Dosing regimens of Anti-CD38 antibodies for treatment of subjects with immunoglobulin a nephropathy

Abstract

Methods for treating subjects with autoimmune diseases such as immunoglobulin A nephropathy (IgAN) 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 IgAN.

Description

DOSING REGIMENS OF ANTI-CD38 ANTIBODIES FOR TREATMENT OF SUBJECTS WITH IMMUNOGLOBULIN A NEPHROPATHYCross Reference to Related Applications

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 63 / 644,913 filed on May 9, 2024, U.S. Provisional Application Serial No. 63 / 694,484 filed on September 13, 2024, and U.S. Provisional Application Serial No. 63 / 751,190 filed on January 29, 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 May 7, 2025, is named 101588-5019-WO Sequence Listing.xml and is 14,612 bytes in size.Field

[0003] Methods for treating subjects with autoimmune diseases such as immunoglobulin A nephropathy (IgAN) 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 IgAN.Background

[0004] Immunoglobulin A nephropathy (IgAN) (also known as Berger’s disease) is an immune complex-mediated inflammation of the kidney. This inflammation (glomerulonephritis) is a rare, serious condition that can lead to chronic kidney disease (CKD) and, eventually, to end-stage kidney disease (ESKD)et al., Kidney Int. , 2009, 76(5), 534-45; Coppo et al., KidneyInt., 2021, 77(10), 921-7).

[0005] IgAN is characterized by the synthesis of IgAl antibodies that display aberrant glycosylation profiles (specifically a deficiency in O-linked carbohydrate polymer attachment) within the hinge region (so-called galactose-deficient IgAl, or gd-IgAl) (Novak etal., Semin. Nephrol., 2008, 28(1), 78-87; Tomana et al., Kidney Int., 1997, 52(2), 509-16). The galactose- deficient region acts as an antigen for IgG or IgA antibodies that may bind to gd-IgAl and formcirculating immune complexes (CIC) (Wyatt and Julian, N. Engl. J. Med., 2013, 368(25), 2402- 14). These CIC, or gd-IgAl alone, deposit in the glomerular mesangium (the supporting structure of the glomeruli), resulting in local inflammation and complement activation (Lafayette and Kelepouris, Am. J. Nephrol., 2018, 47 Suppl 1, 43-52; Lai etal., Nephrol. Dial. Transplant., 2009, 24(1), 62-72). Over time, this chronic inflammation may lead to reduced kidney function, scarring, and irreversible damage, leading to kidney failure and the need for dialysis.

[0006] IgAN is the most common form of primary glomerulonephritis worldwide. In the US, more than 200,000 patients are living with IgAN. The true prevalence is difficult to determine because of regional differences in kidney biopsy thresholds. The incidence is estimated to be between 20 to 31 cases / million / year in the United States and Europe, and 45 cases / million / year in Asia (Schena and Nistor, Semin. Nephrol., 2018, 38(5), 435-42). The prevalence is highest in East Asian and Northern European countries, which may reflect differences in genetic predisposition and diagnostic sophistication (Kiryluk etal.,Annu. Rev. Med, 2013, 64, 339-56).

[0007] IgAN generally presents as an asymptomatic finding of microscopic blood in the urine (hematuria) or gross (visible) hematuria following a gastrointestinal or respiratory infection. Proteinuria (abnormal leaking of protein into the urine), hypertension, and progressive kidney impairment are long-term consequences of untreated IgAN (Gutierrez et al., Nephrol. Dial. Transplant., 2018, 33(3), 472-7). In about 30% of subjects with IgAN, the condition progresses to end stage kidney disease (ESKD) over a 20-year period (D'Amico, Semin. Nephrol., 2004, 24(3), 179-96), with a greater risk for progression in subjects with persistent proteinuria (>1 g / day), sustained hypertension (>140 / 90 mmHg), impaired glomerular filtration rate (GFR), and unfavorable findings on kidney biopsy, such as glomerular crescents or scarring (Barbour et al., JAMA Intern. Med., 2019,179(7), 942-52; Reich et al, J. Am. Soc. Nephrol., 2007, 18(12), 3177- 83). In addition, the risk of cardiovascular mortality is 45% higher in subjects with IgAN compared to age / sex matched controls (Lee et al., J. Glaucoma, 2012, 27(9), e 145-e7).

[0008] Currently, effective therapeutic options for IgAN are limited. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend long-term use of renin- angiotensin-aldosterone system (RAAS) blocking agents (angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blocker (ARB)) to achieve control of blood pressure and reduce proteinuria; in a large proportion of subjects treated with these agents, however,proteinuria levels fail to drop below 0.5 to 1 g / day, despite administration of maximal doses (Barratt et al., Kidney Int. Rep., 2019, 4(11), 1633-7; Thompson etal., Clin. J. Am. Soc. Nephrol., 2019, 14(3), 469-81). For these subjects, the only additional treatment modality includes a 6-month course of corticosteroids; however, this treatment option is also limited by both safety concerns and lack of sufficient evidence that corticosteroids provide an additional benefit to optimized supportive care with RAAS blocking agents (KDIGO 2012). As such, there is an urgent unmet medical need for novel treatments that induce long-term reduction in proteinuria and stabilize the GFR in subjects for whom proteinuria is not controlled by maximally-tolerated ACE-I or ARB alone. There are currently no effective and well -tolerated therapies approved for IgAN that slow or prevent progression to kidney failure (Gutierrez etal., Nephron., 2020, 144(11), 555-71).Summary

[0009] IgAN is the most prevalent form of primary glomerulonephritis worldwide and is associated with a poor prognosis, including progression to end-stage kidney disease or death in some cases. Within 20-30 years of diagnosis, 40% of people with IgAN develop end-stage kidney disease. Currently, therapeutic options for IgAN are limited.

[0010] 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 immunoglobulin A nephropathy (IgAN).

[0011] Mezagitamab (TAK-079) is a fully human IgGl monoclonal antibody (mAb) that eliminates cells with high expression of cell-surface CD38. CD38 is constitutively highly expressed on the cell surfaces of plasma cells, plasmablasts, and on subsets of natural killer cells, T-cells, and B-cells. Mezagitamab depletes these cells by a variety of mechanisms, including apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity (Smithson et al., J. Immunol, 2017, 198(1 Supplement), 224.20). Mezagitamab depletes the cells that produce the pathogenic autoantibodies (plasmablasts, plasma cells, and especially long- lived plasma cells). Mezagitamab depletes the cells that produce the pathogenic autoantibodies (plasmablasts, plasma cells, and especially long-lived plasma cells). A reduction in plasmablasts and plasma cells by mezagitamab is expected to result in a reduction in the levels of immunoglobulins and pathogenic autoantibodies, which could provide benefit in subjectssuffering from various antibody-mediated autoimmune diseases, including IgAN. Specifically, mezagitamab can potentially suppress gut-associated lymphoid tissue (GALT) immune responses by depleting IgA-producing plasma cells, decreasing galactose-deficient IgAl (Gd- IgAl) and autoantibody production resulting in decreased immune complex formation, thus stabilizing kidney function. Mezagitamab is, therefore, a promising treatment for adult subjects with IgAN.

[0012] Thus, it is an objective of the present invention to provide methods of treating subjects with autoimmune diseases such as IgAN by subcutaneous administration of an anti-CD38 antibody (e.g., mezagitamab).

[0013] 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 IgAN. In some embodiments, the isolated 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 isolated 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 about 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 about 80%, 85%, 90%, 95%, 97% or 99% sequence identity thereto). In some embodiments, the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 mg to about 600 mg.

[0014] In some embodiments, the disclosure provides a method of treating immunoglobulin A nephropathy (IgAN) in a subject in need thereof, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof.

[0015] In some embodiments, the disclosure provides a method of treating immunoglobulin A nephropathy (IgAN) in a subject in need thereof, the method comprising administering to thesubject 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.

[0016] 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.

[0017] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered subcutaneously.

[0018] In some embodiments, the disclosure provides a method of treating immunoglobulin A nephropathy (IgAN) 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.

[0019] 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 immunoglobulin A nephropathy (IgAN), 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, aCDR2 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.

[0020] In some embodiments, the disclosure provides a method of reducing the level of immunoglobulin(s) in a subject diagnosed with immunoglobulin A nephropathy (IgAN), 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.

[0021] In some embodiments, the immunoglobulin(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM.

[0022] In some embodiments, the immunoglobulin comprises galactose-deficient IgAl (gd- IgAl).

[0023] 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.

[0024] In some embodiments, the immunoglobulin(s) is 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).

[0025] In some embodiments, the disclosure provides a method of reducing the level of anti- galactose-deficient IgAl (anti-gd-IgAl) autoantibodies in a subject diagnosed with immunoglobulin A nephropathy (IgAN), 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 regioncomprising 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.

[0026] In some embodiments, the anti-gd-IgAl autoantibodies comprise IgA and / or IgG.

[0027] In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

[0028] In some embodiments, the disclosure provides a method of reducing immunoglobulin A nephropathy (IgAN) disease activity and / or progression in a subject diagnosed with IgAN, 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.

[0029] In some embodiments, the IgAN disease activity and / or progression is measured by one or more assessments selected from the group consisting of: percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.}, levels of serum IgGand IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc. , change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) score; Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores.

[0030] In some embodiments, the disclosure provides a method of reducing proteinuria in a subject diagnosed with IgAN, 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.

[0031] In some embodiments, proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE).

[0032] In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering.

[0033] In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR.

[0034] In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline to about 104 weeks after the administering in UACR.

[0035] In some embodiments, proteinuria is 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 proteinuria.

[0036] In some embodiments, proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

[0037] In some embodiments, the disclosure provides a method of achieving durable proteinuria reduction in a subject diagnosed with IgAN, 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, durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after theadministering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering.

[0039] In some embodiments, proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks.

[0040] In some embodiments, the disclosure provides a method of achieving a complete response on the basis of proteinuria in a subject diagnosed with IgAN, 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.

[0041] In some embodiments, the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE).

[0042] In some embodiments, the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection.

[0043] In some embodiments, the disclosure provides a method of stabilizing glomerular filtration rate (GFR) relative to baseline levels of GFR in a subject diagnosed with IgAN, 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.

[0044] In some embodiments, GFR is measured by estimated glomerular filtration rate (eGFR).

[0045] In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering.

[0046] In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks or about 1 year after the administering and / or from baseline to about 104 weeks or about 2 years after the administering.

[0047] In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering.

[0048] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality.

[0049] In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering.

[0050] In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 104 weeks after the administering.

[0051] In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering.

[0052] In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 104 weeks after the administering.

[0053] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure.

[0054] In some embodiments, stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2.

[0055] In some embodiments, GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

[0056] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -3 to about 8, or from about -3 to about 4. In some embodiments, the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering.

[0057] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2. In some embodiments, the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering

[0058] In some embodiments, the disclosure provides a method of treating immunoglobulin A nephropathy (IgAN) in a subject diagnosed with IgAN, 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 a treatment cycle comprises: (a) subcutaneously administering the isolated antibody in a dosage of about 600 mg once every week (QW) for a total of 9 times; and (b), following (a),subcutaneously administering the isolated antibody or antigen binding fragment thereof in a dosage of about 600 mg once every 2 weeks (Q2W) for a total of 7 times, optionally (c), following (b), not administering the isolated antibody for a period of about 30 weeks, and optionally wherein the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

[0059] In some embodiments, the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months or about every twelve months.

[0060] In some embodiments, the IgAN is primary IgAN.

[0061] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day.

[0062] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g or >1.0 g / g.

[0063] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPE of from about 500 to about 5000 mg / day.

[0064] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPCR of from about 0.5 to about 3 g / g.

[0065] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an estimated glomerular filtration rate (eGFR) of >30 mL / min / 1.73 m2.

[0066] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an estimated glomerular filtration rate (eGFR) of >45 mL / min / 1.73 m2.

[0067] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an eGFR of from about 30 to about 150 mL / min / 1.73 m2.

[0068] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has serum creatinine levels of from about 10 to about 200 pmol / L and / or from about 0.5 to about 2 mg / dL.

[0069] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgA levels of from about 1 to about 5.5 g / L.

[0070] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has Gd-IgAl levels of from about 1,000 to about 15,500 ng / mL.

[0071] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgG levels of from about 7 to about 15 g / L.

[0072] In some embodiments, the subject is diagnosed with IgAN by a biopsy performed <10 years ago.

[0073] In some embodiments, the subject is diagnosed with IgAN from about 0.1 to about 30 years ago.

[0074] In some embodiments, the subject is diagnosed with IgAN from about 1 to about 10 years ago.

[0075] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered once every week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0076] In some embodiments, a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times.

[0077] In some embodiments, a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for a total of 9 times.

[0078] In some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times.

[0079] some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for a total of 7 times.

[0080] In some embodiments, the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of 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.

[0081] In some embodiments, the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of about 30 weeks.

[0082] In some embodiments, the treatment cycle is performed more than one time.

[0083] In some embodiments, the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

[0084] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than about 75%, less than about 50%, or less than about 25% incidence of use of a rescue therapy and / or non-permitted IgAN therapy.

[0085] In some embodiments, the subject has not received a rescue therapy and / or nonpermitted IgAN therapy in the previous four weeks.

[0086] In some embodiments, the method does not include the use of a rescue therapy and / or non-permitted IgAN therapy.

[0087] 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.

[0088] In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0089] In some embodiments, the glycosylation is N-linked glycosylation.

[0090] 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 about 90% to SEQ ID NO: 9.

[0091] In some embodiments, 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 about 90% to SEQ ID NO: 10.

[0092] 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 about 95% to SEQ ID NO: 9.

[0093] In some embodiments, 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 about 95% to SEQ ID NO: 10.

[0094] 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 about 99% to SEQ ID NO: 9.

[0095] In some embodiments, 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 about 99% to SEQ ID NO: 10.

[0096] 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 about 95% to SEQ ID NO: 11.

[0097] 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 about 95% to SEQ ID NO: 14.

[0098] In some embodiments, the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 12.

[0099] 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.

[0100] 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.

[0101] In some embodiments, the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10.

[0102] 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.

[0103] 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.

[0104] In some embodiments, 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.

[0105] In some embodiments, the isolated antibody or antigen binding fragment is a human IgG antibody.

[0106] In some embodiments, the human IgG antibody is a human IgGl antibody.

[0107] In some embodiments, the subject receives background IgAN medication(s).

[0108] In some embodiments, the background IgAN medication(s) is one or more selected from the group consisting of renin-angiotensin-aldosterone system (RAAS) blocking agent, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), endothelin receptor antagonist (ERA), mineralocorticoid receptor antagonist (MRA), sodiumglucose cotransporter 2 inhibitor (SGLT2-I), hydroxychloroquine, statins, omega-3 fish oil, and dipyridamole.

[0109] In some embodiments, wherein the background IgAN medication(s) is administered in combination with the isolated antibody or antigen binding fragment thereof.

[0110] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than about 20% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs).[OHl] In some embodiments, the TRAEs or TEAEs are selected from the group consisting of infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs.

[0112] In some embodiments, the TRAEs or TEAEs are selected from the group consisting of upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID-19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs).

[0113] In some embodiments, a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of grade 1 or grade 2.

[0114] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in the level of plasmablasts, plasma cells, and / or NK cells.

[0115] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in the level of immunoglobulin(s). In some embodiments, the immunoglobulin(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM. In some embodiments, the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl). In some embodiments, administering the isolated antibody or antigen bindingfragment 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) is 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).

[0116] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies comprise IgA and / or IgG. In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

[0117] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in IgAN disease activity and / or progression. In some embodiments, the IgAN disease activity and / or progression is measured by one or more assessments selected from the group consisting of: percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.); levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc. , change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) score;Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores.

[0118] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in proteinuria. In some embodiments, proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio(UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline to about 104 weeks after the administering in UACR. In some embodiments, proteinuria is 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 proteinuria. In some embodiments, proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

[0119] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in durable proteinuria reduction. In some embodiments, durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, frombaseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering. In some embodiments, proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks.

[0120] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a complete platelet response on the basis of proteinuria. In some embodiments, the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection.

[0121] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a stabilization of glomerular filtration rate (GFR) relative to baseline levels of GFR. In some embodiments, GFR is measured by estimated glomerular filtration rate (eGFR). In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks after the administering, from baseline to about 1 year after the administering, from baseline to about 104 weeks after the administering, and / or from baseline to 2 years after the administering. In some embodiments, stabilizing GFR is measured by a chroniceGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality. In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks and / or from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure.

[0122] In some embodiments, stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2

[0123] In some embodiments, GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -3 to about 8, or from about -3 to about 4. In some embodiments, the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2. In some embodiments, the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

[0124] 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.

[0125] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0126] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] In some embodiments, the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0131] 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 immunoglobulin A nephropathy (IgAN).

[0132] 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 binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the isolated antibody in the treatment of primary IgAN at a dosage of about 600 mg in a treatmentcycle comprising: (a) subcutaneously administering the isolated antibody once every week (QW) for a total of 9 times; and (b), following (a), subcutaneously administering the isolated antibody once every 2 weeks (Q2W) for a total of 7 times, optionally (c), following (b), not administering the isolated antibody for a period of about 30 weeks, and optionally wherein the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

[0133] In some embodiments, the treatment cycle is performed more than one time.

[0134] In some embodiments, the treatment cycle is performed about every six months or about every twelve months.

[0135] 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.

[0136] In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0137] In some embodiments, the glycosylation is N-linked glycosylation.

[0138] 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 about 90% to SEQ ID NO: 9.

[0139] In some embodiments, 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 about 90% to SEQ ID NO: 10.

[0140] In some embodiments, the variable heavy chain region comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 9.

[0141] In some embodiments, the variable light chain region comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 10.

[0142] In some embodiments, the variable heavy chain region comprises an amino acid sequence having an identity of at least about 99% to SEQ ID NO: 9.

[0143] In some embodiments, the variable light chain region comprises an amino acid sequence having an identity of at least about 99% to SEQ ID NO: 10.

[0144] 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 about 95% to SEQ ID NO: 11.

[0145] 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 about 95% to SEQ ID NO: 14.

[0146] In some embodiments, the light chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 12.

[0147] 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.

[0148] 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.

[0149] In some embodiments, the variable heavy chain region comprises SEQ ID NO: 9 and the variable light chain region comprises SEQ ID NO: 10.

[0150] 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.

[0151] 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.

[0152] In some embodiments, the isolated antibody or antigen binding fragment thereof further comprises an Fc domain.

[0153] In some embodiments, the Fc domain is a human Fc domain or a variant Fc domain.

[0154] In some embodiments, the isolated antibody or antigen binding fragment is a human IgG antibody.

[0155] In some embodiments, the human IgG antibody is a human IgGl antibody.

[0156] In some embodiments, the isolated antibody or antigen binding fragment thereof is used in combination with one or more background IgAN medication(s).

[0157] In some embodiments, the background IgAN medication(s) is one or more selected from the group consisting of renin-angiotensin-aldosterone system (RAAS) blocking agent, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), endothelin receptor antagonist (ERA), mineralocorticoid receptor antagonist (MRA), sodiumglucose cotransporter 2 inhibitor (SGLT2-I), hydroxychloroquine, statins, omega-3 fish oil, and dipyridamole.

[0158] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in less than about 20% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs).

[0159] In some embodiments, the TRAEs or TEAEs are selected from the group consisting of infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs.

[0160] In some embodiments, the TRAEs or TEAEs are selected from the group consisting of upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID-19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs).

[0161] In some embodiments, a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of grade 1 or grade 2.

[0162] 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.

[0163] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0164] In some embodiments, the IgAN is primary IgAN.

[0165] In some embodiments, the unit dosage form is administered to a subject having a 24-h urine protein excretion (UPE) of >1 g / day.

[0166] In some embodiments, the unit dosage form is administered to a subject having a 24-h urine protein-to-creatinine ratio (UPCR) of >1.0 g / g.

[0167] In some embodiments, the unit dosage form is administered to a subject having a 24-h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g.

[0168] In some embodiments, the unit dosage form is administered to a subject having a 24-h UPE of from about 500 to about 5000 mg / day.

[0169] In some embodiments, the unit dosage form is administered to a subject having a 24-h UPCR of from about 0.5 to about 3 g / g.

[0170] In some embodiments, the unit dosage form is administered to a subject having an estimated glomerular filtration rate (eGFR) of >30 mL / min / 1.73 m2.

[0171] In some embodiments, the unit dosage form is administered to a subject having an estimated glomerular filtration rate (eGFR) of >45 mL / min / 1.73 m2.

[0172] In some embodiments, the unit dosage form is administered to a subject having an estimated glomerular filtration rate (eGFR) of from about 30 to about 150 mL / min / 1.73 m2.

[0173] In some embodiments, the unit dosage form is administered to a subject having serum creatinine levels of from about 10 to about 200 pmol / L and / or from about 0.5 to about 2 mg / dL.

[0174] In some embodiments, the unit dosage form is administered to a subject having IgA levels of from about 1 to about 5.5 g / L.

[0175] In some embodiments, the unit dosage form is administered to a subject having Gd-IgAl levels of from about 1,000 to about 15,500 ng / mL.

[0176] In some embodiments, the unit dosage form is administered to a subject having IgG levels of from about 7 to about 15 g / L.

[0177] In some embodiments, the unit dosage form is administered to a subject diagnosed with IgAN by a biopsy performed <10 years ago.

[0178] In some embodiments, the unit dosage form is administered to a subject diagnosed with IgAN from about 0.1 to about 30 years ago.

[0179] In some embodiments, unit dosage form is administered to a subject diagnosed with IgAN from about 1 to about 10 years ago.

[0180] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered once every week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0181] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a treatment cycle comprising (a) subcutaneously administering the isolated antibody once every week (QW) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times.

[0182] In some embodiments, the isolated antibody or antigen binding fragment thereof is administered in a treatment cycle comprising (a) subcutaneously administering the isolated antibody once every week (QW) for a total of 9 times.

[0183] In some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times.

[0184] In some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for a total of 7 times.

[0185] In some embodiments, the treatment cycle further comprises (c), following (b), not administering the isolated antibody for a period of about 10 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks.

[0186] In some embodiments, treatment cycle further comprises (c), following (b), not administering the isolated antibody for a period of about 30 weeks.

[0187] In some embodiments, the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

[0188] In some embodiments, the unit dosage form comprises at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0189] 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.

[0190] 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.

[0191] In some embodiments, the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0192] In some embodiments, administering the unit dosage form results in a reduction in the level of plasmablasts, plasma cells, and / or NK cells.

[0193] In some embodiments, administering the unit dosage form results in a reduction in the level of immunoglobulin(s). In some embodiments, the immunoglobulin(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM. In some embodiments, the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl). In some embodiments, administering the unit dosage form 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) is 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).

[0194] In some embodiments, administering the unit dosage form results in a reduction in the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies comprise IgA and / or IgG. In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

[0195] In some embodiments, administering the unit dosage form results in a reduction in IgAN disease activity and / or progression. In some embodiments, the IgAN disease activity and / or progression is measured by one or more assessments selected from the group consisting of: percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.), levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc.) change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score; Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C),_EuroQol- 5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores.

[0196] In some embodiments, administering the unit dosage form results in a reduction in proteinuria. In some embodiments, proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g. 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR to about 104 weeks after the administering. In some embodiments, proteinuria is 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 proteinuria. In some embodiments, proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

[0197] In some embodiments, administering the unit dosage form results in durable proteinuria reduction. In some embodiments, durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering. In some embodiments, proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks.

[0198] In some embodiments, administering the unit dosage form results in a complete platelet response on the basis of proteinuria. In some embodiments, the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection.

[0199] In some embodiments, administering the unit dosage form results in a stabilization of glomerular filtration rate (GFR) relative to baseline levels of GFR. In some embodiments, GFR is measured by estimated glomerular filtration rate (eGFR). In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks or about 1 year after the administering and / or from baseline to about 104 weeks or about 2 years after theadministering; optionally wherein stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality. In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering and / or from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure. In some embodiments, GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, frombaseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -3 to about 8, or from about -3 to about 4. In some embodiments, the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2. In some embodiments, the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

[0200] In some embodiments, administering the unit dosage form results in less than about 75%, less than about 50%, or less than about 25% incidence of use of a rescue therapy and / or nonpermitted IgAN therapy. In some embodiments, the subject has not received a rescue therapy and / or non-permitted IgAN therapy in the previous four weeks. In some embodiments, the unit dosage form is not administered in combination with a rescue therapy and / or non-permitted IgAN therapy.

[0201] In some embodiments, the disclosure provides an isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of 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.

[0202] In some embodiments, the disclosure provides a pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treatingimmunoglobulin A nephropathy (IgAN) 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.

[0203] In some embodiments, the disclosure provides a medicament for treating immunoglobulin A nephropathy (IgAN) 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.

[0204] 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: 8Brief Description of the Drawings

[0205] The objects and features of the invention may be better understood by reference to the drawings described below.

[0206] Figure 1 shows a schematic of the Phase lb study design, including the interim analyses at Week 36 and Week 48 (N=17).

[0207] Figure 2A shows serum IgA levels demonstrated rapid and sustained reduction during the treatment period at the Week 36 interim analysis (% change from baseline).

[0208] Figure 2B shows rapid, profound, and sustained reductions in IgA at the Week 48 interim analysis (% change from baseline).

[0209] Figure 3 shows serum IgA levels demonstrated rapid and sustained reduction during the treatment period at the Week 36 interim analysis (observed values).

[0210] Figure 4A shows serum IgG levels demonstrated rapid and sustained reduction during the treatment period at the Week 36 interim analysis (% change from baseline).

[0211] Figure 4B shows rapid, profound, and sustained reductions in IgG at the Week 48 interim analysis (% change from baseline).

[0212] Figure 5 shows serum IgG levels demonstrated rapid and sustained reduction during the treatment period at the Week 36 interim analysis (observed values).

[0213] Figure 6A shows serum gd-IgAl levels demonstrated rapid and sustained reduction during the treatment period at the Week 36 interim analysis (% change from baseline).

[0214] Figure 6B shows rapid, sustained reduction in gd-IgA through Week 48 at the Week 48 interim analysis (% change from baseline).

[0215] Figure 7 shows individual serum IgA / IgG and serum gd-IgA change from baseline over time at the Week 36 interim analysis.

[0216] Figure 8 shows individual serum IgA / IgG and serum gd-IgA over time at the Week 36 interim analysis. Dashed line refers to lower and upper limits of normal range: IgG: 7 - 16 g / L; IgA: 0.7 - 4 g / L; and IgM: 0.4 - 2.3 g / L.

[0217] Figure 9A shows serum PK spaghetti plots (trough) for Part 1 of the phase lb study at Week 36 interim analysis. Dashed line refers to lower limit of quantification of PK of 10 ng / mL.

[0218] Figure 9B shows serum PK spaghetti plots (trough) for the ITP study at dosages of 100, 300, and 600 mg mezagitamab.

[0219] Figure 10 shows low ADA incidence following the repeated dosing at 600 mg of mezagitamab based on available data at Week 36 interim analysis. 1 / 17 (5.8%) subjects had transient post-treatment ADA at Week 36 (titer of 1 : 160).

[0220] Figure 11A shows rapid and sustained reduction in proteinuria (UPCR), with -54.9% at Week 36 at Week 36 interim analysis from a mixed-effects model for repeated measures analysis with the change from baseline in proteinuria as the outcome, visit as the factor, and adjusted baseline value and baseline-by-visit interaction.

[0221] Figure 11B shows rapid and sustained reduction in proteinuria (UPCR) through Week 48 at the Week 48 interim analysis.

[0222] Figure 11C shows the percentage change from baseline in proteinuria based on 24-hour UPCR over time. Data presented as model-based mean and 95% CI. eGFR, estimated glomerular filtration rate; UPCR, urine protein to creatinine ratio.

[0223] Figure 11D Change from baseline in eGFR. Data presented as model-based mean and 95% CI. eGFR, estimated glomerular filtration rate; UPCR, urine protein to creatinine ratio.

[0224] Figure 12 shows rapid and sustained reduction in proteinuria (UPCR) at the Week 36 interim analysis.

[0225] Figure 13A shows estimated glomerular filtration rate (eGFR) was stable up to Week 36 (Mean Change from Baseline, mU / min / 1.73m2).

[0226] Figure 13B shows stable renal function to Week 48 (eGFR).

[0227] Figure 14 shows estimated glomerular filtration rate (eGFR) over time (Mean Observed Values, mU / min / 1.73m2) at the Week 36 interim analysis.

[0228] Figure 15 shows analysis of change from baseline in estimated glomerular filtration rate (eGFR) (mU / min / 1.73m2) from a mixed-effects model for repeated measures analysis over all postbaseline visits, with the change from baseline in eGFR as the outcome and visit as the factor. Main Study (completed) and LTE (ongoing - in participants without retreatment) - Full Analysis Set.

[0229] Figure 16A shows that mezagitamab demonstrated competitive proteinuria reduction compared with data from registrational trials for approved drugs for IgAN.

[0230] Figure 16B shows that mezagitamab demonstrated competitive proteinuria reduction compared with data from registrational trials for approved drugs for IgAN.

[0231] Figure 17 shows the Phase 3 trial design (option 1).

[0232] Figure 18 shows the Phase 3 trial design (option 2).

[0233] Figure 19 shows that in Phase lb, mezagitamab demonstrated greater mean UPCR % change from baseline (-54.9%) versus felzartamab its Phase 2 (-30%).

[0234] Figure 20 shows that in Phase lb, mezagitamab demonstrated greater IgG and IgA reduction relative to felzartamab in its Phase 2.

[0235] Figure 21A shows the trial schema for the Phase 3 study in Example 2. eGFR: estimated glomerular filtration rate; EOS: end of study; IMP: investigational medicinal product; N: number; QW: weekly; Q2W: every other week; UPCR: urine protein creatinine ratio.aIMP dosing: 600 mg SC QW for 9 doses followed by SC Q2W for 7 doses (participants must meet predosing criteria before initiating each dose).bAn interim analysis IA1 is performed when at least 119 (79 on mezagitamab and 40 on placebo) clinical trial participants have completed the Week 36 visit.CUPCR: urine protein creatinine ratio derived from 24-hour urine collection.dA second interim analysis (IA2) is performed to assess eGFR slope at 1 year when at least 272 (181 participants on mezagitamab and 91 on placebo) clinical trial participants have completed the Week 52 visit.

[0236] Figure 21B shows the trial schema for the Phase 3 study in Example 2. In addition to the blinded IMP dosing groups in the main study, approximately 50 participants meeting the openlabel cohort eligibility criteria are enrolled to receive mezagitamab and follow the same dosing regimen and schedule of activities as the main study.aIMP dosing: mezagitamab and open-label mezagitamab groups 600 mg SC QW for 9 doses followed by SC Q2W for 7 doses; placebo group receive matching placebo. All participants will receive IgAN SOC.bUPCR: urine protein creatinine ratio derived from 24-hour urine collection

[0237] Figure 22 shows the graphical testing strategy. Overall Type I error is controlled at the study level at 1 -sided 0.025. This is a graphical approach for testing the primary (UPCR at 9 months) and all secondary endpoints. Alpha splitting between interim analysis 2 (IA2) and final analysis (FA): 0.005 is allocated to total 1-year eGFR slope at IA2 and 0.02 to total 2-year eGFR slope at FA. This strategy ensures a higher probability of success at FA.Detailed Description

[0238] Increased expression of CD38 has been documented in a variety of diseases, including autoimmune diseases such as immunoglobulin A nephropathy (IgAN). 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 IgAN. 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.

[0239] Mezagitamab (TAK-079) is a fully human IgGl monoclonal antibody (mAb) that eliminates cells with high expression of cell-surface CD38. CD38 is constitutively highly expressed on the cell surfaces of plasma cells, plasmablasts, and on subsets of natural killer cells, T-cells, and B-cells. Mezagitamab depletes these cells by a variety of mechanisms, including apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity (Smithson et al., J. Immunol, 2017, 198(1 Supplement), 224.20). Mezagitamab depletes the cells that produce the pathogenic autoantibodies (plasmablasts, plasma cells, and especially long- lived plasma cells). Depletion of plasma cells and plasmablasts is expected to lead to a reduction of immunoglobulins and pathogenic autoantibodies, which could provide benefit in subjects suffering from various antibody-mediated autoimmune diseases, including IgAN. In particular, mezagitamab depletes the plasma cells that produce galactose-deficient IgAl (Gd-IgAl) and autoantibodies against Gd-IgAl. This mechanism of action results in decreased immune complex formation, reducing proteinuria and thus promoting stabilization of kidney function over time. Mezagitamab is, therefore, a promising treatment for adult subjects with IgAN.

[0240] Other anti-CD38 antibodies are known in the art. For example, daratumumab (DARZALEX®), a commercially available anti-CD38 antibody administered intravenously, has been approved for subjects with multiple myeloma (relapsed and newly diagnosed). However, the most frequent adverse reactions (>20%) with daratumumab monotherapy or in combinationwith 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 has also been shown to bind to red blood cells 610% and platelets 622% more intensively than mezagitamab, which can compromise downstream binding to target cells (Fedyk et al., Blood, 2019, 134(Supplement_l): 3136, incorporated by reference herein in its entirety). Daratumumab can also 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.

[0241] Another anti-CD38 antibody, isatuximab (SARCLISA®), is approved for treating multiple myeloma in combination with dexamethasone and pomalidomide or carfilzomib. In patients receiving isatuximab, serious adverse events were found to occur in about 60% of patients (SARCLISA® USPI). Other notable adverse events included IRRs which occurred in approximately 40% of patients receiving the treatments.

[0242] Table 1 shows a comparison of the pharmacological profiles of TAK-079, daratumumab, and isatuximab (based on study reports of TAK-079 non-clinical pharmacology).Table 1. Summary of Pharmacological Profiles of TAK-079, Daratumumab (“Dara”) and Isatuximab (“Isa”)

[0243] Table 2 shows a comparison of TAK-079, daratumumab, isatuximab, and MOR202 (i.e., felzartamab).Table 2. Comparison of Therapeutic Anti-CD38 Antibodies

[0244] Other antibodies targeting CD38 are also known (see, e.g., WO 2006 / 125640 incorporated herein by reference in its entirety, which discloses four human antibodies: MOR03077, MOR03079, MOR03080, and MOR03100 and two murine antibodies: OKT10 and IB4). These prior art antibodies are inferior to 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 witha 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. MOR03 100 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.

[0245] 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 -turn or 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 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 MGsymptom 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 IgAN was unknown.

[0246] 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 IgAN.

[0247] 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 IgAN. 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 about 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 about 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.

[0248] 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 theevent 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.

[0249] 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.

[0250] 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.

[0251] Select terms are defined below in order for the present disclosure to be more readily understood.

[0252] 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 the amino acid sequence of SEQ ID NO: 2, which is 92% identical to the amino acid sequence of human CD38 (Table 3). Synonyms for CD38 include cyclic ADP ribose hydrolase; cyclic ADP ribose-hydrolase 1; ADP ribosyl cyclase; ADP -ribosyl cyclase 1; cADPr hydrolase 1; CD38-rsl; 1-19; 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 3. Amino Acid Sequence of Human and Cynomolgus Monkey CD38

[0253] 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 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 inwhich any toxic or detrimental effects of the antibody or antigen binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0254] 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.

[0255] 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.

[0256] 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%.

[0257] 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 fdler, 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.

[0258] 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.

[0259] 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 IgGl, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgMl 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 IgGl, IgG2, IgG3, IgG4, IgAl, IgA2, IgMl, IgM2, IgD, and IgE. Therapeutic antibodies can also comprise hybrids of isotypes and / or subclasses.

[0260] 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 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.

[0261] 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 OfImmunological 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)

[0262] 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.

[0263] 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: “CHI” 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.

[0264] 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 CHI 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 IgGl) to 236 (G236 in IgGl), 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.

[0265] The term “Fc region” refers to the polypeptide comprising the constant region of an antibody excluding the CHI 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 Cy2 and Cy3 (Cy2 and Cy3) and the lower hinge region between Cyl (Cyl) and Cy2 (Cy2). Although the boundaries of the Fc region may vary, the human IgGHC 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 FcyR receptors or to the FcRn receptor.CD38 Antibodies

[0266] 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 IgAN. 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”).

[0267] “Mezagitamab” or “TAK-079” is a therapeutic protein comprising a fully human immunoglobulin IgGl monoclonal antibody that binds specifically to 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 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 4.Table 4: Amino Acid Sequences of Mezagitamab

[0268] 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 etal. (2022) Eur. J. Neurol. 29(6): 1847-1854).

[0269] 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).

[0270] 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.

[0271] 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, theantibody 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 about 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 about 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 about 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 about 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 about 95% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as defined by SEQID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 and the remainder of the VH region sequence may have at least about 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 about 99% sequence identity to SEQ ID NO: 9.

[0272] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO: 9.

[0273] In some embodiments, the antibody comprises an LC comprising a VL region amino acid sequence having at least about 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 about 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 about 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 about 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 about 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 about 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 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least about 99% sequence identity to SEQ ID NO: 10.

[0274] In some embodiments, the antibody comprises an LC comprising the VL region amino acid sequence of SEQ ID NO: 10.

[0275] 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.

[0276] As will be appreciated by those in the art, the VH and VL regions can be joined to human IgG constant domain sequences, generally IgGl, IgG2, or IgG4.

[0277] In some embodiments, the antibody comprises a HC comprising or consisting of an amino acid sequence having at least about 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 about 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 about 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 about 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 about 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 about 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 about 99% sequence identity to SEQ ID NO 11.

[0278] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11.

[0279] In some embodiments, the antibody comprises a HC comprising or consisting of an amino acid sequence having at least about 80%, 85%, 90%, 95%, 97% or 99% 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 about 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 about 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 about 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 SEQID NO: 5 and the remainder of the HC may have at least about 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 about 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 about 99% sequence identity to SEQ ID NO 14.

[0280] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 14.

[0281] In some embodiments, the antibody comprises a LC comprising or consisting of an amino acid sequence having at least about 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 about 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 about 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 about 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 about 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 about 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 and SEQ ID NO: 8 and the remainder of the LC may have at least about 99% sequence identity to SEQ ID NO 12.

[0282] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12.

[0283] 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.

[0284] 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.

[0285] The present disclosure encompasses antibodies that bind to both human and cynomolgus CD38 and interact with at least about 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 about 90% of these amino acid residues. Suitably, the antibody may interact with at least about 95% of these amino acid residues. Suitably, the antibody may interact with at least about 97% of these amino acid residues. Suitably, the antibody may interact with at least about 98% of these amino acid residues. Suitably, the antibody may interact with at least about 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.

[0286] 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.

[0287] 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 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 CHI domains, (ii) the Fd fragment consisting of the VH and CHI domains, (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward etal. (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 whichallows the two domains to associate to form an antigen binding site (Bird et al. (1988) Science 242: 423-426, Huston etal. (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).

[0288] 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.

[0289] 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.

[0290] In some embodiments, the isolated antibody of the present disclosure is mezagitamab.Antibody Modifications

[0291] 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.

[0292] 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. Fcvariant 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.

[0293] 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.

[0294] 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.

[0295] 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 about 80% sequence identity to the parent sequence. Suitably, the variant may have at least about 85% sequence identity to the parent sequence. Suitably, the variant may have at least about 90% sequence identity to the parent sequence. Suitably, the variant may have at least about 92% sequence identity to the parent sequence. Suitably, the variant may have at least about 95% sequence identity to the parent sequence. Suitably, the variant may have at least about 97% sequence identity to the parent sequence. Suitably, the variant may have at least about 98% sequence identity to the parent sequence. Suitably, the variant may have at least about 99% sequence identity to the parent sequence.

[0296] 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.

[0297] 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.

[0298] 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 5 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 5. Conservative Substitutions

[0299] The term “amino acid insertion” means the addition of an amino acid at a particular position in a parent polypeptide sequence.

[0300] The term “amino acid deletion” means the removal of an amino acid at a particular position in a parent polypeptide sequence.

[0301] 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.

[0302] 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.

[0303] 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, 8 9 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.

[0304] 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.

[0305] 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 etal. (1994) Proc. Nat. Acad. Sci. USA 91 : 3809-3813; Shier et al. (1995) Gene 169: 147-155; Yelton etal. (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).

[0306] 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).

[0307] 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.

[0308] 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.Glycosylation

[0309] 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 engineeredglycoform is afucosylation, which has been shown to be correlated to an increase in ADCC function, presumably through tighter binding to the FcyRIIIa 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 FcyRIIIa receptor.

[0310] 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.

[0311] 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.

[0312] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are 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 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.

[0313] 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 throughchanges 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.

[0314] 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 W087 / 05330 and in Aplin and Wriston (1981) CRC Crit. Rev. Biochem. 10(4): 259-306, both entirely incorporated by reference.

[0315] 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 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.

[0316] 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 entirelyincorporated 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 / 0114037A1, entirely incorporated herein by reference.

[0317] 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.

[0318] 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.

[0319] 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 CD 157.

[0320] 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.Side Effect Reduction

[0321] 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 5.0, 2017, 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.

[0322] 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-CD 8 antibodies from grade 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.

[0323] 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 groupconsisting of infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs. 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 upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID-19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, and urticaria. 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.

[0324] In some embodiments, administering the antibody or antigen binding fragment thereof of the present disclosure results in less than about 20%, less than about 15%, or less than about 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 infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs; optionally wherein the TRAEs or TEAEs are selected from the group consisting of upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID-1 , nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs).

[0325] 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 grade 1 or grade 2.Disease Indication

[0326] The antibodies or antigen binding fragment thereof, methods, and dosage units of the disclosure find use in treating subjects with IgAN.Immune Thrombocytopenia (IgAN)

[0327] IgAN is the most common form of glomerular disease worldwide. The disease is caused by deposits of the protein immunoglobulin A (IgA) inside the filters (glomeruli) in the kidney. These glomeruli normally filter waste and excess water from the blood and send them to the bladder as urine. However, the presence of IgA protein prevents this filtering process.

[0328] IgAN has a poor prognosis; it is estimated individuals with IgAN experience kidney failure or death within 10-15 years (Kwon etal., J. Health Econ. Outcomes Res., 2021, 8(2): 36- 45). Clinical presentations of IgAN include hematuria, proteinuria, hypertension, rapidly progressive glomerulonephritis, and kidney failure.

[0329] The pathophysiology of IgAN e.g., primary IgAN) is hypothesized to conform to the multi-hit hypothesis: hit 1, production of galactose-deficient IgAl (Gd-IgAl); hit 2, IgG or IgA autoantibodies that recognize Gd-IgAl; hit 3, immune complex formation; and hit 4, kidney deposition and glomerular damage (Suzuki, Clin. Exp. Nephrol., 2019, 23:26-31). In individuals with IgAN, higher serum levels of gd-IgAl have been associated with greater severity of disease, suggesting that reduction in serum levels of gd-IgAl may slow disease progression (Suzuki et al., Clin. Exp. Nephrol., 2014, 18(5), 770-7).

[0330] Proteinuria, or elevated protein in the urine, is a prognostic marker for IgAN.Incremental levels of sustained proteinuria above 1 g / day are associated with marked changes in the risk of loss of kidney function; reduction of proteinuria, ideally to under 1 g / day, is associated with favorable outcomes (Pattrapornpisut et al., Am. J. Kidney Dis., 2021, 78(3): 429- 441). Urine protein to creatinine ratio (UPCR) is a validated surrogate biomarker for disease progression change in proteinuria (Inker etal., Am. J. Kidney Dis., 2016, 68(3): 392-401).

[0331] Estimated glomerular filtration rate (eGFR) is a measure of renal function and predictor of prognosis. Kidney failure expected in lifetime unless eGFR is preserved and the loss is maintained at <1 mL / min / 1.73 m2per year.

[0332] Current management strategies for IgAN include reducing protein loss, controlling blood pressure, and controlling inflammation (KDIGO 2012). There are very limited treatment options for individuals with IgAN. As of 2023, there are no effective and well-tolerated therapies approved that slow or prevent progression to kidney failure. Moreover, approved therapies for treating IgAN have serious limitations:• Sparsentan (FILSPARI®) ETAR, Ang-II inhibitor approved Feb. 2023:• Black Box Warning for hepatotoxicity and embryo-fetal toxicity• Contraindicated with ARBs due to risk of hyperkalemia (ARB - 1stline treatment)• Dapagliflozin (Farxiga®), SGLT2 inhibitor approved April 2021 :• Not IgAN specific - proteinuria reduction• Risk of volume depletion when eGFR <60 mL / min / 1.73 m2• Budesonide delayed release capsules (TARPEYO®), corticosteroid approved Dec. 2021 :• Adverse events associated with long term use of corticosteroid (11 of 13 subjects in the phase 2 trial had serious TEAEs)

[0333] Despite US FDA approval of Tarpeyo® (budesonide), Filspari® (sparsentan), and Fabhalta® (iptacopan), unmet need remains for safe and efficacious medications for IgAN.

[0334] As such, there is an urgent unmet medical need for novel treatments that induce longterm reduction in proteinuria and stabilize the GFR in subjects for whom proteinuria is not controlled by maximally -tolerated ACE-I or ARB alone.

[0335] Targeting and eliminating B-cells is a promising approach to impact IgAN disease progression (e.g., CD38, B-cell activating factor (BAFF) / B lymphocyte stimulator (BLyS), a proliferation-inducing ligand (APRIL)). Among B-cell targets, CD38 may be preferred because it selectively targets plasma cells, plasmablasts, other B-cell subsets in addition to other cell types (NK cells, pDCs) while sparing memory B-cells and naive B-cells. In contrast, BLyS and APRIL agents deplete memory B cells and naive B cells, which may have safety issues with long term use (e.g., serious infections).

[0336] In some embodiments, the disclosure provides methods of treating IgAN in a subject. In some embodiments, the disclosure provides methods of treating primary IgAN in a subject. In some embodiments, the disclosure provides methods of treating secondary IgAN in a subject.

[0337] In some embodiments, the subject is diagnosed with IgAN. In some embodiments, the subject is diagnosed with primary IgAN.

[0338] 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.

[0339] In some embodiments, the disclosure provides methods of treating IgAN 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.

[0340] In some embodiments, the disclosure provides methods of treating IgAN 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.

[0341] In some embodiments, the disclosure provides methods of treating IgAN 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 sequenceof 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.

[0342] In some embodiments, the disclosure provides methods of reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with IgAN, 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 IgAN, 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.

[0343] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with IgAN, 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 IgAN, 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 immunoglobulin is IgA, IgG and / or IgM. In some embodiments, theimmunoglobulin comprises IgA. In some embodiments, the immunoglobulin comprises IgG. In some embodiments, the immunoglobulin comprises IgM. In some embodiments, the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl).

[0344] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with IgAN, wherein the immunoglobulin(s) (e.g., IgA, IgG, IgM, and / or gd-IgAl) 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, gd-IgAl 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 gd-IgAl . In some embodiments, IgA is reduced by at least about 60%, IgG is reduced by at least about 25%, and gd-IgAl is reduced by at least about 55%.

[0345] In some embodiments, the disclosure provides methods of reducing the level of immunoglobulin(s) in a subject diagnosed with IgAN, wherein the method results in a reduction in immunoglobulin(s) (e.g., IgA, IgG, IgM, and / or gd-IgAl) 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 results in a reduction in immunoglobulin(s) in one week or less.

[0346] In some embodiments, the disclosure provides methods of reducing the level of autoantibodies in a subject diagnosed with IgAN, 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 IgAN, 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-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies comprise IgA and / or IgG. In some embodiments, the autoantibodies 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%, or at least about 60% relative to baseline levels of the autoantibodies.

[0347] In some embodiments, the disclosure provides methods of reducing the level of antigalactose-deficient IgAl (anti-gd-IgAl) autoantibodies in a subject diagnosed with immunoglobulin A nephropathy (IgAN), 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 regioncomprising 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 anti-gd-IgAl autoantibodies comprise IgA and / or IgG. In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

[0348] In some embodiments, the disclosure provides methods of reducing IgAN disease activity and / or progression in a subject diagnosed with IgAN, 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.

[0349] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the IgAN disease activity and / or progression is measured one or more assessments selected from the group consisting of percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate(eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, efc.); levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, efc.); change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) score;Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores. In some embodiments, the IgAN disease activity and / or progression is measured by percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in estimated glomerular filtration rate (eGFR). In some embodiments, the IgAN disease activity and / or progression is measured by annualized total eGFR slope. In some embodiments, the IgAN disease activity and / or progression is measured by a complete response (CR) on the basis of proteinuria assessment. In some embodiments, the IgAN disease activity and / or progression is measured by presence or absence of hematuria. In some embodiments, hematuria is resolved in less than or equal to about 2 years, less than or equal to about 1 year, less than or equal to about 104 weeks, less than or equal to about 100 weeks, less than or equal to about 75 weeks, less than or equal to about 52 weeks, less than or equal to about 50 weeks, less than or equal to about 45 weeks, less than or equal to about 40 weeks, less than or equal to about 36 weeks, less than or equal to about 35 weeks, less than or equal to about 30 weeks, less than or equal to about 25 weeks, or less than or equal to about 20 weeks. In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in immune cell subsets by flow cytometry. In some embodiments, the IgAN disease activity and / or progression is measured by levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.). In some embodiments, the IgAN disease activity and / or progression is measured by levels of serum IgG and IgM levels. In some embodiments, the IgAN disease activity and / or progression is measured by levels of urinebiomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc. . In some embodiments, the IgAN disease activity and / or progression is measured by change in levels of vaccine-protective antibodies (e.g, measles, mumps, rubella, diphtheria, tetanus). In some embodiments, the IgAN disease activity and / or progression is measured by use of rescue therapy and / or non-permitted IgAN therapy. In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) score. In some embodiments, the IgAN disease activity and / or progression is measured by Patient Global Impression of Severity (PGI-S). In some embodiments, the IgAN disease activity and / or progression is measured by Patient Global Impression of Change (PGLC). In some embodiments, the IgAN disease activity and / or progression is measured by EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index. In some embodiments, the IgAN disease activity and / or progression is measured by visual analogue scale (VAS) scores. In some embodiments, the IgAN disease activity and / or progression is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering.

[0350] In some embodiments, the disclosure provides methods of reducing proteinuria in a subject diagnosed with IgAN, 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 theamino 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.

[0351] In some embodiments, proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g, 24-h UPGR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, proteinuria is measured by urine protein to creatinine ratio (UPCR). In some embodiments, proteinuria is measured by 24-h urine protein to creatinine ratio (UPCR). In some embodiments, proteinuria is measured by urine albumin to creatinine ratio (UACR). In some embodiments, proteinuria is measured by urine protein excretion (UPE). In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline. In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering. In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering.In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR to about 104 weeks after the administering.

[0352] In some embodiments, proteinuria is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60% relative to baseline levels of proteinuria. In some embodiments, proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering. In some embodiments, proteinuria is reduced for from about 12 weeks to about 75 weeks, from about 24 weeks to about 75 weeks, from about 12 weeks to about 52 weeks, or from about 24 weeks to about 52 weeks.

[0353] In some embodiments, the disclosure provides methods of achieving durable proteinuria reduction in a subject diagnosed with IgAN, 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.

[0354] In some embodiments, durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, durable proteinuria reduction is measured by a change from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks afterthe administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, durable proteinuria reduction is measured by a change from baseline to 104 weeks after the administering in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR).

[0355] In some embodiments, proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 64 weeks, at least about 66 weeks, at least about 72 weeks, at least about 74 weeks, at least about 78 weeks, at least about 84 weeks, at least about 88 weeks, at least about 90 weeks, at least about 96 weeks, at least about 100 weeks, at least about 102 weeks, or at least about 104 weeks.

[0356] In some embodiments, the disclosure provides methods of achieving a complete response on the basis of proteinuria in a subject diagnosed with IgAN, 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 IDNO: 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.

[0357] In some embodiments, the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, the complete response is measured by urine protein to creatinine ratio (UPCR). In some embodiments, the complete response is measured by urine albumin to creatinine ratio (UACR). In some embodiments, the complete response is measured by urine protein excretion (UPE). In some embodiments, the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection.

[0358] In some embodiments, the disclosure provides methods of stabilizing glomerular filtration rate (GFR) relative to baseline levels of GFR in a subject diagnosed with IgAN, 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.

[0359] In some embodiments, GFR is measured by estimated glomerular filtration rate (eGFR). In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline toabout 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 2 years after the administering.

[0360] In some embodiments, stabilizing GFR is measured by a rate of change in eGFR. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 18 weeks after the administering, from about 12 weeks to about 22 weeks after the administering, from about 12 weeks to about 24 weeks after the administering, from about 12 weeks to about 30 weeks after the administering, from about 12 weeks to about 36 weeks after the administering, from about 12 weeks to about 42 weeks after the administering, from about 12 weeks to about 48 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from about 12 weeks to about 54 weeks after the administering, from about 12 weeks to about 60 weeks after the administering, from about 12 weeks to about 64 weeks after the administering, from about 12 weeks to about 66 weeks after the administering, from about 12 weeks to about 72 weeks after the administering, from about 12 weeks to about 74 weeks after the administering, from about 12 weeks to about 78 weeks after the administering, from about 12 weeks to about 84 weeks after the administering, from about 12 weeks to about 88 weeks after the administering, from about 12 weeks to about 90 weeks after the administering, from about 12 weeks to about 96 weeks after the administering, from about 12 weeks to about 100 weeks after the administering, from about 12 weeks to about 104 weeks after the administering, from about12 weeks to about 1 year after the administering, or from about 12 weeks to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 52 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 2 years after the administering.

[0361] In some embodiments, stabilizing GFR is measured by a total eGFR slope. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to 2 years after the administering.

[0362] In some embodiments, stabilizing GFR is measured by a chronic eGFR slope. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, frombaseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to 2 years after the administering.

[0363] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of a 30% or more reduction in eGFR. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of eGFR<15mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of dialysis. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of all-cause mortality.

[0364] In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after theadministering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering. In some embodiments, stabilizing eGFR is measured by a change in eGFR from baseline to about 104 weeks after the administering.

[0365] In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering. In some embodiments,stabilizing eGFR is measured by a change in eGFR slope from baseline to about 104 weeks after the administering.

[0366] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence sustained decline in eGFR of >30% from baseline to at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained eGFR <15 mL / min / 1.73 m2over at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of initiation of maintenance dialysis defined as dialysis performed for at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of receipt of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of death from kidney failure. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of receipt of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of death from kidney failure.

[0367] In some embodiments, stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2

[0368] In some embodiments, GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering. In some embodiments, GFR is stabilized for at least about 52 weeks after the administering.

[0369] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -4.5 to about 10,from about -4 to about 10, from about -3.5 to about 10, from about -3 to about 10, from about -2.5 to about 10, from about -2 to about 10, from about -1 to about 10, from about 0.5 to about 10, from about 1 to about 10, from about -5 to about 8, from about -4.5 to about 8, from about -4 to about 8, from about -3.5 to about 8, from about -3 to about 8, from about -2.5 to about 8, from about -2 to about 8, from about -1 to about 8, from about 0.5 to about 8, from about 1 to about 8, from about -5 to about 5, from about -4.5 to about 5, from about -4 to about 5, from about -3.5 to about 5, from about -3 to about 5, from about -2.5 to about 5, from about -2 to about 5, from about -1 to about 5, from about 0.5 to about 5, from about 1 to about 5, from about -5 to about 4, from about -4.5 to about 4, from about -4 to about 4, from about -3.5 to about 4, from about -3 to about 4, from about -2.5 to about 4, from about -2 to about 4, from about -1 to about 4, from about 0.5 to about 4, or from about 1 to about 4. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -3 to about 8. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -3 to about 4.

[0370] In some embodiments, the LS mean annualized eGFR slope is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2years after the administering. In some embodiments, the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering.

[0371] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR from about -5 to about 10 mL / min / 1.73m2, from about -4.5 to about 10 mL / min / 1.73m2, from about -4 to about 10 mL / min / 1.73m2, from about -3.5 to about 10 mL / min / 1.73m2, from about -3 to about 10 mL / min / 1.73m2, from about -2.5 to about 10 mL / min / 1.73m2, from about -2 to about 10 mL / min / 1.73m2, from about -1 to about 10 mL / min / 1.73m2, from about 0.5 to about 10 mL / min / 1.73m2, from about 1 to about 10 mL / min / 1.73m2, from about -5 to about 8 mL / min / 1.73m2, from about -4.5 to about 8 mL / min / 1.73m2, from about -4 to about 8 mL / min / 1.73m2, from about -3.5 to about 8 mL / min / 1.73m2, from about -3 to about 8 mL / min / 1.73m2, from about -2.5 to about 8 mL / min / 1.73m2, from about -2 to about 8 mL / min / 1.73m2, from about -1 to about 8 mL / min / 1.73m2, from about 0.5 to about 8 mL / min / 1.73m2, from about 1 to about 8 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4.5 to about 5 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, from about -3.5 to about 5 mL / min / 1.73m2, from about -3 to about 5 mL / min / 1.73m2, from about -2.5 to about 5 mL / min / 1.73m2, from about -2 to about 5 mL / min / 1.73m2, from about -1 to about 5 mL / min / 1.73m2, from about 0.5 to about 5 mL / min / 1.73m2, from about 1 to about 5 mL / min / 1.73m2, from about -5 to about 4 mL / min / 1.73m2, from about -4.5 to about 4 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3.5 to about 4 mL / min / 1.73m2, from about -3 to about 4 mL / min / 1.73m2, from about -2.5 to about 4 mL / min / 1.73m2, from about -2 to about 4 mL / min / 1.73m2, from about -1 to about 4 mL / min / 1.73m2, from about 0.5 to about 4 mL / min / 1.73m2, from about 1 to about 4 mL / min / 1.73m2, from about -5 to about 3 mL / min / 1.73m2, from about -4.5 to about 3 mL / min / 1.73m2, from about -4 to about 3 mL / min / 1.73m2, from about -3.5 to about 3 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, from about -2.5 to about 3 mL / min / 1.73m2, from about -2 to about 3 mL / min / 1.73m2, from about -1 to about 3 mL / min / 1.73m2, from about 0.5 to about 3 mL / min / 1.73m2, or from about 1 to about 3 mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2. In someembodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -4 to about 5 mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -4 to about 3 mL / min / 1.73m2.

[0372] In some embodiments, LS mean change from baseline in eGFR is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

[0373] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the dosage is a dosage administered once every week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0374] In some embodiments, the disclosure provides the methods as disclosed herein, wherein a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein a treatmentcycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for a total of 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, or 16 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) at least 9 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for a total of 9 times.

[0375] In some embodiments, the disclosure provides the methods as disclosed herein, wherein a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for at least about 1 week, for at least about 2 weeks, for at least about 3 weeks, for at least about 4 weeks, for at least about 5 weeks, for at least about 6 weeks, for at least about 7 weeks, or for at least about 8 weeks. In some embodiments, the treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) for 8 weeks.

[0376] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for a total of 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, or 16 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof onceevery 2 weeks (Q2W) at least 7 times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for a total of 7 times.

[0377] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks. In some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, or 18 weeks. In some embodiments, the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) for 16 weeks.

[0378] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of 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. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of about 10 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of less than or equal to about 100 weeks, less than or equal to about 75 weeks, less than or equal to about 52 weeks, less than or equal to about 50 weeks, less than or equal to about 45 weeks, less than or equal to about 40 weeks, less than or equal to about 35 weeks, less than or equal to about 30 weeks, less than or equal to about 25weeks, or less than or equal to about 20 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of about 30 weeks.

[0379] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of from about 10 to about 100 weeks, from about 10 to about 75 weeks, from about 10 to about 52 weeks, from about 10 to about 50 weeks, from about 10 to about 45 weeks, from about 10 to about 40 weeks, from about 10 to about 35 weeks, from about 10 to about 30 weeks, from about 15 to about 100 weeks, from about 15 to about 75 weeks, from about 15 to about 52 weeks, from about 15 to about 50 weeks, from about 15 to about 45 weeks, from about 15 to about 40 weeks, from about 15 to about 35 weeks, from about 15 to about 30 weeks, from about 20 to about 100 weeks, from about 20 to about 75 weeks, from about 20 to about 52 weeks, from about 20 to about 50 weeks, from about 20 to about 45 weeks, from about 20 to about 40 weeks, from about 20 to about 35 weeks, from about 20 to about 30 weeks, from about 25 to about 100 weeks, from about 25 to about 75 weeks, from about 25 to about 52 weeks, from about 25 to about 50 weeks, from about 25 to about 45 weeks, from about 25 to about 40 weeks, from about 25 to about 35 weeks, or from about 25 to about 30 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of from about 10 to about 50 weeks.

[0380] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle is performed more than one time, more than two times, more than three times, more than four times, or more than five times. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle is performed more than one time.

[0381] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle is performed about every two months, about every three months, about every four months, about every five months, about every six months, about every seven months, about every eight months, about every nine months, about every ten months, about every elevenmonths, about every twelve months, about every thirteen months, about every fourteen months, about every fifteen months, about every sixteen months, about every eighteen months, about every twenty four months, about every 1 year, about every 1.5 years, about every 2 years, about every 2.5 years, about every 3 years, about every 4 years, about every 5 years, or about every 10 years. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle is performed about every six months. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the treatment cycle is performed about every twelve months.

[0382] In some embodiments, the disclosure provides methods of treating immunoglobulin A nephropathy (IgAN) in a subject diagnosed with IgAN, 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 a treatment cycle comprises: (a) subcutaneously administering the isolated antibody in a dosage of about 600 mg once every week (QW) for a total of 9 times; and (b), following (a), subcutaneously administering the isolated antibody in a dosage of about 600 mg once every 2 weeks (Q2W) for a total of 7 times; optionally (c), following (b), not administering the isolated antibody for a period of about 30 weeks; optionally wherein the treatment cycle is performed more than one time; and optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

[0383] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has proteinuria of >150 mg / day, >200 mg / day, >250 mg / day, >300 mg / day, >350 mg / day, >400 mg / day, >450 mg / day, >500 mg / day, >550 mg / day, >600 mg / day, >750 mg / day, >800 mg / day, >850 mg / day, >900 mg / day, >950 mg / day, >1 g / day, >1.5 g / day, or >2 g / day. In someembodiments, the disclosure provides the methods as disclosed herein, wherein the subject in need of treatment has proteinuria of >1 g / day.

[0384] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >150 mg / day, >200 mg / day, >250 mg / day, >300 mg / day, >350 mg / day, >400 mg / day, >450 mg / day, >500 mg / day, >550 mg / day, >600 mg / day, >650 mg / day, >700 mg / day, >750 mg / day, >800 mg / day, >850 mg / day, >900 mg / day, >950 mg / day, >1 g / day, >1.5 g / day, or >2 g / day. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPE of from about 100 to about 5000 mg / day, from about 200 to about 5000 mg / day, from about 300 to about 5000 mg / day, from about 400 to about 5000 mg / day, from about 500 to about 5000 mg / day, from about 600 to about 5000 mg / day, from about 700 to about 5000 mg / day, from about 800 to about 5000 mg / day, from about 900 to about 5000 mg / day, from about 1000 to about 5000 mg / day, from about 1100 to about 5000 mg / day, from about 1200 to about 5000 mg / day, from about 1300 to about 5000 mg / day, from about 1400 to about 5000 mg / day, from about 1500 to about 5000 mg / day, from about 1600 to about 5000 mg / day, from about 1700 to about 5000 mg / day, from about 1800 to about 5000 mg / day, from about 1900 to about 5000 mg / day, or from about 2000 to about 5000 mg / day. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPE of from about 500 to about 5000 mg / day.

[0385] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein-to-creatinine ratio (UPCR) of >0.1 g / g, >0.2 g / g, >0.3 g / g, >0.4 g / g, >0.5 g / g, >0.6 g / g, >0.7 g / g, >0.8 g / g, >0.9 g / g, >1.0 g / g, >1.5 g / g, >2.0 g / g, >2.5 g / g, or >3 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-hUPCR of >1.0 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPCR of from about 0.1 to about 5 g / g, from about 0.5 to about 5 g / g, from about 1 to about 5 g / g, from about 0.1 to about 3 g / g, from about 0.5 to about 3 g / g, from about 0.8 to about 3 g / g, or from about 1 to about 3 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h UPCR of from about 0.5 to about 3 g / g.

[0386] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day and / or a 24-h urine protein-to-creatinine ratio (UPCR) of >1.0 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day or a 24-h urine protein- to-creatinine ratio (UPCR) of >1.0 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day and a 24- h urine protein-to-creatinine ratio (UPCR) of >1.0 g / g.

[0387] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day and / or a 24-h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day or a 24-h urine protein- to-creatinine ratio (UPCR) of >0.8 g / g. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has a 24-h urine protein excretion (UPE) of >1 g / day and a 24- h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g.

[0388] In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an estimated glomerular filtration rate (eGFR) of >10mL / min / 1.73 m2, >20 mL / min / 1.73 m2, >30 mL / min / 1.73 m2, >40 mL / min / 1.73 m2, >45 mL / min / 1.73 m2, or >50 mL / min / 1.73 m2. In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an estimated glomerular filtration rate (eGFR) of >30 mL / min / 1.73 m2. In some embodiments, the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an estimated glomerular filtration rate (eGFR) of >45 mL / min / 1.73 m2.

[0389] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an eGFR of from about 10 to about 200 mL / min / 1.73 m2, from about 30 to about 200 mL / min / 1.73 m2, from about 50 to about 200 mL / min / 1.73 m2, from about 10 to about 150 mL / min / 1.73 m2, from about 30 to about 150 mL / min / 1.73 m2, from about 50 to about 150 mL / min / 1.73 m2, from about 10 to about 125 mL / min / 1.73 m2, from about 30 to about 125 mL / min / 1.73 m2, or from about 50 to about 125 mL / min / 1.73 m2. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has an eGFR of from about 30 to about 150 mL / min / 1.73 m2.

[0390] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has serum creatinine levels of from about 10 to about 200 pmol / L, from about 20 to about 200 pmol / L, from about 30 to about 200 pmol / L, from about 40 to about 200 pmol / L, from about 50 to about 200 pmol / L, from about 60 to about 200 pmol / L, from about 10 to about 175 pmol / L, from about 20 to about 175 pmol / L, from about 30 to about 175 pmol / L, from about 40 to about 175 pmol / L, from about 50 to about 175 pmol / L, from about 60 to about 175 pmol / L, from about 10 to about 150 pmol / L, from about 20 to about 150 pmol / L, from about 30 to about 150 pmol / L, from about 40 to about 150 pmol / L, from about 50 to about 150 pmol / L, or from about 60 to about 150 pmol / L. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has serum creatinine levels of from about 10 to about 200 pmol / L.

[0391] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, hasserum creatinine levels of from about 0.1 to about 2 mg / dL, from about 0.2 to about 2 mg / dL, from about 0.3 to about 2 mg / dL, from about 0.4 to about 2 mg / dL, from about 0.5 to about 2 mg / dL, from about 0.6 to about 2 mg / dL, from about 0.1 to about 1.9 mg / dL, from about 0.2 to about 1.9 mg / dL, from about 0.3 to about 1.9 mg / dL, from about 0.4 to about 1.9 mg / dL, from about 0.5 to about 1.9 mg / dL, from about 0.6 to about 1.9 mg / dL, from about 0.1 to about 1.8 mg / dL, from about 0.2 to about 1.8 mg / dL, from about 0.3 to about 1.8 mg / dL, from about 0.4 to about 1.8 mg / dL, from about 0.5 to about 1.8 mg / dL, from about 0.6 to about 1.8 mg / dL, from about 0.1 to about 1.7 mg / dL, from about 0.2 to about 1.7 mg / dL, from about 0.3 to about 1.7 mg / dL, from about 0.4 to about 1.7 mg / dL, from about 0.5 to about 1.7 mg / dL, or from about 0.6 to about 1.7 mg / dL. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has serum creatinine levels of from about 0.5 to about 2 mg / dL.

[0392] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgA levels of from about 0.5 to about 6 g / L, from about 0.6 to about 6 g / L, from about 0.7 to about 6 g / L, from about 0.8 to about 6 g / L, from about 0.9 to about 6 g / L, from about 1 to about 6 g / L, from about 0.5 to about 5.5 g / L, from about 0.6 to about 5.5 g / L, from about 0.7 to about 5.5 g / L, from about 0.8 to about 5.5 g / L, from about 0.9 to about 5.5 g / L, from about 1 to about 5.5 g / L, from about 0.5 to about 5 g / L, from about 0.6 to about 5 g / L, from about 0.7 to about 5 g / L, from about 0.8 to about 5 g / L, from about 0.9 to about 5 g / L, or from about 1 to about 5 g / L. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgA levels of from about 1 to about 5.5 g / L. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgA levels of from about 1.5 to about 5 g / L.

[0393] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has Gd-IgAl levels of from about 1,000 to about 16,000 ng / mL, from about 1,100 to about 16,000 ng / mL, from about 1,200 to about 16,000 ng / mL, from about 1,300 to about 16,000 ng / mL, from about 1,400 to about 16,000 ng / mL, from about 1,500 to about 16,000 ng / mL, from about 1,000to about 15,500 ng / mL, from about 1,100 to about 15,500 ng / mL, from about 1,200 to about 15,500 ng / mL, from about 1,300 to about 15,500 ng / mL, from about 1,400 to about 15,500 ng / mL, from about 1,500 to about 15,500 ng / mL, from about 1,000 to about 15,000 ng / mL, from about 1,100 to about 15,000 ng / mL, from about 1,200 to about 15,000 ng / mL, from about 1,300 to about 15,000 ng / mL, from about 1,400 to about 15,000 ng / mL, or from about 1,500 to about 15,000 ng / mL. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has Gd-IgAl levels of from about 1,000 to about 15,500 ng / mL.

[0394] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgG levels of from about 1 to about 20 g / L, from about 2 to about 20 g / L, from about 3 to about 20 g / L, from about 4 to about 20 g / L, from about 5 to about 20 g / L, from about 6 to about 20 g / L, from about 7 to about 20 g / L, from about 8 to about 20 g / L, from about 1 to about 15 g / L, from about 2 to about 15 g / L, from about 3 to about 15 g / L, from about 4 to about 15 g / L, from about 5 to about 15 g / L, from about 6 to about 15 g / L, from about 7 to about 15 g / L, or from about 8 to about 15 g / L. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has IgG levels of from about 7 to about 15 g / L.

[0395] In some embodiments, the subject is diagnosed with IgAN by a biopsy. In some embodiments, the subject is diagnosed with IgAN by a biopsy performed <20, <15, <12, <10, <9, <8, <7, <6, <5, <4, <3, <2, or <1 years ago. In some embodiments, the subject is diagnosed with IgAN by a biopsy performed <10 years ago.

[0396] In some embodiments, the subject is diagnosed with IgAN from about 0 to about 50 years ago, from about 0 to about 45 years ago, from about 0 to about 40 years ago, from about 0 to about 35 years ago, from about 0 to about 30 years ago, from about 0.1 to about 50 years ago, from about 0.1 to about 45 years ago, from about 0.1 to about 40 years ago, from about 0.1 to about 35 years ago, or from about 0.1 to about 30 years ago. In some embodiments, the subject is diagnosed with IgAN from about 0.1 to about 30 years ago. In some embodiments, the subject is diagnosed with IgAN from about 1 to about 10 years ago.

[0397] 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 about 75%, less than about 50%, or less than about 25% incidence of use of a rescue therapy and / or non-permitted IgAN therapy. In some embodiments, the subject has not received a rescue therapy and / or non-permitted IgAN therapy in the previous four weeks. In some embodiments, the method does not include the use of a rescue therapy and / or non-permitted IgAN therapy.

[0398] 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 plasmablasts, plasma cells, and / or NK cells. 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 plasmablasts. 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 plasma cells. 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 NK cells.

[0399] 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, IgM, and / or gd-IgAl. In some embodiments, the immunoglobulin(s) (e.g., IgA, IgG, IgM, and / or gd-IgAl) 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%, atleast 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, gd-IgAl 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 gd-IgAl . In some embodiments, IgA is reduced by at least about 60%, IgG is reduced by at least about 25%, and gd-IgA is reduced by at least about 55%.

[0400] In some embodiments, administering the isolated antibody or antigen binding fragment thereof results in a reduction in immunoglobulin(s) (e.g., IgA, IgG, IgM, and / or gd-IgAl) 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 results in a reduction in immunoglobulin(s) in one week or less.

[0401] 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 the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies comprise IgA and / or IgG. In some embodiments, the anti-gd- IgAl autoantibodies 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 anti-gd-IgAl autoantibodies. In some embodiments, the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

[0402] 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 IgAN disease activity and / or progression, optionally wherein the IgAN disease activity and / or progression. In some embodiments, the IgAN disease activity and / or progression is measured one or more assessments selected from the group consisting of percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, efc.); levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, efc.); change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) score; Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores. In some embodiments, the IgAN disease activity and / or progression is measured by percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in estimated glomerular filtration rate (eGFR). In some embodiments, the IgAN disease activity and / or progression is measured by annualized total eGFR slope. In some embodiments, the IgAN disease activity and / or progression is measured by a complete response (CR) on the basis of proteinuria assessment. In some embodiments, the IgAN disease activity and / or progression is measured by presence or absence of hematuria. In some embodiments, hematuria is resolved in less than or equal to about 2 years, less than or equal to about 1 year, less than or equal to about 104 weeks, less than or equal to about 100 weeks, less than or equal to about 75 weeks, less than or equal to about 52 weeks, less than or equal to about 50 weeks, less than or equal to about 45 weeks, less than or equal to about 40 weeks, less than or equal to about 36 weeks, less than or equal to about 35 weeks, less than or equal to about 30 weeks, less than or equal to about 25 weeks, or less than or equal to about 20weeks. In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in immune cell subsets by flow cytometry. In some embodiments, the IgAN disease activity and / or progression is measured by levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.). In some embodiments, the IgAN disease activity and / or progression is measured by levels of serum IgG and IgM levels. In some embodiments, the IgAN disease activity and / or progression is measured by levels of urine biomarkers (e.g, creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc.). In some embodiments, the IgAN disease activity and / or progression is measured by change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus). In some embodiments, the IgAN disease activity and / or progression is measured by use of rescue therapy and / or non-permitted IgAN therapy. In some embodiments, the IgAN disease activity and / or progression is measured by change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) score. In some embodiments, the IgAN disease activity and / or progression is measured by Patient Global Impression of Severity (PGI-S). In some embodiments, the IgAN disease activity and / or progression is measured by Patient Global Impression of Change (PGI-C). In some embodiments, the IgAN disease activity and / or progression is measured by EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index. In some embodiments, the IgAN disease activity and / or progression is measured by visual analogue scale (VAS) scores. In some embodiments, the IgAN disease activity and / or progression is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering.

[0403] 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 proteinuria. In some embodiments, proteinuria is reduced by at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60% relative to baseline levels of proteinuria. In some embodiments, proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about100 weeks, or at least about 104 weeks after the administering. In some embodiments, proteinuria is reduced for from about 12 weeks to about 75 weeks, from about 24 weeks to about 75 weeks, from about 12 weeks to about 52 weeks, or from about 24 weeks to about 52 weeks. In some embodiments, proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, proteinuria is measured by urine protein to creatinine ratio (UPCR). In some embodiments, proteinuria is measured by urine albumin to creatinine ratio (UACR). In some embodiments, proteinuria is measured by urine protein excretion (UPE). In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline. In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering. In some embodiments, proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by achange from baseline in UACR to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 100 weeks after the administering, or from baseline to about 104 weeks after the administering. In some embodiments, the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline in UACR to about 104 weeks after the administering.

[0404] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in durable proteinuria reduction. In some embodiments, durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, durable proteinuria reduction is measured by a change from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR). In some embodiments, durableproteinuria reduction is measured by a change from baseline to 104 weeks after the administering in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR).

[0405] In some embodiments, proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 64 weeks, at least about 66 weeks, at least about 72 weeks, at least about 74 weeks, at least about 78 weeks, at least about 84 weeks, at least about 88 weeks, at least about 90 weeks, at least about 96 weeks, at least about 100 weeks, at least about 102 weeks, or at least about 104 weeks.

[0406] 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 on the basis of proteinuria. In some embodiments, the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection. In some embodiments, the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE). In some embodiments, the complete response is measured by urine protein to creatinine ratio (UPCR). In some embodiments, the complete response is measured by urine albumin to creatinine ratio (UACR). In some embodiments, the complete response is measured by urine protein excretion (UPE).

[0407] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the isolated antibody or antigen binding fragment thereof results in a stabilization of glomerular filtration rate (GFR) relative to baseline levels of GFR. In some embodiments, GFR is measured by estimated glomerular filtration rate (eGFR). In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks afterthe administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from baseline to about 2 years after the administering.

[0408] In some embodiments, stabilizing GFR is measured by a rate of change in eGFR. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 18 weeks after the administering, from about 12 weeks to about 22 weeks after the administering, from about 12 weeks to about 24 weeks after the administering, from about 12 weeks to about 30 weeks after the administering, from about 12 weeks to about 36 weeks after the administering, from about 12 weeks to about 42 weeks after the administering, from about 12 weeks to about 48 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from about 12 weeks to about 54 weeks after the administering, from about 12 weeks to about 60 weeks after the administering, from about 12 weeks to about 64 weeks after the administering, from about 12 weeks to about 66 weeks after the administering, from about 12 weeks to about 72 weeks after the administering, from about 12 weeks to about 74 weeks after the administering, from about 12 weeks to about 78 weeks after the administering, from about 12 weeks to about 84 weeks after the administering, from about 12 weeks to about 88 weeks after the administering, from about 12 weeks to about 90 weeks after the administering, from about 12 weeks to about 96 weeks after the administering, from about 12 weeks to about 100 weeks after the administering, from about 12 weeks to about 104 weeks after the administering, from about 12 weeks to about 1 year after the administering, or from about 12 weeks to about 2 years afterthe administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 52 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 104 weeks after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a rate of change in eGFR from about 12 weeks to about 2 years after the administering.

[0409] In some embodiments, stabilizing GFR is measured by a total eGFR slope. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a total eGFR slope from baseline to 2 years after the administering.

[0410] In some embodiments, stabilizing GFR is measured by a chronic eGFR slope. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after theadministering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering. In some embodiments, stabilizing GFR is measured by a chronic eGFR slope from baseline to 2 years after the administering.

[0411] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of a 30% or more reduction in eGFR. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of eGFR<15mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of dialysis. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of all-cause mortality.

[0412] In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering. In some embodiments, stabilizing eGFR is measured by a change in eGFR from baseline to about 104 weeks after the administering.

[0413] In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering. In some embodiments,stabilizing eGFR is measured by a change in eGFR slope from baseline to about 104 weeks after the administering.

[0414] In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence sustained decline in eGFR of >30% from baseline to at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained eGFR <15 mL / min / 1.73 m2over at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of initiation of maintenance dialysis defined as dialysis performed for at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of receipt of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of death from kidney failure. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of receipt of kidney transplant. In some embodiments, stabilizing GFR is measured by time from baseline to a first occurrence of death from kidney failure.I l l

[0415] In some embodiments, stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2

[0416] In some embodiments, GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering. In some embodiments, GFR is stabilized for at least about 52 weeks after the administering.

[0417] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -4.5 to about 10,from about -4 to about 10, from about -3.5 to about 10, from about -3 to about 10, from about -2.5 to about 10, from about -2 to about 10, from about -1 to about 10, from about 0.5 to about 10, from about 1 to about 10, from about -5 to about 8, from about -4.5 to about 8, from about -4 to about 8, from about -3.5 to about 8, from about -3 to about 8, from about -2.5 to about 8, from about -2 to about 8, from about -1 to about 8, from about 0.5 to about 8, from about 1 to about 8, from about -5 to about 5, from about -4.5 to about 5, from about -4 to about 5, from about -3.5 to about 5, from about -3 to about 5, from about -2.5 to about 5, from about -2 to about 5, from about -1 to about 5, from about 0.5 to about 5, from about 1 to about 5, from about -5 to about 4, from about -4.5 to about 4, from about -4 to about 4, from about -3.5 to about 4, from about -3 to about 4, from about -2.5 to about 4, from about -2 to about 4, from about -1 to about 4, from about 0.5 to about 4, or from about 1 to about 4. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -3 to about 8. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -3 to about 4.

[0418] In some embodiments, the LS mean annualized eGFR slope is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2years after the administering. In some embodiments, the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering.

[0419] In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR from about -5 to about 10 mL / min / 1.73m2, from about -4.5 to about 10 mL / min / 1.73m2, from about -4 to about 10 mL / min / 1.73m2, from about -3.5 to about 10 mL / min / 1.73m2, from about -3 to about 10 mL / min / 1.73m2, from about -2.5 to about 10 mL / min / 1.73m2, from about -2 to about 10 mL / min / 1.73m2, from about -1 to about 10 mL / min / 1.73m2, from about 0.5 to about 10 mL / min / 1.73m2, from about 1 to about 10 mL / min / 1.73m2, from about -5 to about 8 mL / min / 1.73m2, from about -4.5 to about 8 mL / min / 1.73m2, from about -4 to about 8 mL / min / 1.73m2, from about -3.5 to about 8 mL / min / 1.73m2, from about -3 to about 8 mL / min / 1.73m2, from about -2.5 to about 8 mL / min / 1.73m2, from about -2 to about 8 mL / min / 1.73m2, from about -1 to about 8 mL / min / 1.73m2, from about 0.5 to about 8 mL / min / 1.73m2, from about 1 to about 8 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4.5 to about 5 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, from about -3.5 to about 5 mL / min / 1.73m2, from about -3 to about 5 mL / min / 1.73m2, from about -2.5 to about 5 mL / min / 1.73m2, from about -2 to about 5 mL / min / 1.73m2, from about -1 to about 5 mL / min / 1.73m2, from about 0.5 to about 5 mL / min / 1.73m2, from about 1 to about 5 mL / min / 1.73m2, from about -5 to about 4 mL / min / 1.73m2, from about -4.5 to about 4 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3.5 to about 4 mL / min / 1.73m2, from about -3 to about 4 mL / min / 1.73m2, from about -2.5 to about 4 mL / min / 1.73m2, from about -2 to about 4 mL / min / 1.73m2, from about -1 to about 4 mL / min / 1.73m2, from about 0.5 to about 4 mL / min / 1.73m2, from about 1 to about 4 mL / min / 1.73m2, from about -5 to about 3 mL / min / 1.73m2, from about -4.5 to about 3 mL / min / 1.73m2, from about -4 to about 3 mL / min / 1.73m2, from about -3.5 to about 3 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, from about -2.5 to about 3 mL / min / 1.73m2, from about -2 to about 3 mL / min / 1.73m2, from about -1 to about 3 mL / min / 1.73m2, from about 0.5 to about 3 mL / min / 1.73m2, or from about 1 to about 3 mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2. In someembodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -4 to about 5 mL / min / 1.73m2. In some embodiments, stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -4 to about 3 mL / min / 1.73m2.

[0420] In some embodiments, LS mean change from baseline in eGFR is measured from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 30 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 1 year after the administering, or from baseline to about 2 years after the administering. In some embodiments, the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

[0421] 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.

[0422] 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.

[0423] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0424] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is O-linked glycosylation.

[0425] 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 about 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 about 90% to SEQ ID NO: 10.

[0426] 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 about 95% to SEQ ID NO: 9.

[0427] 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 about 95% to SEQ ID NO: 10.

[0428] 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 about 99% to SEQ ID NO: 9.

[0429] 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 about 99% to SEQ ID NO: 10.

[0430] 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 about 95% to SEQ ID NO: 11.

[0431] 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 about 95% to SEQ ID NO: 14.

[0432] 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 about 95% to SEQ ID NO: 12.

[0433] 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, 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.

[0434] 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 1 O’8M or a greater affinity, and wherein the affinity is measured by a standard Biacore assay.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof further comprises an Fc domain.

[0439] 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.

[0440] 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 IgGl antibody.

[0441] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject receives background IgAN medication(s).

[0442] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background IgAN medication(s) is one or more selected from the group consisting of a renin-angiotensin-aldosterone system (RAAS) blocking agent, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), endothelin receptor antagonist (ERA), mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 inhibitor (SGLT2- I), hydroxychloroquine, statins, omega-3 fish oil, and dipyridamole. In some embodiments, the background IgAN medication is a RAAS blocking agent (e.g., ACE-I and / or ARB). In some embodiments, the background IgAN medication is an angiotensin converting enzyme inhibitor (ACE-I). Examples of ACE-I include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. In some embodiments, the background IgAN medication is an angiotensin receptor blocker (ARB). Examples of ARBs include, but are not limited to, azilsartan medoxomil, candesartan, eprosartan mesylate, irbesartan, losartan, olmesartan, telmisartan, and valsartan. In some embodiments, the background IgAN medication is a sodium-glucose cotransporter 2 inhibitor (SGLT2-I).Examples of SGLT2-I include, but are not limited to, bexaglifloxin, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Examples of ERA agents include, but are not limited to, BQ- 123, darusentan, atrasentan, sitaxentan, ambrisentan, macitentan, avosentan, zibotentan, BQ-788, bosentan, tezosentan, aprocitentan, and sparsentan. Examples of MRA agents include, but are not limited to, progesterone, spironolactone, eplerenone, canrenone, drospirenone, finerenone, esaxerenone, apararenone, AZD9977, KBP-5074, and LY2623091.

[0443] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background IgAN medication(s) is administered in combination with the antibody or antigen binding fragment thereof.

[0444] 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 100mg 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 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.

[0445] 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.

[0446] 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.

[0447] 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 engineeredglycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

[0448] 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 glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

[0449] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0450] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the antibody or antigen binding fragment thereof results in less than about 20%, less than about 15%, or less than about 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 upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID-19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs).

[0451] 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 grade 1 or grade 2.

[0452] In some embodiments, the disclosure provides an isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of 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 acidsequence 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.

[0453] In some embodiments, the disclosure provides a pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treating immunoglobulin A nephropathy (IgAN) 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.

[0454] In some embodiments, the disclosure provides a medicament for treating immunoglobulin A nephropathy (IgAN) 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.

[0455] 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 CDR2having 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

[0456] 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.

[0457] 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.

[0458] In some embodiments, two mezagitamab drug product formulations have been developed, referred to as Process A and Process B as disclosed herein.

[0459] In one embodiment, the Process A mezagitamab drug product is a clear-to-opalescent, colorless solution containing AB...

Claims

1. We Claim:

1. A method of treating immunoglobulin A nephropathy (IgAN) in a subj ect 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 immunoglobulin A nephropathy (IgAN) 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:

83. 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 immunoglobulin A nephropathy (IgAN) 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 immunoglobulin A nephropathy (IgAN), the method comprisingadministering 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 immunoglobulin A nephropathy (IgAN), 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(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM; optionally wherein the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl).

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) is 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 reducing the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies in a subject diagnosed with immunoglobulin A nephropathy (IgAN), 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.

11. The method of claim 10, wherein the anti-gd-IgAl autoantibodies comprise IgA and / or IgG.

12. The method of claim 10 or 11, wherein the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies.

13. A method of reducing immunoglobulin A nephropathy (IgAN) disease activity and / or progression in a subject diagnosed with IgAN, 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.

14. The method of claim 13, wherein the IgAN disease activity and / or progression is measured by one or more assessments selected from the group consisting of:percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.); levels of serum IgG and IgM levels; levels of urine biomarkers e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc.),' change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy -Fatigue (FAC IT -Fatigue) score;Patient Global Impression of Severity (PGI-S);Patient Global Impression of Change (PGI-C);EuroQol-5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores.

15. A method of reducing proteinuria in a subject diagnosed with IgAN, 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.

16. The method of claim 15, wherein proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE); optionally wherein proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering; optionally wherein the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline to about 104 weeks after the administering in UACR.

17. The method of claim 15 or 16, wherein proteinuria is 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 proteinuria; optionally wherein proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

18. A method of achieving durable proteinuria reduction in a subject diagnosed with IgAN, 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.

19. The method of claim 18, wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR); optionally wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering.

20. The method of claim 18 or 19, wherein proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks.

21. A method of achieving a complete response on the basis of proteinuria in a subject diagnosed with IgAN, 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.

22. The method of claim 21, wherein the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE).

23. The method of claim 21 or 22, wherein the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection.

24. A method of stabilizing glomerular filtration rate (GFR) relative to baseline levels of GFR in a subject diagnosed with IgAN, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen binding fragment thereof, wherein the isolatedantibody 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.

25. The method of claim 24, wherein GFR is measured by estimated glomerular filtration rate (eGFR); optionally wherein stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering; and / or optionally wherein stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks or about 1 year after the administering and / or from baseline to about 104 weeks or about 2 years after the administering; and / or optionally wherein stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering; optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality; and / or optionally wherein stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering; and / oroptionally wherein stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering; and / or optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure; and / or optionally wherein stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2.

26. The method of claim 24 or 25, wherein GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, atleast about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering.

27. The method of any one of claims 24-26, wherein stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -3 to about 8, or from about -3 to about 4; optionally wherein the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering.

28. The method of any one of claims 24-27, wherein stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2; optionally wherein the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

29. A method of treating immunoglobulin A nephropathy (IgAN) in a subject diagnosed with IgAN, 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 a treatment cycle comprises:(a) subcutaneously administering the isolated antibody in a dosage of about 600 mg once every week (QW) for a total of 9 times; and(b), following (a), subcutaneously administering the isolated antibody in a dosage of about 600 mg once every 2 weeks (Q2W) for a total of 7 times, optionally (c), following (b), not administering the isolated antibody for a period of about 30 weeks,optionally wherein the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

30. The method of any one of the preceding claims, wherein the IgAN is primary IgAN.

31. The method of any one of the preceding claims, wherein the subject, prior to treatment with the isolated antibody or antigen binding fragment thereof, has: a 24-h urine protein excretion (UPE) of >1 g / day and / or a 24-h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g or >1.0 g / g; and / or a 24-h UPE of from about 500 to about 5000 mg / day; and / or a 24-h UPCR of from about 0.5 to about 3 g / g; and / or an estimated glomerular filtration rate (eGFR) of >30 mL / min / 1.73 m2, optionally an eGFR of >45 mL / min / 1.73 m2, optionally an eGFR of from about 30 to about 150 mL / min / 1.73 m2; and / or serum creatinine levels of from about 10 to about 200 pmol / L and / or from about 0.5 to about 2 mg / dL; and / orIgA levels of from about 1 to about 5.5 g / L; and / orGd-IgAl levels of from about 1,000 to about 15,500 ng / mL; and / orIgG levels of from about 7 to about 15 g / L.

32. The method of any one of the preceding claims, wherein the subject is diagnosed with IgAN by a biopsy performed <10 years ago.

33. The method according to any one of the preceding claims, wherein the subject is diagnosed with IgAN from about 0.1 to about 30 years ago; optionally from about 1 to about 10 years ago.

34. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof is administered once every week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

35. The method of any one of the preceding claims, wherein a treatment cycle comprises (a) subcutaneously administering the isolated antibody once every week (QW) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times; optionally 9 times.

36. The method of claim 35, wherein the treatment cycle further comprises (b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times; optionally 7 times.

37. The method of claim 36, wherein the treatment cycle further comprises (c), following (b), not administering the isolated antibody or antigen binding fragment thereof for a period of about 10 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks; optionally about 30 weeks.

38. The method of any one of clams 35-37, wherein the treatment cycle is performed more than one time; optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

39. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in less than about 75%, less than about 50%, or less than about 25% incidence of use of a rescue therapy and / or non-permitted IgAN therapy; optionally wherein the subject has not received a rescue therapy and / or nonpermitted IgAN therapy in the previous four weeks; optionally wherein the method does not include the use of a rescue therapy and / or non-permitted IgAN therapy.

40. 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, whereinthe 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.

41. 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 about 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 about 90% 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 about 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 about 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 about 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 about 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 about 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 about 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 about 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 about 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; 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.

42. 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 IgGl antibody.

43. The method of any one of the preceding claims, wherein the subject receives background IgAN medication(s); optionally wherein the background IgAN medication(s) is one or more selected from the group consisting of renin-angiotensin-aldosterone system (RAAS) blocking agent, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), endothelin receptor antagonist (ERA), mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 inhibitor (SGLT2-I), hydroxychloroquine, statins, omega-3 fish oil, and dipyridamole.

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

45. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in less than about 20% 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 infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs; optionally wherein the TRAEs or TEAEs are selected from the group consisting of upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID- 19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs); and optionally wherein a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of grade 1 or grade 2.

46. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in: a reduction in the level of plasmablasts, plasma cells, and / or NK cells; and / or a reduction in the level of immunoglobulin(s), optionally wherein the immunoglobulin(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM, optionally wherein the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl), 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) is 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 a reduction in the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies, optionally wherein the anti-gd-IgAl autoantibodies comprise IgA and / or IgG, and optionally wherein the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies; and / or a reduction in IgAN disease activity and / or progression, optionally wherein the IgAN disease activity and / or progression is measured by one or more assessments selected from thegroup consisting of: percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.); levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc.); change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score; Patient Global Impression of Severity (PGLS), Patient Global Impression of Change (PGLC), EuroQol- 5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores; and / or a reduction in proteinuria, optionally wherein proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE); optionally wherein proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering, optionally wherein the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline to about 104 weeks after the administering in UACR; optionally wherein proteinuria is 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 proteinuria; and optionally wherein proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering; and / or durable proteinuria reduction, optionally wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein tocreatinine ratio (UPCR), optionally wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering, optionally wherein proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks; and / or a complete platelet response on the basis of proteinuria, optionally wherein the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE), and optionally wherein the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection; and / or a stabilization of glomerular filtration rate (GFR) relative to baseline levels of GFR, optionally wherein GFR is measured by estimated glomerular filtration rate (eGFR); optionally wherein stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering; optionally wherein stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks or about 1 year after the administering and / or from baseline to about 104 weeks or about 2 years after the administering; optionally wherein stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering; optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality; optionally wherein stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering; optionally wherein stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering,and / or from baseline to about 104 weeks after the administering; optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure; optionally wherein stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7 mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2; optionally wherein GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering; optionally wherein stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10,from about -3 to about 8, or from about -3 to about 4; optionally wherein the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering; optionally wherein stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2; and optionally wherein the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering.

47. 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; and optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

48. 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.

49. 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 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.

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

51. 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 immunoglobulin A nephropathy (IgAN).

52. 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 binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the isolated antibody in the treatment of primary immunoglobulin A nephropathy (IgAN) at a dosage of about 600 mg in a treatment cycle comprising:(a) subcutaneously administering the isolated antibody once every week (QW) for a total of 9 times; and(b), following (a), subcutaneously administering the isolated antibody once every 2 weeks (Q2W) for a total of 7 times, optionally (c), following (b), not administering the isolated antibody for a period of about 30 weeks, and optionally wherein the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

53. The unit dosage form of claim 51 or 52, 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.

54. The unit dosage form of any one of claims 51-53, 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 about 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 about 90% to SEQ ID NO: 10; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least about 95% to SEQ ID NO: 10; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least about 99% to SEQ ID NO: 9, and / or the variable light chain region comprises an amino acid sequence having an identity of at least about 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 about 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 about 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 about 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 about 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.

55. The unit dosage form of any one of claims 51-54, 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 IgGl antibody.

56. The unit dosage form of any one of claims 51-55, wherein the isolated antibody or antigen binding fragment thereof is used in combination with one or more background IgAN medication(s); optionally wherein the background IgAN medication(s) is one or more selected from the group consisting of renin-angiotensin-aldosterone system (RAAS) blocking agent, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), endothelin receptor antagonist (ERA), mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 inhibitor (SGLT2-I), hydroxychloroquine, statins, omega-3 fish oil, and dipyridamole.

57. The unit dosage form of any one of claims 51-56, wherein administering the isolated antibody or antigen binding fragment thereof results in less than about 20% 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 infectious TEAEs, opportunistic infectious TEAEs, hypersensitivity TEAEs, and anaphylaxis TEAEs; optionally wherein the TRAEs or TEAEs are selected from the group consisting of upper respiratory tract infection, pyrexia, oropharyngeal pain, cytokine release syndrome, headache, injection site erythema, COVID- 19, nasopharyngitis, seasonal allergy, neutrophil count decreased, pain, influenza, tonsillitis, cough, infection, opportunistic infection, dermatitis contact, hypotension, urticaria, and infusion-related reactions (IRRs); and optionally wherein a TRAE or TEAE resulting from administering the isolated antibody or antigen binding fragment thereof has a maximum intensity of grade 1 or grade 2.

58. The unit dosage form of any one of claims 51-57, 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; and optionally wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

59. The unit dosage form of any one of claims 51-58, wherein the IgAN is primary IgAN.

60. The unit dosage form of any one of claims 51-59, wherein the unit dosage form is administered to a subject having: a 24-h urine protein excretion (UPE) of >1 g / day and / or a 24-h urine protein-to-creatinine ratio (UPCR) of >0.8 g / g or >1.0 g / g; and / or a 24-h UPE of from about 500 to about 5000 mg / day; and / or a 24-h UPCR of from about 0.5 to about 3 g / g; and / or an estimated glomerular filtration rate (eGFR) of >30 mL / min / 1.73 m2, optionally >45 mL / min / 1.73 m2, optionally an eGFR of from about 30 to about 150 mL / min / 1.73 m2; and / orserum creatinine levels of from about 10 to about 200 pmol / L and / or from about 0.5 to about 2 mg / dL; and / orIgA levels of from about 1 to about 5.5 g / L; and / orGd-IgAl levels of from about 1,000 to about 15,500 ng / mL; and / orIgG levels of from about 7 to about 15 g / L.

61. The unit dosage form of any one of claims 51-60, wherein the unit dosage form is administered to a subject diagnosed with IgAN by a biopsy performed <10 years ago.

62. The unit dosage form of any one of claims 51-61, wherein the unit dosage form is administered to a subject diagnosed with IgAN from about 0.1 to about 30 years ago; optionally from about 1 to about 10 years ago.

63. The unit dosage form of any one of claims 51-62, wherein the isolated antibody or antigen binding fragment thereof is administered once every week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

64. The unit dosage form of any one of claims 51-63, wherein the isolated antibody or antigen binding fragment thereof is administered in a treatment cycle comprising (a) subcutaneously administering the isolated antibody once every week (QW) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times; optionally 9 times.

65. The unit dosage form of claim 64, wherein the treatment cycle further comprises(b), following (a), subcutaneously administering the isolated antibody or antigen binding fragment thereof once every 2 weeks (Q2W) at least 1 time, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, or at least 16 times; optionally 7 times.

66. The unit dosage form of claim 65, wherein the treatment cycle further comprises(c), following (b), not administering the isolated antibody for a period of about 10 weeks, about15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks; optionally about 30 weeks.

67. The unit dosage form of any one of claims 63-66, wherein the treatment cycle is performed more than one time, optionally wherein the treatment cycle is performed about every six months, about every twelve months, about every eighteen months, or about every twenty four months.

68. The unit dosage form of any one of claims 51-67, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

69. The unit dosage form of any one of claims 51-68, 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 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.

70. The unit dosage form of any one of claims 51-69, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

71. The unit dosage form of any one of claims 51-70, wherein administering the unit dosage form results in: a reduction in the level of plasmablasts, plasma cells, and / or NK cells; and / or a reduction in the level of immunoglobulin(s), optionally wherein the immunoglobulin(s) is one or more immunoglobulin selected from the group consisting of IgA, IgG, and IgM, optionally wherein the immunoglobulin comprises galactose-deficient IgAl (gd-IgAl), 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) is reduced by at least about 10%, atleast 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 a reduction in the level of anti-galactose-deficient IgAl (anti-gd-IgAl) autoantibodies, optionally wherein the anti-gd-IgAl autoantibodies comprise IgA and / or IgG, and optionally wherein the anti-gd-IgAl autoantibodies 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 anti-gd-IgAl autoantibodies; and / or a reduction in IgAN disease activity and / or progression, optionally wherein the IgAN disease activity and / or progression is measured by one or more assessments selected from the group consisting of: percent change in proteinuria from baseline based on a 24-hr urine protein to creatinine ratio (UPCR); change from baseline in estimated glomerular filtration rate (eGFR); change from baseline in estimated glomerular filtration rate (eGFR) slope; annualized total eGFR slope; a complete response (CR) on the basis of proteinuria assessment; presence or absence of hematuria; change from baseline in immune cell subsets by flow cytometry; levels of serum biomarkers of disease activity (such as gd-IgAl, anti-gd-IgAl antibodies, immune complexes, complement, cytokines, etc.), levels of serum IgG and IgM levels; levels of urine biomarkers (e.g., creatinine normalized complement levels, e.g., sC5b-9, C3, C4, etc.), change in levels of vaccine-protective antibodies (e.g., measles, mumps, rubella, diphtheria, tetanus); use of rescue therapy and / or non-permitted IgAN therapy; change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score; Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), EuroQol- 5 Dimensions-5 levels (EQ-5D-5L) utility index; and visual analogue scale (VAS) scores; and / or a reduction in proteinuria, optionally wherein proteinuria is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR) (e.g., 24-h UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE); optionally wherein proteinuria is measured by a change in proteinuria levels as assessed by 24-hr UPCR from baseline to about 36 weeks after the administering, optionally wherein the proteinuria is albuminuria, and the albuminuria is measured by a change from baseline to about 104 weeks after the administering in UACR; optionally wherein proteinuria is 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 proteinuria; and optionally wherein proteinuria is reduced for at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering; and / or durable proteinuria reduction, optionally wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR), optionally wherein durable proteinuria reduction is measured by a change from baseline in proteinuria levels as assessed by 24-hr urine protein to creatinine ratio (UPCR) from baseline to about 104 weeks after the administering, optionally wherein proteinuria reduction is durable for at least about 1 week, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, at least about 36 weeks, at least about 42 weeks, at least about 48 weeks, at least about 52 weeks, at least about 54 weeks, at least about 60 weeks, at least about 66 weeks, at least about 72 weeks, at least about 78 weeks, at least about 84 weeks, at least about 90 weeks, at least about 96 weeks, at least about 102 weeks, or at least about 104 weeks; and / or a complete platelet response on the basis of proteinuria, optionally wherein the complete response is measured by one or more measurements selected from the group consisting of urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), and urine protein excretion (UPE), and optionally wherein the complete response is defined as UPCR <0.3 mg / mg and UPE <0.3 g / day based on a 24-hour urine collection; and / or a stabilization of glomerular filtration rate (GFR) relative to baseline levels of GFR, optionally wherein GFR is measured by estimated glomerular filtration rate (eGFR); optionally wherein stabilizing GFR is measured by a rate of change in eGFR from baseline to about 52 weeks after the administering, from about 12 weeks to about 52 weeks after the administering, from baseline to about 104 weeks after the administering, from baseline to about 2 years after the administering, and / or from about 12 weeks to about 104 weeks after the administering;optionally wherein stabilizing GFR is measured by a total eGFR slope from baseline to about 52 weeks or about 1 year after the administering and / or from baseline to about 104 weeks or about 2 years after the administering; optionally wherein stabilizing GFR is measured by a chronic eGFR slope from baseline to about 1 year after the administering and / or from baseline to 2 years after the administering; optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of at least one of a 30% or more reduction in eGFR, eGFR<15mL / min / 1.73m2, dialysis, kidney transplant, and all-cause mortality; optionally wherein stabilizing GFR is measured by a change in eGFR from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering; optionally wherein stabilizing GFR is measured by a change in eGFR slope from baseline to about 52 weeks after the administering, and / or from baseline to about 104 weeks after the administering; optionally wherein stabilizing GFR is measured by time from baseline to a first occurrence of an outcome selected from the group consisting of sustained decline in eGFR of >30% from baseline to at least about 4 weeks after the administering; sustained eGFR <15 mL / min / 1.73 m2over at least about 4 weeks; initiation of maintenance dialysis defined as dialysis performed for at least about 4 weeks; receipt of kidney transplant; and death from kidney failure; optionally wherein stabilizing GFR is measured as a mean change in eGFR from baseline to about 12 weeks after the administering, from baseline to about 18 weeks after the administering, from baseline to about 22 weeks after the administering, from baseline to about 24 weeks after the administering, from baseline to about 36 weeks after the administering, from baseline to about 42 weeks after the administering, from baseline to about 48 weeks after the administering, from baseline to about 52 weeks after the administering, from baseline to about 54 weeks after the administering, from baseline to about 60 weeks after the administering, from baseline to about 64 weeks after the administering, from baseline to about 66 weeks after the administering, from baseline to about 72 weeks after the administering, from baseline to about 74 weeks after the administering, from baseline to about 78 weeks after the administering, from baseline to about 84 weeks after the administering, from baseline to about 88 weeks after the administering, from baseline to about 90 weeks after the administering, from baseline to about 96 weeks after the administering, from baseline to about 100 weeks after the administering, from baseline to about 104 weeks after the administering of from about -10 to about 10 mL / min / 1.73m2, from about -9 to about 9 mL / min / 1.73m2, from about -8 to about 8 mL / min / 1.73m2, from about -7 to about 7mL / min / 1.73m2, from about -6 to about 6 mL / min / 1.73m2, from about -5 to about 5 mL / min / 1.73m2, from about -4 to about 4 mL / min / 1.73m2, from about -3 to about 3 mL / min / 1.73m2, or from about -2 to about 2 mL / min / 1.73m2; optionally wherein GFR is stabilized for at least about 24 weeks, at least about 28 weeks, 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, at least about 52 weeks, at least about 56 weeks, at least about 60 weeks, at least about 64 weeks, at least about 68 weeks, at least about 72 weeks, at least about 76 weeks, at least about 80 weeks, at least about 84 weeks, at least about 88 weeks, at least about 92 weeks, at least about 96 weeks, at least about 100 weeks, or at least about 104 weeks after the administering; optionally wherein stabilizing GFR is measured as a least squares (LS) mean annualized eGFR slope of from about -5 to about 10, from about -3 to about 8, or from about -3 to about 4; optionally wherein the LS mean annualized eGFR slope is measured from baseline to 48 weeks after the administering; optionally wherein stabilizing GFR is measured as a least squares (LS) mean change from baseline in eGFR of from about -5 to about 10 mL / min / 1.73m2, from about -4 to about 5 mL / min / 1.73m2, or from about -4 to about 3 mL / min / 1.73m2; and optionally wherein the LS mean change from baseline in eGFR is measured from baseline to 48 weeks after the administering; and / or less than about 75%, less than about 50%, or less than about 25% incidence of use of a rescue therapy and / or non-permitted IgAN therapy; optionally wherein the subject has not received a rescue therapy and / or non-permitted IgAN therapy in the previous four weeks; optionally wherein the unit dosage form is not administered in combination with a rescue therapy and / or non-permitted IgAN therapy.

72. An isolated human anti-CD38 antibody or antigen binding fragment thereof for use in the treatment of 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.

73. A pharmaceutical composition comprising an isolated human anti-CD38 antibody or antigen binding fragment thereof for treating immunoglobulin A nephropathy (IgAN) 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.

74. A medicament for treating immunoglobulin A nephropathy (IgAN) 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.

75. 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.

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