85% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least 90% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least 95% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least 97% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least 99% sequence identity to SEQ ID NO: 9.

[0196] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO: 9.

[0197] In some embodiments, the antibody comprises an 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 as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 85% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 90% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 95% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 97% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 DB2 / 47155346.6 48Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 99% sequence identity to SEQ ID NO: 10.

[0198] In some embodiments, the antibody comprises an LC comprising the VL region amino acid sequence of SEQ ID NO: 10.

[0199] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein and an LC comprising the VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0200] As will be appreciated by those in the art, the VH and VL regions can be joined to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4.

[0201] In some embodiments, the antibody comprises a 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 the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 85% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 90% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 95% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 97% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 99% sequence identity to SEQ ID NO 11.

[0202] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11.

[0203] In some embodiments, the antibody comprises a HC comprising or consisting of an amino acid sequence having at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity to DB2 / 47155346.6 49Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 SEQ ID NO: 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 85% sequence identity to SEQ ID NO 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 90% sequence identity to SEQ ID NO 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 95% sequence identity to SEQ ID NO 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 97% sequence identity to SEQ ID NO 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 99% sequence identity to SEQ ID NO 14.

[0204] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 14.

[0205] In some embodiments, the antibody comprises a 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 the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 80% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 85% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 90% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 95% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 97% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 DB2 / 47155346.6 50Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 and SEQ ID NO: 8 and the remainder of the LC may have at least 99% sequence identity to SEQ ID NO 12.

[0206] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12.

[0207] In some embodiments, the antibody comprises or consists of the HC amino acid sequence of SEQ ID NO: 11 or a variant thereof as described herein and the LC amino acid sequence of SEQ ID NO: 12 or a variant thereof as described herein.

[0208] In some embodiments, the antibody comprises or consists of the HC amino acid sequence of SEQ ID NO: 14 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.

[0209] The present disclosure encompasses antibodies that bind to both human and cynomolgus CD38 and interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the following amino acid residues: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human numbering. Suitably, the antibody may interact with at least 90% of these amino acid residues. Suitably, the antibody may interact with at least 95% of these amino acid residues. Suitably, the antibody may interact with at least 97% of these amino acid residues. Suitably, the antibody may interact with at least 98% of these amino acid residues. Suitably, the antibody may interact with at least 99% of these amino acid residues. Suitably, the antibody may interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human numbering.

[0210] In some embodiments, the antibodies are 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.

[0211] Alternatively, the antibodies can be a variety of structures, including, but not limited to, antibody fragments, antigen binding fragment, 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 DB2 / 47155346.6 51Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 as “antibody conjugates”), and fragments of each, respectively. Specific antibody fragments include, but are not limited to, (i) the Fab fragment consisting of VL, VH, CL and CH1 domains, (ii) the Fd fragment consisting of the VH and CH1 domains, (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward et al. (1989) Nature 341: 544-546) which consists of a single variable, (v) isolated CDR regions, (vi) F(ab’)2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al. (1988) Science 242: 423-426, Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883), (viii) bispecific single chain Fv (WO 03 / 11161) and (ix) “diabodies” or “triabodies”, 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).

[0212] Suitably, the antibody may be a Fab fragment. Suitably, the antibody may be an Fv fragment. Suitably, the antibody may be an Fd fragment. Suitably, the antibody structure may be isolated CDR regions. Suitably, the antibody may be a F(ab’)2 fragment. Suitably, the antibody may be an scFv fragment.

[0213] In some embodiments, the antibody or antigen binding fragment thereof of the present disclosure further comprises one or more engineered glycoforms. In some embodiments, the engineered glycoform comprises glycosylation of one or more polypeptides. In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. In some embodiments, the glycosylation is O-linked glycosylation.

[0214] In some embodiments, the isolated antibody of the present disclosure is mezagitamab. Antibody Modifications

[0215] The present disclosure further provides variant anti-CD38 antibodies. That is, there are a number of modifications that can be made to the antibodies of the disclosure, including, but not limited to, amino acid modifications in the CDRs (affinity maturation), amino acid modifications in the VH region and / or VL region, amino acid modifications in the HC and / or LC, amino acid modifications in the Fc region, glycosylation variants, covalent modifications of other types, etc. DB2 / 47155346.6 52Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0216] The term “variant” means a polypeptide that differs from that of a parent polypeptide. Amino acid variants can include substitutions, insertions, and deletions of amino acids. In general, variants can include any number of modifications, as long as the function of the protein is still present, as described herein. That is, in the case of amino acid variants generated with the CDRs of mezagitamab, for example, the antibody should still specifically bind to both human and cynomolgus CD38. The term “variant Fc region” means an Fc sequence that differs from that of a wild-type or parental Fc sequence by virtue of at least one amino acid modification. Fc variant may refer to the Fc polypeptide itself, compositions comprising the Fc variant polypeptide, or the amino acid sequence. If amino acid variants are generated with the Fc region, for example, the variant antibodies should maintain the required functions for the particular application or indication of the antibody. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions can be utilized, for example, 1-10, 1-5, 1-4, 1-3, and 1-2 substitutions. Suitable modifications can be made at one or more positions as is generally outlined, for example in US Patent Application Serial Nos.11 / 841,654 and 12 / 341,769; US Patent Publication Nos. 2004013210; 20050054832; 20060024298; 20060121032; 20060235208; and 20070148170; and US Patent Nos.6,737,056; 7,670,600; 6,086,875; and 8,937,158, all of which are expressly incorporated by reference in their entirety, and in particular for specific amino acid substitutions that increase binding to Fc receptors.

[0217] A variant can be considered in terms of similarity (i.e., amino acid residues having similar chemical properties / functions), but preferably a variant is expressed in terms of sequence identity.

[0218] Sequence comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These publicly and commercially available computer programs can calculate sequence identity between two or more sequences.

[0219] It may be desirable to have from 1-5 modifications in the Fc region of wild-type or engineered proteins, as well as from 1 to 5 modifications in the Fv region, for example. A variant polypeptide sequence will preferably possess at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the parent sequences (e.g., the VH or VL regions, the constant regions, and / or the HC and LC sequences for mezagitamab). Suitably, the variant may have at least 80% sequence identity to the parent sequence. Suitably, the variant DB2 / 47155346.6 53Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 may have at least 85% sequence identity to the parent sequence. Suitably, the variant may have at least 90% sequence identity to the parent sequence. Suitably, the variant may have at least 92% sequence identity to the parent sequence. Suitably, the variant may have at least 95% sequence identity to the parent sequence. Suitably, the variant may have at least 97% sequence identity to the parent sequence. Suitably, the variant may have at least 98% sequence identity to the parent sequence. Suitably, the variant may have at least 99% sequence identity to the parent sequence.

[0220] In one embodiment, the sequence identity is determined across the entirety of the sequence. In one embodiment, the sequence identity is determined across the entirety of the candidate sequence being compared to a sequence recited herein.

[0221] The term “amino acid substitution” means the replacement of an amino acid at a particular position in a parent polypeptide sequence with another amino acid. For example, the substitution S100A refers to a variant polypeptide in which the serine at position 100 is replaced with alanine. Suitably, the amino acid substitution may be a conservative amino acid substitution. Suitably, a variant may comprise one or more, e.g., two or three conservative amino acid substitutions. A “conservative substitution” is defined as one in which one amino acid is substituted for another having similar biochemical properties.

[0222] Unless otherwise explicitly stated herein by way of reference to a specific, individual amino acid, amino acids may be substituted using conservative substitutions as recited below. An aliphatic, polar uncharged amino 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 and preferably in the same line in the third column may be substituted for each other: Table 3. Conservative Substitutions ALIPHATIC Non-polar G A PDB2 / 47155346.6 54Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 N Q Polar – charged D E

[0223] The term amino acid insertion means the addition of an amino acid at a particular position in a parent polypeptide sequence.

[0224] The term “amino acid deletion” means the removal of an amino acid at a particular position in a parent polypeptide sequence.

[0225] The terms “parent antibody” and “precursor antibody” mean an unmodified antibody that is subsequently modified to generate a variant. In an embodiment, the parent antibody herein is mezagitamab. In an embodiment, the parent antibody herein comprises a VH region having the amino acid sequence of SEQ ID NO: 9 and the VL region having the amino acid sequence of SEQ ID NO: 10. In an embodiment, the parent antibody herein comprises an HC amino acid sequence of SEQ ID NO: 11 and an LC amino acid sequence of SEQ ID NO: 12. In an embodiment, the parent antibody herein comprises an HC amino acid sequence of SEQ ID NO: 14 and an LC amino acid sequence of SEQ ID NO: 12. Parent antibody may refer to the polypeptide itself, compositions that comprise the parent antibody, or the amino acid sequence that encodes it. Accordingly, the term “parent Fc polypeptide” means an Fc polypeptide that is modified to generate a variant.

[0226] The terms “wild type,” “WT,” and “native” mean an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein, polypeptide, antibody, immunoglobulin, IgG, etc., has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0227] In some embodiments, one or more amino acid modifications are made in one or more of the CDRs of the anti-CD38 antibody. In general, only 1, 2, or 3 amino acids are substituted in any single CDR, and generally no more than from 4, 5, 6, 7, 89 or 10 changes are made within a set of CDRs. However, it should be appreciated that any combination of no substitutions, 1, 2 or 3 substitutions in any CDR can be independently and optionally combined with any other substitution. DB2 / 47155346.6 55Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0228] In some cases, amino acid modifications in the CDRs are referred to as “affinity maturation”. An “affinity matured” antibody is one having one or more alteration(s) in one or more CDRs which results in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess those alteration(s). In some cases, it may be desirable to decrease the affinity of an antibody to its antigen.

[0229] Affinity maturation can be done to increase the binding affinity of the antibody for the antigen by at least about 10% to 50%, 100%, 150% or more, or from 1- to 5-fold as 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; incorporated herein by reference in their entirety).

[0230] Alternatively, amino acid modifications can be made, e.g., in one or more of the CDRs of the antibodies of the disclosure that are “silent”, e.g., that do not significantly alter the affinity of the antibody for the antigen. These can be made for a number of reasons, including optimizing expression (as can be done for the nucleic acids encoding the antibodies of the disclosure).

[0231] Thus, included within the definition of the CDRs and antibodies of the disclosure are variant CDRs and antibodies; that is, the antibodies of the disclosure can include 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 also independently and optionally be made in any region outside the CDRs, including framework and constant regions.

[0232] In some embodiments, variant antibodies of mezagitamab that are specific for human CD38 (SEQ ID NO: 1) and cynomolgus CD38 (SEQ ID NO: 2) is described. This antibody is composed of six CDRs, wherein each CDR of this antibody can 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. DB2 / 47155346.6 56Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 Glycosylation

[0233] Another type of modification is alterations in glycosylation. In one embodiment, the antibodies disclosed herein can be modified to include one or more engineered glycoforms. By “engineered glycoform” as used herein is meant a carbohydrate composition that is covalently attached to the antibody, wherein said carbohydrate composition differs chemically from that of a parent antibody. Engineered glycoforms may 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 be correlated to an increase in ADCC function, presumably through tighter binding to the FcγRIIIa receptor. In this context, “afucosylation” means that the majority of the antibody produced in the host cells is substantially devoid of fucose, e.g., about 90-95-98% of the generated antibodies do not have appreciable fucose as a component of the carbohydrate moiety of the antibody (generally attached at N297 in the Fc region). Defined functionally, afucosylated antibodies generally exhibit at least a 50% or higher affinity to the FcγRIIIa receptor.

[0234] Engineered glycoforms may be generated by a variety of methods known in the art (US Patent No.8,362,211, incorporated herein by reference in its entirety). “Engineered glycoform” typically refers to the different carbohydrate or oligosaccharide; thus, an antibody can include an engineered glycoform.

[0235] Alternatively, “engineered glycoform” may refer to the IgG variant that comprises the different carbohydrate or oligosaccharide. As is known in the art, glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Particular expression systems are discussed below.

[0236] 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 tri- peptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tri-peptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the DB2 / 47155346.6 57Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 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 may also be used.

[0237] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tri-peptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). For ease, the antibody amino acid sequence is preferably altered through changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

[0238] Another means of increasing the number of carbohydrate moieties on the 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, the 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 WO87 / 05330 and in Aplin and Wriston (1981) CRC Crit. Rev. Biochem.10(4): 259-306, both entirely incorporated by reference.

[0239] Removal of carbohydrate moieties present on the starting antibody (e.g., post- translationally) may 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 by Edge et al., 1981, Anal. Biochem.118: 131, both entirely incorporated by reference. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol.138:350, entirely incorporated by reference. Glycosylation at potential glycosylation DB2 / 47155346.6 58Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 sites may be prevented by the use of the compound tunicamycin as described by Duskin et al. (1982) J. Biol. Chem.257: 3105, entirely incorporated by reference. Tunicamycin blocks the formation of protein-N-glycoside linkages.

[0240] Another type of covalent modification of the antibody comprises linking the antibody to various nonproteinaceous polymers, including, but not limited to, various polyols such as polyethylene glycol, polypropylene glycol or other polyoxyalkylenes, in the manner set forth in, for example, 2005-2006 PEG Catalog from Nektar Therapeutics (available at the Nektar website) US Patents 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337, all entirely incorporated herein by reference. In addition, as is known in the art, amino acid substitutions may be made in various positions within the antibody to facilitate the addition of polymers such as PEG. See for example, U.S. Publication No.2005 / 0114037Al, entirely incorporated herein by reference.

[0241] In addition to the modifications outlined above, other modifications can be made. For example, the molecules may 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). In addition, there are a variety of covalent modifications of antibodies that can be made as outlined below.

[0242] Covalent modifications of antibodies are included within the scope of this disclosure, and are generally, but not always, done post-translationally. For example, several types of covalent modifications of the antibody are introduced into the molecule by reacting specific amino acid residues of the antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.

[0243] In some embodiments, the anti-CD38 antibody of the present disclosure specifically binds to one or more residues or regions in CD38 but also does not cross-react with other proteins with homology to CD38, such as BST-1 (bone marrow stromal cell antigen-1) and / or Mo5, also called CD157.

[0244] Typically, a lack of cross-reactivity means less than about 5% relative competitive inhibition between the molecules when assessed by ELISA and / or FACS analysis using sufficient amounts of the molecules under suitable assay conditions. DB2 / 47155346.6 59Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 Side Effect Reduction

[0245] An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it did not necessarily have to have a causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that occurred after the first dose of study drug received in the treatment period and until the end of safety follow-up. The terms “serious TEAEs” and “treatment-emergent SAEs” and can be considered interchangeable in this document. PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0. TEAEs are typically referred to by grades 1, 2, 3, 4, and 5, grade 1 being the least severe and grade 5 being the most severe TEAE. Based on FDA and other guidelines for Common Terminology Criteria for Adverse Events (CTCAE) standards for oncology drugs (see, e.g., U.S. Department of Health and Human Services, Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, 2010 and Nilsson and Koke (2001) Drug Inform. J.35: 1289-1299, incorporated herein by reference in its entirety) the following is how such grades are generally determined. Grade 1 is mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated. Grade 2 is moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (“ADL”). Grade 3 is severe or medically significant but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 is life-threatening consequence: urgent intervention indicated. Grade 5 is death related to AE.

[0246] The anti-CD38 antibodies of the present disclosure allow for reduced side effects compared to prior art anti-CD38 antibodies. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, does not induce TEAEs. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the incidence of TEAEs in a subject population as compared to other anti- CD38 antibodies, such as MOR202. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the grade of the TEAEs in a subject population as compared to other anti-CD38 antibodies, such as MOR202. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade DB2 / 47155346.6 60Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 5 to grade 4. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the grade of the TEAEs as compared to other anti- CD38 antibodies from grade 4 to grade 3. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade 3 to grade 2. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade 2 to grade 1.

[0247] In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, lymphopenia, and nausea. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab, 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 (IRRs), leukopenia, lymphopenia, and nausea.

[0248] In some embodiments, administering the antibody or antigen binding fragment thereof of the present disclosure results in less than 10% incidence of grade 3 or 4 of one or more TRAEs or TEAEs; optionally wherein the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst.

[0249] In some embodiments, a TRAE or TEAE resulting from administering the antibody or antigen binding fragment thereof of the present disclosure has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0250] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP-associated bleeding adverse events (AEs) relative to placebo. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25% reduction in ITP-associated bleeding adverse events (AEs) relative to placebo. DB2 / 47155346.6 61Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 Disease Indication

[0251] The antibodies or antigen binding fragment thereof, methods, and dosage units of the disclosure find use in treating subjects with ITP. Immune Thrombocytopenia (ITP)

[0252] Immune thrombocytopenic purpura (ITP), also referred to as “idiopathic thrombocytopenic purpura,” “immune thrombocytopenia,” “autoimmune thrombocytopenic purpura,” “Werlhof disease,” and “autoimmune thrombocytopenia,” is a rare, IgG mediated autoimmune disease caused, in part, by the development of autoantibodies to platelets (and / or megakaryocytes), which are blood cells responsible for preventing or stopping bleeding. ITP is characterized by the accelerated destruction of platelets (with or without impaired production), resulting in a decreased platelet count and an increased risk of bleeding, which can be debilitating, or which in severe cases may be life-threatening. (Tsuda et al. (2017) Ann. Hematol., 96(11), 1915-1920; Zitek et al. (2022) Open Access Emerg. Med.14, 25-34, incorporated herein by reference in their entireties).

[0253] There are two types of ITP: primary ITP and secondary ITP. Primary ITP is idiopathic, whereas secondary ITP is linked to an underlying condition. The rate of secondary ITP in children has not been studied in detail but is assumed to be rare (2.4%). In adults, ~18-38% of ITP subjects have an underlying disease, comorbid condition, and / or comedication, making the diagnosis of secondary ITP more probable. Secondary ITP is known to be caused by systemic autoimmune disorders, primary or secondary immunodeficiency, infectious diseases, paraneoplastic syndromes (e.g., lymphomas and other malignancies), and drug-dependent antibodies.

[0254] The International Working Group on ITP further defines ITP according to the following clinical phases: (1) newly diagnosed ITP is in the first three months post-diagnosis; (2) persistent ITP is for 3-12 months; (3) chronic ITP is for >1 year; and (4) refractory ITP.

[0255] Refractory ITP was traditionally generally defined based on the absence of response or relapse after splenectomy before the advent of medical alternatives. Approximately 20% of subjects do not attain a hemostatic platelet count after splenectomy or fail to respond to initial or subsequent medical approaches; an additional 20% to 30% of splenectomy responders eventually DB2 / 47155346.6 62Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 relapse. More recently, the definition of refractory ITP has been extended to include subjects who require treatment but are unable or unwilling to undergo splenectomy. In practice, refractory ITP is often defined as the persistence of low platelet counts despite appropriate use of all conventional therapies deemed safe for the specific subject, regardless of hemorrhagic manifestations. The threshold value to identify “low” platelet count is variable depending on the subject’s age, comorbidities, and concomitant therapies (e.g., antiplatelet or anticoagulant agents). As used herein, “refractory ITP” refers to subjects who are refractory to other treatments, for example, corticosteroids, immunoglobulins, and / or splenectomy.

[0256] The treatment strategy in ITP is to prevent or stop bleeding by maintaining the platelet count at or above a minimum threshold of ≥50,000 / μL. Disease remission (or functional restoration to normal) is defined as a platelet count of ≥100,000 / μL at 1 year after treatment is completed.

[0257] Various pharmacological agents, approved and unapproved, are currently available for treatment of ITP. Surgical removal of the spleen (splenectomy) is an invasive and aggressive treatment available in severe cases. All existing treatments have important limitations including significant adverse events such as chronic immunosuppression and in the case of splenectomy, the potential for overwhelming infections. Figure 1 shows the mechanism of action of various pharmacological agents.

[0258] The various existing agents for ITP can be loosely categorized into first-line and second- line treatments. In adults, the corticosteroids, namely prednisone and dexamethasone, are the prototypical first line agents. First-line treatment for ITP relies on general immunosuppression with corticosteroids and the initial response rate is 50–90%. However, sustained remission is only achieved for 10–30% of patients and adverse events including infection are a concern. Intravenous immunoglobulin (IVIG) has also been used in the first line setting. Although corticosteroids may be effective in the short term, the response is poorly sustained after drug discontinuation with up to 70% of patients experiencing relapse in the long term. Their utility in ITP is further limited by well-known corticosteroid-related adverse effects such as hypertension, hyperglycemia, sleep and mood disturbances, gastric irritation or ulcer formation, glaucoma, myopathy, and osteoporosis (Al-Samkari et al. (2020) Blood Adv., 4(1), 9-18, incorporated herein by reference in its entirety). Approved second line agents include thrombopoietin DB2 / 47155346.6 63Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 receptor agonists (TPO-RAs) (e.g., avatrombopag, eltrombopag, and romiplostim), indicated for patients who have an insufficient response with glucocorticoids, as well as fostamatinib, which is indicated for patients with an insufficient response to previous treatment. Empiric use of rituximab or IVIG is also seen in second-line treatment, with splenectomy being a surgical option.

[0259] Approximately 20% of ITP subjects do not respond at all (do not achieve a platelet count >50,000 / µL) to these first- and second-line agents or experience a loss of response or intolerance. An additional 20% to 30% of subjects with an initial response eventually relapse, resulting in increased bleeding-related morbidity and diminished quality of life (Provan et al. (2019) Blood Adv., 3(22), 3780-3817; Rodeghiero (2023) Int. J. Hematol., 117(3), 316-330, incorporated herein by reference in their entireties). In addition to the well-known safety and tolerability issues with the first-line treatments (corticosteroids and IVIG), the available second- line therapies (including investigational agents) have significant safety or tolerability risks as outlined in Table 4. Of note, each of the second-line therapies have treatment-limiting safety or tolerability concerns per approved US labeling: arterial and venous thrombosis, increase in bone marrow reticulin formation, collagen fibrosis and hepatotoxicity with TPO-RAs as well as hypotension, hepatoxicity, diarrhea, and neutropenia with fostamatinib. These side effects can limit the potential benefits from these treatments. A shared limitation of these existing approved therapies is their inability to deliver long-term sustained responses off treatment. As such, there is an unmet need for improved treatments for treating ITP. Table 4. Safety and tolerability risks of available 2ndline therapies. 2ndLine Therapy Safety and Tolerability Risks Ri i Bl k i f f l i f i i s nDB2 / 47155346.6 64Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 Anti-FcRn The most common side effects are respiratory tract infection, (Efgartigimod Ph3) headache, and urinary tract infection

[0260] The available second line therapies include TPO-RAs (e.g., romiplostim, eltrombopag, avatrombopag), the recently approved Syk inhibitor (fostamatinib), a monoclonal antibody (rituximab), a small molecule Syk inhibitor (fostamatinib), splenectomy and an anti-FcRn antagonist (efgartigimod (IV)). In addition, several additional MOAs are in clinical development, including anti-BAFF antibody, BTK inhibitor, and Syk inhibitors.

[0261] Pivotal studies in this indication generally assess response to treatment by measuring durable platelet response, i.e., the proportion of treated subjects that experience a sustained increase in their platelet count over time. In most of the studies performed to date, these assessments were conducted while subjects were still receiving treatment.

[0262] In six pivotal studies for the two approved TPO-RA agents (romiplostim and eltrombopag), initial platelet responses on treatment ranged between 50-90%. However, over time, approximately one third of subjects who remained either on once-daily or weekly treatments would go on to either experience recurrences and / or discontinue TPO-RAs due to lack of response.

[0263] The most recently approved ITP treatment, fostamatinib, prevents platelet destruction by inhibiting Syk-mediated IgG Fcγ receptor signaling, thus interfering with phagocytosis of antibody-covered platelets as well as antibody formation. This is a more downstream effect as it does not affect the upstream production of pathogenic autoantibodies. Fostamatinib is a chronic oral treatment administered twice daily. In its registrational studies the durable platelet response on therapy was 18%. See TAVALISSE® FDA Full Prescribing Information, revised November 2020, which is herein incorporated by reference in its entirety.

[0264] Anti-FcRns such as efgartigimod also deplete pathogenic IgGs by interfering with their recycling. They deplete IgG more rapidly and to a greater extent than mezagitamab; however, anti-FcRns do not affect the plasma cells that produce pathogenic autoantibodies (or other DB2 / 47155346.6 65Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 antibodies). This means that the activity of all anti-FcRn therapies is dependent on continuous administration, precluding any potential for a durable off-therapy effect. Efgartigimod ran two Phase 3 studies in subjects with ITP, utilizing a weekly IV formulation in the first study and a weekly subcutaneously administered treatment in the second study. The weekly IV treatment achieved a 22% durable response rate at 12 weeks (on therapy) in comparison to 5% in placebo (Broome, C. M. et al., Lancet, 2023, 402: 1648-1659, which is herein incorporated by reference in its entirety). Similarly, the topline results from the Phase 3 study using weekly subcutaneously administered treatment failed its primary endpoint, achieving a durable platelet response on therapy in 13% of treated subjects (vs 16% in the placebo arm).

[0265] The combination of inadequate / suboptimal efficacy and the serious adverse effects of the available therapies reveals an unmet need for a safe and effective treatment option for long-term treatment of these subjects.

[0266] In some embodiments, the disclosure provides methods of treating ITP in a subject. In some embodiments, the disclosure provides methods of treating primary ITP in a subject. In some embodiments, the disclosure provides methods of treating secondary ITP in a subject.

[0267] In some embodiments, the disclosure provides methods of treating newly diagnosed ITP in a subject. In some embodiments, the disclosure provides methods of treating acute ITP in a subject. In some embodiments, the disclosure provides methods of treating persistent ITP in a subject. In some embodiments, the disclosure provides methods of treating chronic ITP in a subject. In some embodiments, the disclosure provides methods of treating refractory ITP in a subject.

[0268] In some embodiments, the disclosure provides methods of treating newly diagnosed primary ITP in a subject. In some embodiments, the disclosure provides methods of treating acute primary ITP in a subject. In some embodiments, the disclosure provides methods of treating persistent primary ITP in a subject. In some embodiments, the disclosure provides methods of treating chronic primary ITP in a subject. In some embodiments, the disclosure provides methods of treating refractory primary ITP in a subject.

[0269] In some embodiments, the subject is diagnosed with ITP. In some embodiments, the subject is diagnosed with primary ITP. In some embodiments, the subject is diagnosed with DB2 / 47155346.6 66Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 persistent ITP. In some embodiments, the subject is diagnosed with chronic ITP. In some embodiments, the subject is diagnosed with persistent or chronic primary ITP.

[0270] In some embodiments, the primary ITP has persisted for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or at least about 12 months. In some embodiments, the primary ITP has persisted for at least about 3 months.

[0271] In some embodiments, some embodiments, the disclosure provides the methods disclosed herein, wherein a subject has had an insufficient response or intolerance to other therapy. As used herein, “other therapy” generally refers to first-line and / or second-line ITP therapies, including standard-of-care therapies and background ITP medication(s). In some embodiments, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and / or background ITP medication(s). In some embodiments, the other therapy comprises one or more of immunoglobulins, splenectomy, romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone. In some embodiments, the insufficient response to other treatment is defined as failure to achieve a sustained platelet count of at least 50,000 / µL or doubling of baseline platelet count after an appropriate course of the other therapy. In some embodiments, the intolerance to other therapy is defined as a documented side effect causing discontinuation of the therapy.

[0272] In some embodiments, the subject has had a prior response to other therapy. In some embodiments, the subject has had a prior response to other therapy excluding a thrombopoietin receptor agonist (TPO-RA). In some embodiments, the prior response is defined as achieving a platelet count of ≥10,000 / mL, ≥20,000 / mL, ≥30,000 / mL, ≥40,000 / mL, or ≥50,000 / mL. In some embodiments, the prior response is defined as achieving a platelet count of ≥50,000 / mL.

[0273] In some embodiments, the subject has a baseline mean platelet count of <10,000 / µL, <20,000 / µL, <30,000 / µL, <40,000 / µL, or <50,000 / µL from at least 2 consecutive measurements taken at least about 1 day apart, at least about 3 days apart, at least about 5 days apart, or at least DB2 / 47155346.6 67Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 about 10 days apart. In some embodiments, the subject has a baseline mean platelet count of <30,000 / µL from at least about 2 consecutive measurements taken at least about 5 day apart. In some embodiments, the baseline mean platelet count comprises individual values ≤35,000 / µL.

[0274] The therapeutic anti-CD38 antibodies of the present disclosure bind to CD38 positive cells, resulting in depletion of these cells through multiple mechanisms of action, including both CDC and ADCC pathways.

[0275] In some embodiments, the disclosure provides methods of treating ITP in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the isolated human anti- CD38 antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg. In some embodiments, the isolated human anti-CD38 antibody or antigen binding fragment thereof is administered subcutaneously.

[0276] In some embodiments, the disclosure provides methods of treating ITP in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the isolated human anti-CD38 antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg. In some embodiments, the isolated human anti-CD38 antibody or antigen binding fragment thereof is administered subcutaneously.

[0277] In some embodiments, the disclosure provides methods of treating ITP in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: DB2 / 47155346.6 68Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0278] In some embodiments, the disclosure provides methods of reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0279] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the DB2 / 47155346.6 69Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. 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.

[0280] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with ITP, wherein the immunoglobulin(s) (e.g., IgA, IgG, and / or IgM) are reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the immunoglobulin(s). In some embodiments, IgA is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the IgA. In some embodiments, IgG is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the IgG. In some embodiments, IgM is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of IgM. In some embodiments, IgA is reduced by at least about 50% relative to baseline levels of IgA. In some embodiments, IgG is reduced by at least about 30% relative to baseline levels of IgG. In some embodiments, IgM is reduced by at least about 40% relative to baseline levels of IgM.

[0281] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with ITP, wherein administering the isolated antibody DB2 / 47155346.6 70Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 or antigen binding fragment thereof results in a reduction in immunoglobulin(s) (e.g., IgA, IgG, and / or IgM) in six weeks or less, five weeks or less, four weeks or less, three weeks or less, two weeks or less, or one week or less. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in one week or less.

[0282] In some embodiments, the disclosure provides methods of increasing platelet counts in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of increasing platelet counts in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL.

[0283] In some embodiments, the disclosure provides methods of achieving platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of achieving platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid DB2 / 47155346.6 71Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, or ≥150,000 / μL. In some embodiments, the platelet response is defined as a platelet count of ≥20,000 / μL above baseline, for example, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL and ≥20,000 / μL above baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL and / or the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL. In some embodiments, the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, the platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, or ≥50,000 / μL at about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, or about 20 weeks after the administering. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering.

[0284] In some embodiments, the disclosure provides methods of achieving platelet response in a subject in need thereof, wherein the method achieves a platelet response in six weeks or less, five weeks or less, four weeks or less, three weeks or less, two weeks or less, or one week or less. In some embodiments, the method achieves a platelet response in one week or less.

[0285] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of DB2 / 47155346.6 72Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

[0286] In some embodiments, the disclosure provides methods of achieving durable platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of achieving durable platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the durable platelet response is defined as a sustained platelet response for at least 1 of 6 biweekly measurements, at least 2 of 6 biweekly measurements, at least 3 of 6 biweekly measurements, at least 4 of 6 biweekly measurements, or at least 5 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy. In some embodiments, the durable platelet response is defined as a sustained platelet response for at least 1 of 6 weekly measurements, at least 2 of 6 weekly measurements, at least 3 of 6 weekly measurements, at least 4 of 6 weekly measurements, or at least 5 of 6 weekly platelet measurements from baseline to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a sustained platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy. In some embodiments, the platelet response is defined at a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, or ≥150,000 / μL. In some embodiments, the platelet response is defined at a platelet count of ≥50,000 / μL. In some DB2 / 47155346.6 73Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 embodiments, the durable platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, or ≥50,000 / μL on at least 1 of 6, at least 2 of 6, at least 3 of 6, or at least 4 of 6 weekly platelet measurements from baseline to about 24 weeks after the administering, from about 5 weeks to about 24 weeks after the administering, from about 10 weeks to about 24 weeks after the administering, from about 15 weeks to about 24 weeks after the administering, or from about 19 weeks to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL). In some embodiments, the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, at least about 45 weeks, or at least about 50 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0287] In some embodiments, the disclosure provides methods of achieving complete platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of achieving complete platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 DB2 / 47155346.6 74Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the complete platelet response is defined as a platelet count of ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, ≥150,000 / μL, ≥175,000 / μL, or ≥200,000 / μL. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL. In some embodiments, the complete platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, or from baseline to about 24 weeks after the administering, optionally wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the complete platelet response is measured in at least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, or from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering. DB2 / 47155346.6 75Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0288] In some embodiments, the disclosure provides methods of achieving a clinically meaningful platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of achieving a clinically meaningful platelet response in a subject in need thereof the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL above baseline. In some embodiments, the clinically meaningful platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured on at least two visits from baseline to about 16 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at DB2 / 47155346.6 76Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at least two measurements from baseline to about 16 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

[0289] In some embodiments, the disclosure provides methods of achieving hemostatic platelet response in a subject in need thereof having a baseline platelet count of <15,000 / μL, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of achieving hemostatic platelet response in a subject in need thereof having a baseline platelet count of <15,000 / μL, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence DB2 / 47155346.6 77Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the baseline platelet count is <12,000 / μL, <10,000 / μL, <8,000 / μL, <5,000 / μL, or <1,000 / μL. In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL. In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline. In some embodiments, the hemostatic platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the hemostatic platelet response is measured on at least two visits from baseline to about 18 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the hemostatic platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the hemostatic platelet response is measured in at least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. DB2 / 47155346.6 78Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 In some embodiments, the hemostatic platelet response is measured in at least two measurements from baseline to about 18 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL.

[0290] In some embodiments, the disclosure provides methods of reducing the level of autoantibodies in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, the disclosure provides methods of reducing the level of autoantibodies in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the autoantibodies are anti-platelet autoantibodies.

[0291] In some embodiments, the disclosure provides methods of reducing ITP disease activity and / or progression in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the DB2 / 47155346.6 79Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

[0292] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the ITP disease activity and / or progression is measured one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ), and / or 5-Level EuroQol Five Dimensions (EQ-5D-5L). In some embodiments, the ITP disease activity and / or progression is measured by World Health Organization (WHO) Bleeding Scale. In some embodiments, the ITP disease activity and / or progression is measured by Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ). In some embodiments, the ITP disease activity and / or progression is measured by 5-Level EuroQol Five Dimensions (EQ-5D-5L). In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is DB2 / 47155346.6 80Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

[0293] In some embodiments, the disclosure provides methods of reducing bleeding events in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP-BAT). In some embodiments, the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

[0294] In some embodiments, the disclosure provides methods of achieving immune thrombocytopenia (ITP) remission in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. In some embodiments, ITP remission is defined as all platelet counts ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, or ≥50,000 / μL for at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 DB2 / 47155346.6 81Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks, at least about 45 weeks, or at least about 50 weeks after any treatment cycle with isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

[0295] In some embodiments, the disclosure provides methods of treating immune thrombocytopenia (ITP) in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody, wherein the isolated antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the ITP is chronic primary ITP or persistent primary ITP, the subject has had an insufficient response or intolerance to other therapy, the other therapy is a first-line ITP therapy and / or a second-line ITP therapy, the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone), the isolated antibody is subcutaneously administered in a dosage of about 600 mg in a course of once per week for 8 weeks, optionally wherein the isolated antibody is further administered in more than one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 courses, etc.) course of once per week for 8 weeks; and / or optionally wherein the isolated antibody is not further administered for a period of 8 weeks. DB2 / 47155346.6 82Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0296] In some embodiments, the disclosure provides the methods as disclosed herein, wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (c) the isolated antibody is administered once per week for from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks. In some embodiments, (b) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, (c) the isolated antibody is administered once per week for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is DB2 / 47155346.6 83Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 administered once per week for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, further comprising (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks. In some embodiments, (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg, for example, about 100 mg, about 300 mg, or about 600 mg. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody is subcutaneously administered. DB2 / 47155346.6 84Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0297] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject in need thereof has a baseline mean platelet count of less than or equal to about 100×109 / L, less than or equal to about 50×109 / L, less than or equal to about 45×109 / L, less than or equal to about 40×109 / L, less than or equal to about 35×109 / L, less than or equal to about 30×109 / L, less than or equal to about 25×109 / L, less than or equal to about 20×109 / L, less than or equal to about 15×109 / L, or less than or equal to about 10×109 / L.

[0298] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject in need thereof has an ITP disease duration (e.g., mean ITP disease duration) of at least about 0.1 years, at least about 0.2 years, at least about 0.3 years, at least about 0.4 years, at least about 0.5 years, at least about 0.6 years, at least about 0.7 years, at least about 0.8 years, at least about 0.9 years, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 11 years, at least about 12 years, at least about 13 years, at least about 14 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, or at least about 35 years.

[0299] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject in need thereof has received a mean of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13 prior ITP treatments.

[0300] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a length of platelet response of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, at least about 45 weeks, or at least about 50 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, or ≥150,000 / μL. In some embodiments, the length of platelet response is at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, DB2 / 47155346.6 85Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 at least about 45 weeks, or at least about 50 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥50,000 / μL.

[0301] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, or ≥150,000 / μL. In some embodiments, the platelet response is defined as a platelet count of ≥20,000 / μL above baseline, for example, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL and ≥20,000 / μL above baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL and / or the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL. In some embodiments, the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline. In some embodiments, the platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, or ≥50,000 / μL at about 2 weeks after the administering, about 4 weeks after the administering, about 6 weeks after the administering, about 8 weeks after the administering, about 10 weeks after the administering, about 12 weeks after the administering, about 14 weeks after the administering, about 16 weeks after the administering, about 18 weeks after the administering, or about 20 weeks after the administering. In some embodiments, the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering.

[0302] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response in six weeks or less, five weeks or less, four weeks or less, three weeks or less, two weeks or less, or one week or less. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response in one week or less. DB2 / 47155346.6 86Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0303] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

[0304] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a durable platelet response for at least 1 of 6 biweekly measurements, at least 2 of 6 biweekly measurements, at least 3 of 6 biweekly measurements, at least 4 of 6 biweekly measurements, or at least 5 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, optionally wherein the subject has not received a rescue therapy. In some embodiments, the durable platelet response is defined as a durable platelet response for at least 1 of 6 weekly measurements, at least 2 of 6 weekly measurements, at least 3 of 6 weekly measurements, at least 4 of 6 weekly measurements, or at least 5 of 6 weekly platelet measurements from baseline to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a durable platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy. In some embodiments, the platelet response is defined at a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, or ≥150,000 / μL. In some embodiments, the platelet response is defined at a platelet count of ≥50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL). In some embodiments, the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least DB2 / 47155346.6 87Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 about 35 weeks, at least about 40 weeks, at least about 45 weeks, or at least about 50 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is defined as a durable platelet response for at least 4 of 6 biweekly measurements from about 10 weeks to about 24 weeks after the administering, wherein the subject has not received a rescue therapy, and wherein the platelet response is defined at a platelet count of ≥50,000 / μL. In some embodiments, the durable platelet response is defined as a platelet count of ≥10,000 / μL, ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, or ≥50,000 / μL on at least 1 of 6, at least 2 of 6, or at least 3 of 6 weekly platelet measurements from baseline to about 24 weeks after the administering, from about 5 weeks to about 24 weeks after the administering, from about 10 weeks to about 24 weeks after the administering, from about 15 weeks to about 24 weeks after the administering, or from about 19 weeks to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering. In some embodiments, the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering.

[0305] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, ≥100,000 / μL, ≥110,000 / μL, ≥120,000 / μL, ≥130,000 / μL, ≥140,000 / μL, ≥150,000 / μL, ≥175,000 / μL, or ≥200,000 / μL. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL. In some embodiments, the complete platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, or from DB2 / 47155346.6 88Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 baseline to about 24 weeks after the administering, optionally wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the complete platelet response is measured in at least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, or from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering. In some embodiments, the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering.

[0306] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL above baseline. In some embodiments, the clinically meaningful platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, DB2 / 47155346.6 89Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 or from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured on at least two visits from baseline to about 16 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, or from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at least two measurements from baseline to about 16 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, the clinically meaningful platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. DB2 / 47155346.6 90Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0307] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL. In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥20,000 / μL, ≥30,000 / μL, ≥40,000 / μL, ≥50,000 / μL, ≥60,000 / μL, ≥70,000 / μL, ≥80,000 / μL, ≥90,000 / μL, or ≥100,000 / μL above baseline. In some embodiments, the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline. In some embodiments, the hemostatic platelet response is measured on at least one visit, at least two visits, at least three visits, at least four visits, or at least five visits from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured on at least two visits from baseline to about 18 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured in at least one measurement, at least two measurements, at least three measurements, at least four measurements, or at least five measurements from baseline to about 10 weeks after the administering, from baseline to about 12 weeks after the administering, from baseline to about 14 weeks after the administering, from baseline to about 16 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 20 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, or from baseline to about 32 weeks after the administering, wherein the subject has not received a rescue therapy in the DB2 / 47155346.6 91Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured in at least two measurements from baseline to about 18 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the hemostatic platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, the baseline platelet count is <12,000 / μL, <10,000 / μL, <8,000 / μL, <5,000 / μL, or <1,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL.

[0308] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL.

[0309] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less DB2 / 47155346.6 92Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 than 10%, or less than 5% incidence of use of a rescue therapy. In some embodiments, the method does not include the use of a rescue therapy.

[0310] As used herein, “rescue therapy” refers to a dosing of concomitant medications (except for a bridging therapy) in accordance with institutional practices or the physician’s best medical judgment to control and manage ITP during or after administration of the isolated anti-CD38 antibody or antigen binding fragment thereof. Rescue therapies include, but are not limited to, high-dose corticosteroids, high-dose IVIg, and / or increased or added SOC ITP therapies.

[0311] Because platelet counts may not be affected until several weeks after initiation of treatment with the isolated anti-CD38 antibody or antigen binding fragment thereof, subjects may receive a “bridging therapy.” Bridging therapies include, but are not limited to, a one-time infusion of platelets; a single dose of IVIg (up to 1 g / kg); or an additional 20 mg of prednisone (or equivalent) per day for up to 7 days.

[0312] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP disease activity and / or progression in a subject diagnosed with ITP. In some embodiments, the ITP disease activity and / or progression is measured one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ), and / or 5-Level EuroQol Five Dimensions (EQ-5D-5L). In some embodiments, the ITP disease activity and / or progression is measured by World Health Organization (WHO) Bleeding Scale. In some embodiments, the ITP disease activity and / or progression is measured by Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ). In some embodiments, the ITP disease activity and / or progression is measured by 5-Level EuroQol Five Dimensions (EQ-5D-5L). In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within DB2 / 47155346.6 93Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 12 months before the receiving the isolated antibody. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. In some embodiments, the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

[0313] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in in a reduction in bleeding events in the subject. In some embodiments, bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP-BAT). In some embodiments, the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

[0314] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in ITP remission. In some embodiments, ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

[0315] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s). In some embodiments, the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM. In some embodiments, the immunoglobulin(s) (e.g., IgA, IgG, and / or IgM) are reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the immunoglobulin(s). In some embodiments, IgA is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about DB2 / 47155346.6 94Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the IgA. In some embodiments, IgG is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of the IgG. In some embodiments, IgM is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% relative to baseline levels of IgM. In some embodiments, IgA is reduced by at least about 50% relative to baseline levels of IgA. In some embodiments, IgG is reduced by at least about 30% relative to baseline levels of IgG. In some embodiments, IgM is reduced by at least about 40% relative to baseline levels of IgM.

[0316] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) (e.g., IgA, IgG, and / or IgM) in six weeks or less, five weeks or less, four weeks or less, three weeks or less, two weeks or less, or one week or less. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in one week or less.

[0317] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms.

[0318] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, and wherein the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0319] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0320] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is O-linked glycosylation. DB2 / 47155346.6 95Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0321] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 9, and / or the VL region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10.

[0322] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 9.

[0323] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10.

[0324] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 9.

[0325] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10.

[0326] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the HC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11.

[0327] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the HC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 14.

[0328] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the LC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0329] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof interacts with at least K121, F135, DB2 / 47155346.6 96Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 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.

[0330] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10-8M or a greater affinity, and wherein the affinity is measured by a standard Biacore assay.

[0331] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises SEQ ID NO: 9 and the VL region comprises SEQ ID NO: 10.

[0332] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 11 and an LC as set forth in SEQ ID NO: 12.

[0333] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 14 and an LC as set forth in SEQ ID NO: 12.

[0334] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof further comprises an Fc domain.

[0335] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0336] In some embodiments, the disclosure provides the methods 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.

[0337] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject receives background ITP medication(s).

[0338] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background ITP medication(s) is one or more selected from the group consisting of a thrombopoietin receptor agonist (TPO-RA), a corticosteroid, an immunosuppressant, and / or an DB2 / 47155346.6 97Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 inhibitor. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background ITP medication(s) is one or more selected from the group consisting of romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and dexamethasone.

[0339] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background ITP medication(s) is administered in combination with the antibody or antigen binding fragment thereof.

[0340] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or 600 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg, from about 100 mg to about 575 mg, from about 100 mg to about 550 mg, from about 100 mg to about 525 mg, from about 100 mg to about 500 mg, from about 100 mg to about 475 mg, from about 100 mg to about 450 mg, from about 100 mg to about 425 mg, from about 100 mg to about 400 mg, from about 100 mg to about 375 mg, from about 100 mg to about 350 mg, from about 100 mg to about 325 mg, from about 100 mg to about 300 mg, from about 300 mg to about 600 mg, from about 300 mg to about 575 mg, from about 300 mg to about 550 mg, from about 300 mg to about 525 mg, from about 300 mg to about 500 mg, from about 300 mg to about 475 mg, from about 300 mg to about 450 mg, from about 300 mg to about 425 mg, from about 300 mg to about 400 mg, from about 300 mg to about 375 mg, from about 300 mg to about 350 mg, from about 300 mg to about 325 mg, from about 125 mg to about 600 mg, from about 150 mg to about 600 mg, from about 175 mg to about 600 mg, from about 200 mg to about 600 mg, from about 225 mg to about 600 mg, from about 250 mg to about 600 mg, from about 275 mg to about 600 mg, from about 325 mg to about 600 mg, from about 350 mg to about 600 mg, from about 375 mg to about 600 mg, from about 400 mg to about 600 mg, from about 425 mg to about 600 mg, from about 450 mg to about 600 mg, from about 475 mg to about 600 mg, from about 500 mg to about 600 mg, from about 525 mg to about 600 DB2 / 47155346.6 98Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 mg, from about 550 mg to about 600 mg, or from about 575 mg to about 600 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg. In some embodiments, wherein the antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0341] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the dosage is a dosage administered once every week, once every two weeks, once every three weeks or once every four weeks.

[0342] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0343] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the pharmaceutically acceptable composition comprises the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient, and / or stabilizer.

[0344] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 11 and an LC as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once weekly for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

[0345] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 14 and an LC as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once weekly for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered DB2 / 47155346.6 99Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

[0346] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0347] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment- emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst.

[0348] In some embodiments, the disclosure provides the methods as disclosed herein, wherein a TRAE or TEAE resulting from administering the antibody or antigen binding fragment thereof has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0349] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in dose and / or frequency of use of background ITP medication(s).

[0350] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP-associated bleeding adverse events (AEs) relative to placebo. In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25% reduction in ITP-associated bleeding adverse events (AEs) relative to placebo.

[0351] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof is from about 2 times to about 4 times more efficacious than fostamatinib and / or efgartigimod. In some embodiments, the isolated antibody or antigen binding fragment thereof results in from about 2 times to about 4 times more durable or sustained platelet response as compared to fostamatinib and / or efgartigimod. DB2 / 47155346.6 100Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0352] In some embodiments, the disclosure provides an isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of immune thrombocytopenia (ITP), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0353] In some embodiments, the disclosure provides a pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0354] In some embodiments, the disclosure provides a medicament for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0355] In some embodiments, the disclosure provides a use of an isolated human anti-CD38 antibody or antigen binding fragment thereof in the manufacture of a medicament for treating immunoglobulin A nephropathy (IgAN), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: DB2 / 47155346.6 101Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8. Antibody Compositions for In Vivo Administration

[0356] Formulations of the antibodies or antigen binding fragments thereof used in accordance with the present disclosure are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers (Remington’s Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed.; incorporated herein by reference in its entirety), in the form of lyophilized formulations or aqueous solutions.

[0357] The formulations herein may also contain more than one active compound as necessary 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 antibodies or antigen binding fragments thereof with other specificities. Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine, growth inhibitory agent and / or small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0358] In some embodiments, two mezagitamab drug product formulations have been developed, referred to as Process A and Process B as disclosed herein.

[0359] In one embodiment, the Process A mezagitamab drug product is a clear-to-opalescent, colorless solution containing AB79 (20 mg / mL) aqueous solution of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at approximately pH 6.5. The Process A placebo is a clear, colorless solution containing an aqueous solution of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at approximately pH 6.5. The Process A mezagitamab drug product and placebo are supplied in aseptically filled, single-use, clear, type I borosilicate glass vials with fluoropolymer coated butyl rubber stoppers and aluminum crimp seals with flip-off caps.

[0360] In another embodiment, the Process B mezagitamab drug product is made in 2 strengths, 5 mg / mL or 100 mg / mL. Each strength is a clear-to-opalescent, colorless-to-brownish-yellow DB2 / 47155346.6 102Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 solution containing mezagitamab in an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at approximately pH 5.9. The Process B placebo is a clear, colorless solution containing an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at approximately pH 5.9. The Process B mezagitamab drug product and placebo are supplied in aseptically filled, single use, clear, type I, borosilicate glass vials with fluoropolymer coated butyl rubber stoppers and aluminum crimp seals with flip-off caps. Subcutaneous Administration

[0361] The anti-CD38 antibodies described herein, such as mezagitamab, can be administered at sufficiently dosages that are therapeutically effective, thereby allowing for subcutaneous administration. Subcutaneous administration is a minimally invasive mode of administration and is considered the most versatile and therefore desirable mode of administration that can be used for short-term and long-term therapies. In some embodiments, subcutaneous administration can be performed by injection. In some embodiments, the site of the injection or device can be rotated when multiple injections or devices are needed.

[0362] Accordingly, subcutaneous formulations are much easier for a subject to self-administer, especially since the formulation may have to be taken regularly during the subject’s entire life. Furthermore, the ease and speed of subcutaneous delivery allows increased subject compliance and quicker access to medication when needed. Thus, the subcutaneous formulations of the anti- CD38 antibodies provided herein provide a substantial benefit over the prior art and solve certain unmet needs.

[0363] In some embodiments, the antibodies of the disclosure are administered to a subject in accordance with known methods via a subcutaneous route. In some embodiments, antibodies of the present disclosure can be administered by subcutaneous injection. In specific embodiments, the subcutaneous formulation is subcutaneously injected into the same site of a subject (e.g., administered to the upper arm, anterior surface of the thigh, lower portion of the abdomen, or upper back) for repeat or continuous injections. In other embodiments, the subcutaneous formulation is subcutaneously injected into a different or rotating site of a subject. Single or multiple administrations of the formulations may be employed. DB2 / 47155346.6 103Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0364] In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of ITP. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of chronic or persistent primary ITP.

[0365] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasmablasts, plasma cells, NK cells, B cells and / or T cells after subcutaneous administration to a subject. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasmablasts. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasma cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to the depletion of B cells or T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells, as well as increased depletion of NK cells as compared to T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells, as well as increased depletion of B cells as compared to T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells and increased depletion of B cells as compared to T cells. Suitably, the antibodies or antigen binding fragments thereof of the disclosure may allow for increased depletion of CD38+ cells as compared to CD38- cells.

[0366] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to a decrease 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.

[0367] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to a decrease in autoantibodies after subcutaneous administration to a subject. In some embodiments, the autoantibodies are anti-platelet autoantibodies.

[0368] In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least about 50% and at least about 80% as DB2 / 47155346.6 104Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least about 60% and at least about 80% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least about 50% and 70% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least about 55% and 65% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least about 55% and 70% as compared to intravenous administration normalized for the same dose.

[0369] In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is at least about 40%, at least about 45%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, or at least about 85% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least about 50% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least about 60% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least about 70% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least about 80% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least about 90% as compared to intravenous administration normalized for the same dose. DB2 / 47155346.6 105Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01

[0370] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is 50%-80% as compared to intravenous administration normalized for the same dose.

[0371] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 50% as compared to intravenous administration normalized for the same dose.

[0372] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 55% as compared to intravenous administration normalized for the same dose.

[0373] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 60% as compared to intravenous administration normalized for the same dose.

[0374] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 65% as compared to intravenous administration normalized for the same dose.

[0375] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 70% as compared to intravenous administration normalized for the same dose.

[0376] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 75% as compared to intravenous administration normalized for the same dose.

[0377] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least about 80% as compared to intravenous administration normalized for the same dose.

[0378] In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered in a single bolus injection. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered monthly. In certain embodiments, the anti-CD38 antibodies or DB2 / 47155346.6 106Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 antigen binding fragments thereof as described herein are subcutaneously administered every two weeks. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered weekly. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered twice a week. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered daily. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 12 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 8 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 6 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 4 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 2 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every hour. In some embodiments, the antibodies or antigen binding fragments thereof as disclosed herein is subcutaneously administered once weekly for 8 weeks.

[0379] In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as disclosed herein are subcutaneously administered at a dosage of from about 100 mg to about 600 mg. In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as disclosed herein are subcutaneously administered at a dosage of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as disclosed herein are subcutaneously administered at a dosage of from about 100 mg to about 600 mg, from about 100 mg to about 575 mg, from about 100 mg to about 550 mg, from about 100 mg to about 525 mg, from about 100 mg to about 500 mg, from about 100 mg to about 475 mg, from about 100 mg to about 450 mg, from about 100 mg to about 425 mg, from about 100 mg to DB2 / 47155346.6 107Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 about 400 mg, from about 100 mg to about 375 mg, from about 100 mg to about 350 mg, from about 100 mg to about 325 mg, from about 100 mg to about 300 mg, from about 300 mg to about 600 mg, from about 300 mg to about 575 mg, from about 300 mg to about 550 mg, from about 300 mg to about 525 mg, from about 300 mg to about 500 mg, from about 300 mg to about 475 mg, from about 300 mg to about 450 mg, from about 300 mg to about 425 mg, from about 300 mg to about 400 mg, from about 300 mg to about 375 mg, from about 300 mg to about 350 mg, from about 300 mg to about 325 mg, from about 125 mg to about 600 mg, from about 150 mg to about 600 mg, from about 175 mg to about 600 mg, from about 200 mg to about 600 mg, from about 225 mg to about 600 mg, from about 250 mg to about 600 mg, from about 275 mg to about 600 mg, from about 325 mg to about 600 mg, from about 350 mg to about 600 mg, from about 375 mg to about 600 mg, from about 400 mg to about 600 mg, from about 425 mg to about 600 mg, from about 450 mg to about 600 mg, from about 475 mg to about 600 mg, from about 500 mg to about 600 mg, from about 525 mg to about 600 mg, from about 550 mg to about 600 mg, or from about 575 mg to about 600 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg. In some embodiments, wherein the antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg. Unit Dosage Forms

[0380] In some embodiments, the therapeutic anti-CD38 antibodies or antigen binding fragments thereof are formulated as part of a unit dosage form. In some embodiments, the anti-CD38 antibody or antigen binding fragment thereof comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody or antigen binding fragment thereof comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises an HC comprising the following CDR amino acid DB2 / 47155346.6 108Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab). In some embodiments, the antibody comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody or antigen binding fragment thereof comprises an 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 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab) and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO 9. In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGK THYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0381] 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 DB2 / 47155346.6 109Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 following CDR sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab) 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. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVP DRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVT LFPPSSEEL (SEQ ID NO: 10).

[0382] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein and an LC comprising the VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0383] As will be appreciated by those in the art, the VH region and VL region can be joined to human IgG constant domain sequences, generally IgG1, IgG2 or IgG4. In some embodiments, the antibody comprises an HC having amino acid sequence with at least 80% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO 11. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGK THYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0384] In some embodiments, the antibody comprises an HC having amino acid sequence with at least 80% sequence identity to SEQ ID NO: 14. Suitably, the HC may comprise the CDR sequences as defined by SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of DB2 / 47155346.6 110Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 the HC may have at least 80% sequence identity to SEQ ID NO 14. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 14. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGK THYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 14).

[0385] In some embodiments, the antibody comprises an LC having amino acid sequence with at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the LC may have at least 80% sequence identity to SEQ ID NO 12. In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVP DRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 12).

[0386] 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.

[0387] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 14 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.

[0388] In some embodiments, the formulation comprising the anti-CD38 antibody is a unit dosage form. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of from about 100 mg to about 600 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg, about 125 DB2 / 47155346.6 111Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of from about 100 mg to about 600 mg, from about 100 mg to about 575 mg, from about 100 mg to about 550 mg, from about 100 mg to about 525 mg, from about 100 mg to about 500 mg, from about 100 mg to about 475 mg, from about 100 mg to about 450 mg, from about 100 mg to about 425 mg, from about 100 mg to about 400 mg, from about 100 mg to about 375 mg, from about 100 mg to about 350 mg, from about 100 mg to about 325 mg, from about 100 mg to about 300 mg, from about 300 mg to about 600 mg, from about 300 mg to about 575 mg, from about 300 mg to about 550 mg, from about 300 mg to about 525 mg, from about 300 mg to about 500 mg, from about 300 mg to about 475 mg, from about 300 mg to about 450 mg, from about 300 mg to about 425 mg, from about 300 mg to about 400 mg, from about 300 mg to about 375 mg, from about 300 mg to about 350 mg, from about 300 mg to about 325 mg, from about 125 mg to about 600 mg, from about 150 mg to about 600 mg, from about 175 mg to about 600 mg, from about 200 mg to about 600 mg, from about 225 mg to about 600 mg, from about 250 mg to about 600 mg, from about 275 mg to about 600 mg, from about 325 mg to about 600 mg, from about 350 mg to about 600 mg, from about 375 mg to about 600 mg, from about 400 mg to about 600 mg, from about 425 mg to about 600 mg, from about 450 mg to about 600 mg, from about 475 mg to about 600 mg, from about 500 mg to about 600 mg, from about 525 mg to about 600 mg, from about 550 mg to about 600 mg, or from about 575 mg to about 600 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 300 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 600 mg.

[0389] In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 125 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 150 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 175 mg. In DB2 / 47155346.6 112Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 200 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 225 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 250 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 275 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 300 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 325 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 350 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 375 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 400 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 425 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 450 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 475 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 500 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 525 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 550 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 575 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 600 mg.

[0390] In some embodiments, the disclosure provides a unit dosage form comprising an isolated human anti-CD38 antibody that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated DB2 / 47155346.6 113Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 for subcutaneous administration of the isolated antibody or antigen binding fragment thereof at a dosage of about 600 mg in a course of once per week for 8 weeks in the treatment of chronic primary ITP or persistent primary ITP in a subject that has had an insufficient response or intolerance to other therapy; wherein the other therapy is a first-line ITP therapy and / or a second- line ITP therapy, wherein the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); optionally wherein the isolated antibody is further administered in more than one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 courses, etc.) course of once per week for 8 weeks; and / or optionally wherein the isolated antibody is not further administered for a period of 8 weeks.

[0391] In some embodiments, the disclosure provides a unit dosage form wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks. In some embodiments, (a) the isolated antibody is administered once per week for from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to DB2 / 47155346.6 114Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (c) the isolated antibody is administered once per week for from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 weeks to 14 weeks. In some embodiments, (a) the isolated antibody is administered once per week for 8 weeks. In some embodiments, (b) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, (c) the isolated antibody is administered once per week for 8 weeks. In some embodiments, the disclosure provides a unit dosage form wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered once per week for 8 weeks. In some embodiments, disclosure provides a unit dosage form wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks. In some embodiments, disclosure provides a unit dosage form wherein (a) the isolated antibody is subcutaneously administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is subcutaneously administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks. In some embodiments, the disclosure provides a unit dosage form further comprising (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks. In some embodiments, (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks, from 2 weeks to 16 weeks, from 3 weeks to 16 weeks, from 4 weeks to 16 weeks, from 5 weeks to 16 weeks, from 6 weeks to 16 weeks, from 7 weeks to 16 weeks, from 8 weeks to 16 weeks, from 1 week to 15 weeks, from 1 week to 14 weeks, from 1 week to 13 weeks, from 1 week to 12 weeks, from 1 week to 11 weeks, from 1 week to 10 weeks, from 1 week to 9 weeks, from 1 week to 8 weeks, from 7 weeks to 9 weeks, from 6 weeks to 10 weeks, from 5 weeks to 11 weeks, from 4 weeks to 12 weeks, from 3 weeks to 13 weeks, or from 2 DB2 / 47155346.6 115Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks to 14 weeks. In some embodiments, (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides a unit dosage form wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides a unit dosage form wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides a unit dosage form wherein (a) the isolated antibody is subcutaneously administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is subcutaneously administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks. In some embodiments, the disclosure provides a unit dosage form wherein the antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg, for example, about 100 mg, about 300 mg, or about 600 mg. In some embodiments, the disclosure provides a unit dosage form wherein the isolated antibody is administered subcutaneously.

[0392] In some embodiments, the anti-CD38 antibody unit dosage forms provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents. In some embodiments, the anti-CD38 antibody is provided as a pharmaceutical composition which comprises a unit dosage form according to the present disclosure. Suitably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents.

[0393] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit forms as used DB2 / 47155346.6 116Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 herein can, in some embodiments, refer to physically discrete units suited as unitary dosages for the subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0394] The specification for the dosage unit forms of the present disclosure is dictated by and is directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of an individual.

[0395] The efficient dosages and the dosage regimens for the anti-CD38 antibodies or antigen binding fragments thereof used in the present disclosure depend on the severity of the disease or condition to be treated and may be determined by persons skilled in the art.

[0396] In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every week, once every two weeks, once every three weeks or once every four weeks in a dosage of about 100 mg to about 600 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every week in a dosage of about 100 mg to about 600 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every two weeks in a dosage of about 100 mg to about 600 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every three weeks in a dosage of about 100 mg to about 600 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every four weeks in a dosage of about 100 mg to about 600 mg.

[0397] Suitably, the weekly dosage may be about 100 mg. Suitably, the weekly dosage may be about 125 mg. Suitably, the weekly dosage may be about 150 mg. Suitably, the weekly dosage may be about 175 mg. Suitably, the weekly dosage may be about 200 mg. Suitably, the weekly dosage may be about 225 mg. Suitably, the weekly dosage may be about 250 mg. Suitably, the weekly dosage may be about 275 mg. Suitably, the weekly dosage may be about 300 mg. Suitably, the weekly dosage may be about 325 mg. Suitably, the weekly dosage may be about DB2 / 47155346.6 117Attorney Docket No.: 101588-5018-WO Takeda...

Claims

Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 We Claim:

1. A method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof.

2. A method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:

8.

3. The method of claim 1 or 2, wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of from about 100 mg to about 600 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is administered subcutaneously.

4. A method of treating immune thrombocytopenia (ITP) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

5. A method of reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering DB2 / 47155346.6 290Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

6. A method of reducing the level of immunoglobulin(s) in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

7. The method of claim 6, wherein the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM.

8. The method of claim 6 or 7, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in three weeks or less, two weeks or less, or one week or less.

9. The method of any one of claims 6-8, wherein the immunoglobulin(s) are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s).

10. A method of increasing platelet counts in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen DB2 / 47155346.6 291Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

11. A method of achieving platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof.

12. The method of claim 11, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

13. The method of claim 11 or 12, wherein the platelet response is defined as a platelet count of ≥50,000 / μL and / or wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline.

14. The method of any one of claims 11-13, wherein the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering.

15. The method of any one of claims 11-14, the method achieves a platelet response in three weeks or less, two weeks or less, or one week or less.

16. The method of any one of claims 11-15, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least about 2 cumulative number of weeks, at least about 4 cumulative number of weeks, at least about 8 DB2 / 47155346.6 292Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 cumulative number of weeks, at least about 10 cumulative number of weeks, at least about 12 cumulative number of weeks, at least about 14 cumulative number of weeks, at least about 16 cumulative number of weeks, at least about 18 cumulative number of weeks, or at least about 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

17. A method of achieving a durable platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

18. The method of claim 17, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL); optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering; optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering; and optionally wherein the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

19. A method of achieving complete platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a DB2 / 47155346.6 293Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

20. The method of claim 19, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering; optionally wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering.

21. The method of claim 19 or 20, wherein the complete platelet response is measured on at least two visits from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

22. A method of achieving a clinically meaningful platelet response in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

23. The method of claim 22, wherein the clinically meaningful platelet response is defined as a platelet count ≥20,000 / μL above baseline.

24. The method of claim 22 or 23, wherein the clinically meaningful platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks. DB2 / 47155346.6 294Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 25. A method of achieving hemostatic platelet response in a subject in need thereof having a baseline platelet count of <15,000 / μL, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

26. The method of claim 25, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline.

27. The method of claim 25 or 26, wherein the hemostatic platelet response is measured in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

28. A method of reducing the level of anti-platelet autoantibodies in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:8 ; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

29. A method of reducing immune thrombocytopenia (ITP) disease activity and / or progression in a subject diagnosed with ITP, the method comprising administering to the subject DB2 / 47155346.6 295Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

30. The method of claim 29, wherein the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L); optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering. DB2 / 47155346.6 296Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 31. The method of claim 29 or 30, wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering.

32. A method of reducing bleeding events in a subject diagnosed with immune thrombocytopenia (ITP), the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg.

33. The method of claim 32, wherein the bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP-BAT).

34. The method of claim 32 or 33, wherein the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

35. A method of achieving immune thrombocytopenia (ITP) remission in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti- CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 600 mg. DB2 / 47155346.6 297Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 36. The method of claim 35, wherein ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

37. A method of treating immune thrombocytopenia (ITP) in a subject diagnosed with ITP, the method comprising administering to the subject an isolated human anti-CD38 antibody, wherein the isolated antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein: the ITP is chronic primary ITP or persistent primary ITP; the subject has had an insufficient response or intolerance to other therapy; the other therapy is a first-line ITP therapy and / or a second-line ITP therapy, wherein the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); the isolated antibody is subcutaneously administered in a dosage of about 600 mg in a course of once per week for 8 weeks; optionally wherein the isolated antibody is further administered in more than one course of once per week for 8 weeks; and / or optionally wherein the isolated antibody is further not administered for a period of 8 weeks.

38. The method of any one of the preceding claims, wherein the subject in need thereof is diagnosed with immune thrombocytopenia (ITP); optionally wherein the ITP is primary ITP; optionally wherein the ITP is persistent ITP; optionally wherein the ITP is chronic ITP; optionally wherein the ITP is persistent or chronic primary ITP; optionally wherein the primary ITP has persisted for at least about 3 months; DB2 / 47155346.6 298Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein the subject has had a prior response to other therapy excluding a thrombopoietin receptor agonist (TPO-RA), wherein the prior response is defined as achieving a platelet count of ≥50,000 / mL; optionally wherein the subject has a baseline mean platelet count of <30,000 / µL from at least 2 consecutive measurements taken at least about 5 days apart; optionally wherein the baseline mean platelet count comprises individual values ≤35,000 / µL; optionally wherein the subject has had an insufficient response or intolerance to other therapy; optionally wherein the other therapy is a first-line ITP therapy and / or a second-line ITP therapy; optionally wherein the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); optionally wherein the insufficient response to other treatment is defined as failure to achieve a sustained platelet count of at least 50,000 / µL or doubling of baseline platelet count after an appropriate course of the other therapy; and optionally wherein the intolerance to other therapy is defined as a documented side effect causing discontinuation of the therapy.

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

40. The method of any one of the preceding claims, wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10; DB2 / 47155346.6 299Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10; optionally wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11; and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 14; and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12; optionally wherein the isolated antibody or antigen binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human sequence numbering; optionally wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10-8M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay; optionally wherein the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10; optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and DB2 / 47155346.6 300Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO:

12.

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

42. The method of any one of the preceding claims, wherein the subject receives background ITP medication(s); optionally wherein the background ITP medication(s) is one or more selected from the group consisting of a thrombopoietin receptor agonist (TPO-RA), a corticosteroid, an immunosuppressant, and an inhibitor; and optionally wherein the background ITP medication(s) is one or more selected from the group consisting of romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and dexamethasone.

43. The method of claim 42, wherein the background ITP medication(s) is administered in combination with the isolated antibody or antigen binding fragment thereof.

44. The method of any one of the preceding claims, wherein the subject in need thereof has a baseline mean platelet count of less than or equal to about 40×109 / L, less than or equal to about 35×109 / L, less than or equal to about 30×109 / L, less than or equal to about 25×109 / L, or less than or equal to about 20×109 / L.

45. The method of any one of the preceding claims, wherein the subject in need thereof has an ITP disease duration of at least about 0.1 years, at least about 0.3 years, at least about 0.5 years, at least about 1 year, at least about 5 years, or at least about 10 years.

46. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a length of platelet response of at DB2 / 47155346.6 301Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, or at least about 25 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥50,000 / μL.

47. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL and / or wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline; optionally wherein the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response in three weeks or less, two weeks or less, or one week or less; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering.

48. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL); optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 weeks after the administering; optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering; optionally wherein the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 DB2 / 47155346.6 302Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof.

49. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering; optionally wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering.

50. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks.

51. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL.

52. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL.

53. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 75%, less than 50%, or DB2 / 47155346.6 303Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 less than 25% incidence of use of a rescue therapy; optionally wherein the subject has not received a rescue therapy in the previous four weeks; optionally wherein the method does not include the use of a rescue therapy.

54. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in ITP disease activity and / or progression in a subject diagnosed with ITP; optionally wherein the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP- PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L); optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering. DB2 / 47155346.6 304Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 55. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in bleeding events in the subject; optionally wherein the bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP-BAT); optionally wherein the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain.

56. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in ITP remission, optionally wherein ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

57. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s); optionally wherein the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) in three weeks or less, two weeks or less, or one week or less; and optionally wherein the immunoglobulin(s) are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s).

58. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs); optionally wherein the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, DB2 / 47155346.6 305Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst; and optionally wherein a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

59. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in dose and / or frequency of use of background ITP medication(s).

60. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, and about 600 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg; and optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

61. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof is administered once every week, once every two weeks, once every three weeks or once every four weeks; optionally wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; optionally wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered once per week for 8 weeks; DB2 / 47155346.6 306Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; optionally wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; and (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks; optionally wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks; optionally wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks.

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

63. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks, or wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12; and DB2 / 47155346.6 307Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 wherein the antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

64. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

65. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof is from about 2 times to about 4 times more efficacious than fostamatinib and / or efgartigimod; optionally wherein the isolated antibody or antigen binding fragment thereof results in from about 2 times to about 4 times more durable platelet response as compared to fostamatinib and / or efgartigimod.

66. A unit dosage form comprising an isolated antibody or antigen binding fragment thereof that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; 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 isolated antibody or antigen binding fragment thereof at a dosage of from about 100 mg to about 600 mg in the treatment of ITP.

67. A unit dosage form comprising an isolated human anti-CD38 antibody that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8; 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 isolated antibody or antigen binding fragment thereof at a dosage of about 600 mg in a course of once per week for 8 weeks in the treatment of chronic primary ITP or persistent primary ITP in a DB2 / 47155346.6 308Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 subject that has had an insufficient response or intolerance to other therapy; wherein the other therapy is a first-line ITP therapy and / or a second-line ITP therapy, wherein the other therapy comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); optionally wherein the isolated antibody is further administered in more than one course of once per week for 8 weeks; and / or optionally wherein the isolated antibody is not further administered for a period of 8 weeks.

68. The unit dosage form of claim 66 or 67, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

69. The unit dosage form of any one of claims 66-68, wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 9, and / or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11, DB2 / 47155346.6 309Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 14, and / or the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12; optionally wherein the isolated antibody or antigen binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human sequence numbering; optionally wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10-8M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay; optionally wherein the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10; optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO:

12.

70. The unit dosage form of any one of claims 66-69, wherein the isolated antibody or antigen binding fragment thereof further comprises an Fc domain, optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and optionally wherein the isolated antibody or antigen binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgG1 antibody.

71. The unit dosage form of any one of claims 66-70, wherein the isolated antibody or antigen binding fragment thereof is used in combination with one or more background ITP medication(s); DB2 / 47155346.6 310Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein the background ITP medication(s) is one or more selected from the group consisting of a thrombopoietin receptor agonist (TPO-RA), a corticosteroid, an immunosuppressant, and an inhibitor; and optionally wherein the background ITP medication(s) is one or more selected from the group consisting of romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and dexamethasone.

72. The unit dosage form of any one of claims 66-71, wherein administering the isolated antibody or antigen binding fragment thereof results in: a length of platelet response of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, or at least about 25 weeks, wherein the length of the platelet response is defined as the sum of all weeks in which the subject achieves a platelet response, and wherein the platelet response is defined as a platelet count of ≥50,000 / μL; and / or a platelet response, wherein the platelet response is defined as a platelet count of ≥50,000 / μL; optionally wherein the platelet response is defined as a platelet count of ≥30,000 / μL and at least doubled from baseline; optionally wherein the platelet response is defined as a platelet count of ≥50,000 / μL at about 16 weeks after the administering; optionally wherein the platelet response is achieved in three weeks or less, two weeks or less, or one week or less; and optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet response for at least 2 cumulative number of weeks, at least 4 cumulative number of weeks, at least 8 cumulative number of weeks, at least 10 cumulative number of weeks, at least 12 cumulative number of weeks, at least 14 cumulative number of weeks, at least 16 cumulative number of weeks, at least 18 cumulative number of weeks, or at least 20 cumulative number of weeks from baseline to about 24 weeks after the administering; and / or a durable platelet response, wherein the durable platelet response is measured as the cumulative number of weeks in which platelet count is sustained (e.g., ≥30,000 / μL or ≥50,000 / μL); optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 2 of 6 weekly platelet measurements from about 10 weeks to about 24 DB2 / 47155346.6 311Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 weeks after the administering; optionally wherein the durable platelet response is defined as a platelet count of ≥50,000 / μL on at least 4 of 6 weekly platelet measurements from about 19 weeks to about 24 weeks after the administering; optionally wherein the platelet response is sustained for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, or at least about 16 weeks after the administration of the isolated human anti-CD38 antibody or antigen binding fragment thereof; and / or a complete platelet response, wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least one measurement from baseline to about 24 weeks after the administering; optionally wherein the complete platelet response is defined as a platelet count of ≥100,000 / μL in at least two measurements from baseline to about 24 weeks after the administering; and / or a clinically meaningful platelet response, wherein the clinically meaningful platelet response is defined as a platelet count of ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks; and / or a hemostatic platelet response, wherein the hemostatic platelet response is defined as a platelet count of ≥30,000 / μL and ≥20,000 / μL above baseline in at least two measurements from baseline to about 24 weeks after the administering, wherein the subject has not received a rescue therapy in the previous four weeks and the subject has a baseline platelet count of <15,000 / μL; and / or a platelet count of >10,000 / μL, >20,000 / μL, >30,000 / μL, >40,000 / μL, >50,000 / μL, >60,000 / μL, >70,000 / μL, >80,000 / μL, >90,000 / μL, or >100,000 / μL; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >50,000 / μL; optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a platelet count of >100,000 / μL; and / or a reduction in immunoglobulin(s); optionally wherein the immunoglobulin is one or more selected from the group consisting of IgA, IgG, and IgM; optionally wherein the reduction in immunoglobulin(s) is achieved in three weeks or less, two weeks or less, or one week or less; DB2 / 47155346.6 312Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 and optionally wherein the immunoglobulin(s) are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to baseline levels of the immunoglobulin(s); and / or less than 75%, less than 50%, or less than 25% incidence of use of a rescue therapy; and / or a reduction in ITP disease activity and / or progression in a subject diagnosed with ITP; optionally wherein the ITP disease activity and / or progression is measured by one or more assessments selected from the group consisting of World Health Organization (WHO) Bleeding Scale, Immune Thrombocytopenic Purpura Subject Assessment Questionnaire (ITP-PAQ), and 5-Level EuroQol Five Dimensions (EQ-5D-5L); optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in Symptoms, Fatigue / Sleep, Physical Health-Activity, Physical Health-Bother, Psychological Health, Overall Quality of Life, Social Activity, and / or Work scales scores of the ITP‑PAQ from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Menstrual Symptoms subscale scores of the ITP-PAQ from baseline to about 24 weeks after the administering in a female subject who had at least one menstrual period within 12 months before the receiving the isolated antibody; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the Fertility subscale scores of the ITP-PAQ in a female subject from baseline to about 24 weeks after the administering; optionally wherein the ITP disease activity and / or progression is measured by a change from baseline in the EQ-5D-5L utility index score and / or VAS score from baseline to about 24 weeks after the administering; and optionally wherein the ITP disease activity and / or progression is measured by a change in a Symptoms Scale Score of ITP-PAQ from baseline to about 24 weeks after the administering; and / or a reduction in bleeding events in the subject; optionally wherein the bleed events are measured by Immune Thrombocytopenia-specific Bleeding Assessment Tool (ITP-BAT); optionally wherein the bleeding events comprise Grade ≥2 in the Skin domain, Grade ≥1 in the Mucosal domain, and / or Grade ≥1 in the Organ domain; and / or DB2 / 47155346.6 313Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 ITP remission, optionally wherein ITP remission is defined as all platelet counts ≥50,000 / μL for at least about 12 or at least about 24 weeks after any treatment cycle with the isolated antibody or antigen binding fragment thereof in the absence of other therapy for ITP.

73. The unit dosage form of any one of claims 66-72, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs); optionally wherein the TRAEs or TEAEs are selected from the group consisting of gingival bleeding, heavy menstrual bleeding, haematochezia, mouth haemorrhage, haematoma, traumatic haematoma, epistaxis, petechiae, ecchymosis, conjunctival haemorrhage, blood urine, and haemorrhagic ovarian cyst; optionally wherein a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2; and optionally wherein administering the isolated antibody or antigen binding fragment thereof results in a reduction in dose and / or frequency of use of background ITP medication(s).

74. The unit dosage form of any one of claims 66-73, wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, and about 600 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 100 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg; and optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

75. The unit dosage form of any one of claims 66-74, wherein the dosage is a dosage administered once every week, once every two weeks, once every three weeks or once every four weeks; DB2 / 47155346.6 314Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 optionally wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; and (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; optionally wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered once per week for 8 weeks; optionally wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; and (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; optionally wherein (a) the isolated antibody is administered once per week for from 1 week to 16 weeks; (b) the isolated antibody is not administered for a period of from 1 week to 16 weeks; (c) the isolated antibody is administered once per week for from 1 week to 16 weeks; and (d) the isolated antibody is not administered for a period of from 1 week to 16 weeks; optionally wherein (a) the isolated antibody is administered once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks; optionally wherein (a) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; (b) the isolated antibody is not administered for a period of 8 weeks; (c) the isolated antibody is administered at a dosage of from about 100 mg to about 600 mg once per week for 8 weeks; and (d) the isolated antibody is not administered for a period of 8 weeks.

76. The unit dosage form of any one of claims 66-75, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

77. The unit dosage form of any one of claims 66-76, wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a DB2 / 47155346.6 315Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 light chain as set forth in SEQ ID NO: 12; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks, or wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 14 and a light chain as set forth in SEQ ID NO: 12; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

78. The unit dosage form of any one of claims 66-77, wherein the isolated antibody or antigen binding fragment thereof is administered to a subject once a week for 8 weeks; optionally wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of about 600 mg; optionally wherein the isolated antibody or antigen binding fragment thereof is mezagitamab; optionally wherein the ITP is persistent or chronic ITP in an adult human; optionally wherein the subject is an adult; and optionally wherein the subject has had an insufficient response or intolerance to other therapy.

79. The unit dosage form of any one of claims 66-78, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

80. The unit dosage form of any one of claims 66-79, wherein the ITP is primary ITP; optionally wherein the ITP is persistent ITP; optionally wherein the ITP is chronic ITP; and optionally wherein the ITP is persistent or chronic primary ITP; optionally wherein the primary ITP has persisted for at least about 3 months; optionally wherein the subject has had a prior response to other therapy excluding a thrombopoietin receptor agonist (TPO-RA), wherein the prior response is defined as achieving a platelet count of ≥50,000 / mL; optionally wherein the subject has a baseline mean platelet count of <30,000 / µL from at least 2 consecutive measurements taken at least about 5 days apart; optionally wherein the baseline mean platelet count comprises individual values ≤35,000 / µL; optionally wherein the unit dosage form is administered to a subject having an insufficient response or intolerance to other therapy; optionally wherein the other therapy is a first-line ITP therapy and / or a second-line ITP therapy; optionally wherein the other therapy DB2 / 47155346.6 316Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 comprises one or more of a corticosteroid, immunoglobulins, splenectomy, a thrombopoietin receptor agonist (TPO-RA) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag), rituximab, fostamatinib, and background ITP medication(s) (e.g., romiplostim, eltrombopag, avatrombopag, hetrombopag, methotrexate, azathioprine, leflunomide, cyclosporine, fostamatinib, mycophenolate, danazol, dapsone, methylprednisolone, hydrocortisone, cortisone, prednisolone, prednisone, and / or dexamethasone); optionally wherein the insufficient response to other treatment is defined as failure to achieve a sustained platelet count of at least 50,000 / µL or doubling of baseline platelet count after an appropriate course of the other therapy; and optionally wherein the intolerance to other therapy is defined as a documented side effect causing discontinuation of the therapy.

81. The unit dosage form of any one of claims 66-80, wherein the unit dosage form is administered to a subject having a baseline mean platelet count of less than or equal to about 40×109 / L, less than or equal to about 35×109 / L, less than or equal to about 30×109 / L, less than or equal to about 25×109 / L, or less than or equal to about 20×109 / L.

82. The unit dosage form of any one of claims 66-81, wherein the unit dosage form is administered to a subject having an ITP disease duration of at least about 0.1 years, at least about 0.3 years, at least about 0.5 years, at least about 1 year, at least about 5 years, or at least about 10 years.

83. The unit dosage form of any one of claims 66-82, wherein the isolated antibody or antigen binding fragment thereof is from about 2 times to about 4 times more efficacious than fostamatinib and / or efgartigimod; optionally wherein the isolated antibody or antigen binding fragment thereof results in from about 2 times to about 4 times more durable platelet response as compared to fostamatinib and / or efgartigimod.

84. An isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of immune thrombocytopenia (ITP), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a DB2 / 47155346.6 317Attorney Docket No.: 101588-5018-WO Takeda Ref. No.: PAT27339PCT01 CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:

8.

85. A pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:

8.

86. A medicament for treating immune thrombocytopenia (ITP) comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:

8.

87. Use of an isolated human anti-CD38 antibody or antigen binding fragment thereof in the manufacture of a medicament for treating immunoglobulin A nephropathy (IgAN), wherein the isolated antibody or antigen binding fragment thereof comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO:

8. DB2 / 47155346.6 318