Anti-CD38 antibodies and their uses

Abstract

A method of treating a subject suffering from an immune-mediated disease (e.g., IgA nephropathy, primary membranous nephropathy, an antibody-mediated rejection, lupus nephritis, systemic lupus erythematosus (SLE), Graves' Disease, Myasthenia Gravis, Anti-PLA2R positive Membranous Glomerulonephritis (aMN), Pemphigus, Sjögren's syndrome, and / or Anti-NMDA encephalitis) by administering to the subject a regimen of at least five doses of felzartamab and measuring a level of CD19+CD27hiCD38hi plasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hi plasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject.

Description

Atty. Docket No. 2790B-1 18WO1ANTI-CD38 ANTIBODIES AND THEIR USESCross-Reference to Related Application

[0001] This application claims priority benefit of U.S. provisional application numbers: 63 / 704,898, filed Ocotober 8, 2024; 63 / 720,601 , filed November 14, 2024; 63 / 744,692, filed January 13, 2025; 63 / 752,043, filed January 31 , 2025; and 63 / 799,844, filed May 5, 2025, the disclosures of each of which are incorporated herein by reference in their entireties.Sequence Listing

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 7, 2025 is named 2790B-1 18WO1 .XML and is 12,288 bytes in size.Field of the Invention

[0003] The present invention relates to felzartamab (MOR202) or an antibody fragment thereof for use in the treatment and / or prophylaxis of immune-mediated diseases.BackgroundAnti-CD20 resistant B cell depletion

[0004] B cell depletion with the anti-CD20 antibody rituximab (RTX) is widely used for the treatment of autoimmune diseases including IC-mediated diseases. However, the proportion of patients achieving a long-term remission after treatment by anti-CD20 antibody varies greatly depending on the disease and clinical context and many patients frequently relapse after anti- CD20 B cell depletion therapy (Lafayette et al. (2017) J Am Soc Nephrol. 28(4):1306-13).

[0005] Three scenarios may explain these relapses: (i) a new tolerance breakdown may recruit newly formed naive B cells into the autoimmune repertoire; (ii) autoreactive memory B cells that were resistant to RTX may be reactivated and (iii) antibody-secreting long-lived plasma cells leading to immune complexes survived in their niches.IgA nephropathy

[0006] IgA nephropathy (IgAN), also known as Berger's disease is the most prevalent chronic glomerular disease worldwide. The disease derives its name from deposits of immunoglobulin A (IgA) in the glomerular mesangium. The subclass lgA1 is one of the two immunoglobulin types (the other is IgD) that is O-glycosylated on a number of serine and threonine residues in the proline-rich hinge region. Aberrant glycosylation of Ig A1 appears to lead to polymerization of Ig A1 molecules in certain tissues, especially the glomerular mesangium. The triggers and the site for production of galactose-deficient lgA1 (Gd-lgA1 ) are not known In IgAN. Plasma cells, including long-lived plasma cells, are likely the main source of the corresponding antibodies against Gd- lgA1 . A central finding in IgAN patients is the presence of circulating and glomerular ICs comprised of Gd-lgA1 and autoantibody (mainly IgG) directed against the hinge region O-glycans, and C3. These ICs are nephrogenic and contribute to glomerular inflammation and mesangialAtty. Docket No. 2790B-1 18WO1 proliferation. Ultimately, activation of the renin angiotensin system (RAS) and the complement system contributes to glomerulosclerosis and tubulo-interstitial fibrosis, leading to loss of renal function. About 25-30% of patients with IgAN progress to end-stage renal disease (ESRD) within 20-25 years of presentation (KDIGO Clinical Practice Guideline on Glomerular Diseases, 2020). Major risk factors for progression to ESRD are persistent proteinuria, hypertension, and reduced glomerular filtration rate (GFR) (Fellstroem etal. (2017) Lancet 389(10084) :2117-27).

[0007] T reatment of IgAN is focused on non-immunosuppressive strategies as standard of care, to slow the rate of disease progression: blood pressure control, inhibition of the RAS, and lifestyle modification (i.e. weight reduction, exercise, smoking cessation, and dietary sodium restriction etc.). Multiple studies demonstrate that sustained proteinuria is the most powerful predictor of long-term kidney outcome and that reduction in proteinuria is associated with improved kidney outcome regardless of the nature of the intervention, thereby establishing reduction in proteinuria as a valid surrogate marker of improved kidney outcome in IgAN (Thompson A et al. (2019) Clin J Am Soc Nephrol; 14: 469-481 ). Typical target for proteinuria reduction in these trials was < 1 g / day. Thus, reduction of proteinuria to this level is a reasonable target for interventions in patients with IgAN who remain at high risk of progressive chronic kidney disease. For patients with persistent proteinuria of more than 1 g / day and GFR greater than 50 mL / min per 1 .73 m2despite 6 months of optimized RAS blockade, 6 months of treatment with high-dose systemic corticosteroids is suggested. However, clinical benefit is not established and use of high-dose systemic corticosteroids is associated with increased risks of adverse events and sequelae such as serious infections, hypertension, weight gain, diabetes, and osteoporosis (Pozzi C (2016) J Nephrol. (1):21-5). Systemic corticosteroids should be given with extreme caution or avoided entirely in patients with GFR less than 30 mL / min, diabetes, obesity, latent infections (e.g. viral hepatitis, tuberculosis), secondary disease (e.g. cirrhosis), active peptic ulceration or uncontrolled psychiatric disease. Clinical trials for treatment of IgAN with azathioprine, calcineurin inhibitors and rituximab have not provided documented evidence of efficacy (Pozzi (2016) J Nephrol. (1 ) :21 - 25; Rauen ef al. (2020) Kidney Int. 98(4): 1044-52). Mycophenolate mofetil (MMF) reportedly reduced proteinuria and stabilized GFR in Chinese patients (Tang et al. (2005) Kidney Int. 68:802-12., but not in Caucasian patients (Frisch et al (2005) Nephrol Dial Transplant 20:2 39- 45).

[0008] Although evidence for RTX efficacy in some glomerular diseases is promising, early results in IgAN are not encouraging. For example, in a randomized, controlled trial of rituximab in IgAN with proteinuria and renal dysfunction (NCT00498368) treatment with RTX failed to significantly reduce proteinuria or benefit renal function (Lafayette etal. (2017) J Am Soc Nephrol. 28(4): 1306-13).Atty. Docket No. 2790B-1 18WO1Lupus nephritis

[0009] Lupus nephritis (LN) is an inflammation of the kidneys that occurs as consequence of systemic lupus erythematosus (SLE) and occurs in 20% to 60% of patients with SLE. Histopathologically, LN is a glomerulonephritis with IC deposits as result of formation of autoantibodies against nuclear antigens. Further pathological changes may include tubulointerstitial nephritis and vascular changes with IC deposits in the vessels and microangiopathy. Based on disease severity, LN can be classified in at least six categories. Class I disease (minimal mesangial glomerulonephritis) appears with normal clinical urinalysis and an unobtrusive appearance under light microscopy, but reveals mesangial deposits when analyzed by electron microscopy. Class II disease (mesangial proliferative glomerulonephritis) is characterized by mesangial hypercellularity and matrix expansion. Haematuria with or without proteinuria may be present. Class III disease (focal glomerulonephritis) is noted by sclerotic lesions involving less than 50% of the glomeruli, which can be segmental or global with endocapillary or extracapillary proliferative lesions. Clinically, haematuria, proteinuria, hypertension, and elevated serum creatinine are present. Class IV disease (diffuse proliferative nephritis) is the most severe, and the most common subtype. More than 50% of glomeruli are involved that show segmental or global, with endocapillary or extracapillary proliferative lesions. Clinically, haematuria and proteinuria are present, frequently with nephrotic syndrome, hypertension, hypocomplementemia, elevated anti-dsDNA antibody titers and elevated serum creatinine. Class V disease (membranous glomerulonephritis) is characterized by diffuse thickening of the glomerular capillary wall. Clinically, stage V presents with signs of nephrotic syndrome. Stage V can also lead to thrombotic complications such as renal vein thromboses or pulmonary emboli. Class VI, or advanced sclerosing LN is represented by global sclerosis involving more than 90% of glomeruli. This stage is characterized by slowly progressive kidney dysfunction.

[0010] Drug regimens prescribed for LN include cyclophosphamide with corticosteroids, MMF, azathioprine with corticosteroids, and tacrolimus. Cyclophosphamide-containing regimens have a high incidence of adverse events, such as serious infection, hair-loss, and infertility. Furthermore, response to treatment is often slow, and even if remission is achieved, the risk of relapse remains considerable. MMF has emerged as a less toxic alternative to cyclophosphamide and it appears that MMF and cyclophosphamide with corticosteroids are equally effective in achieving remission of the disease. Lupus nephritis (LN) is often resistant to standard of care immunosuppression and relapses are common after achieving clinical remission.

[0011] Overall, LN remains a serious condition, leading to end-stage kidney disease in 15% of patients after 10 years. Improved treatment options (e.g. steroid sparing) are highly needed for patients suffering from LN.Systemic lupus erythematosus (SLE)Atty. Docket No. 2790B-1 18WO1

[0012] SLE is a multi-gene autoimmune disorder with a prevalence of about 50 cases per 100,000 people with women more frequently affected than men. The central immunological disturbance in SLE patients is an inappropriate activation and proliferation of autoreactive memory B cells leading to an expansion of antibody secreting cells and the production of a variety of autoantibodies. The dominant self-antigens in SLE are nuclear components like DNA or ribonucleoproteins (RNPs) and the autoantibodies reactive to these antigens are of high-affinity, somatically mutated and of the IgG isotype. SLE patients show high levels of serum antinuclear antibodies (ANAs). Autoantibodies to cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens may also be present. In SLE, many of these autoantibodies lead to the formation of ICs that appear to be directly pathogenic following deposition in several tissues.Graves’ Disease (Morbus Basedow)

[0013] Graves’ Disease also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. Grave’s disease will develop in about 0.5% of males and 3% of females (Burch & Cooper (2015) JAMA 314(23):2544-54). It frequently results in and is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). Symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea, unintentional weight loss, thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. The direct cause of Graves’ disease are autoantibodies directed against the receptor for thyroid-stimulating hormone (thyroid-stimulating hormone receptor (TSHR)). Autoantibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced. TSHR autoantibodies mimic TSH and activate TSHR in an unregulated manner, thereby causing hyperthyroidism. The treatment options for Graves' disease include antithyroid (thionamide) drugs, thyroid ablation by radioiodine, and surgery (thyroidectomy). The challenge in treating Graves’ Disease remains however, to inhibit the development or ongoing production of TSHR autoantibodies.Myasthenia Gravis (MG)

[0014] MG affects 50 to 200 per million people. It is newly diagnosed in three to 30 per million people each year. MG is a long-term neuromuscular AD that leads to varying degrees of skeletal muscle weakness and abnormal fatigability and is caused by the presence of autoantibodies reactive to components of the postsynaptic muscle endplate localized at the neuromuscular junction (junction between nerve and muscle). In particular, these autoantibodies block or destroy nicotinic acetylcholine receptors, which in turn prevents nerve impulses from triggering muscle contractions. Other autoantibodies are found against a related protein called MuSK, a musclespecific kinase and LRP4, Agrin and titin proteins. Generally, MG is treated with drugs known as acetylcholinesterase inhibitors such as neostigmine and pyridostigmine. Immunosuppressants,Atty. Docket No. 2790B-1 18WO1 such as prednisone or azathioprine are also often used. In certain cases, the surgical removal of the thymus may improve symptoms of the disease. Plasmapheresis and high dose intravenous immunoglobulin (I VIG) may be used during sudden flares of the condition to remove putative autoantibodies from the circulation or to dilute and bind the circulating antibodies, respectively. Both of these treatments have relatively short-lived benefits, typically measured in weeks, and often are associated with high costs. If the breathing muscles become significantly weak, mechanical ventilation may be required.Anti-PLA2R positive Membranous Glomerulonephritis (aMN)

[0015] aMN, historically often referred to as Idiopathic Membranous Glomerulonephritis or idiopathic membranous nephropathy (IMN) is a primary membranous nephropathy and the leading cause of nephrotic syndrome in adults (Ronco & Debiec (2015) Lancet 385(9981 ):1983- 92). About 80% of membranous nephropathies are idiopathic, while 20% are related to other diseases or exposures. The overall global incidence is estimated at 1 .2 per 100,000 per year. Although the disease usually progresses slowly, approximately 30% to 40% of patients eventually develop End Stage Renal Disease. Patients with MN remaining nephrotic are at increased risk for thromboembolic and cardiovascular events. However, although not all aspects of the pathogenesis of MN are understood, the disease can no longer be considered idiopathic. M-type phospholipase A2 receptor (PLA2R), a transmembrane protein expressed on podocytes, has been defined as the major autoantigen of MN (Beck et al. (2009) N Engl J Med. 361 (1 ):11-21 ). Autoantibodies binding to the PLA2R antigen are highly specific to primary MN. Recent investigations revealed the presence of anti-PLA2R autoantibodies in approximately 75% of patients with IMN that considerably correlate with disease activity (Bomback (2018) Clin J Am Soc Nephrol. 13(5) :784— 86). The fact that the disease defining glomerular basement changes contain both PLA2R protein as well as antibody complex deposits provides evidence that anti- PLA2R antibodies play a major causative role in MN. An additional 5% of patients who are negative for anti-PLA2R antibodies have antibodies against another podocyte antigen — the thrombospondin type-1 domain-containing 7A (Tomas et al. (2014) N Engl J Med 371 :2277-87). In rare neonatal MN cases, neutral endopeptidase (NEP) located on the foot process membrane of the podocytes and the brush border of renal tubules has been identified as the relevant antigen (Ronco et al. (2005) J Am Soc Nephrol. 16:1205-13). Taken together, about 80% of patients with IMN have antibodies directed against a specific, identifiable podocyte antigen. Symptoms of membranous nephropathy include, but are not limited to swelling in the legs and ankles, increased protein in urine, edema, hypoalbuminemia, elevated serum lipids, in particular high cholesterol. Thus, autoimmune membranous nephropathy is an immune-mediated glomerular disease that is characterized by the presence of anti-PLA2R autoantibodies and / or anti-THSD7A autoantibodies. In neonatal autoimmune MN, autoantibodies against NEP are present which were transferred from the mother.Atty. Docket No. 2790B-118WO1Pemphigus

[0016] Pemphigus vulgaris is an autoimmune intra-epidermal muco-cutaneous disorder of the skin and mouth resulting in blister formation. Lesions occur with an increased incidence of 0.5 to 3.2 cases per 100,000 people every year. These lesions predominantly occur between age 40 to 60 with equal gender predilection. Pemphigus patients present with circulating autoantibodies against pemphigus antigens (desmoglein 3, desmoglein 1 , desmocollins, plakoglobin) on epithelial keratinocytes. Disruption of these antigens by the antigen-autoantibody reaction has a marked effect on the integrity of the epidermis resulting in cellular detachment (acantholysis), suprabasilar clefting and subsequent bullae formation. Binding of the autoantibodies to keratinocytes also results in release of protease and plasminogen activator (converts plasminogen to plasmin) from the cells further amplifying acantholysis. Treatment options for high-grade lesions include systemic glucocorticoids and combinations of corticosteroids, immunosuppressive agents, pulse therapy, photophoresis and plasmaphoresis.Sjogren’s syndrome

[0017] Sjogren’s syndrome is a systemic autoimmune disease characterized by focal infiltration of lymphocytes into the exocrine glands and lacrimal glands resulting in dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca), respectively. In Sjogren’s syndrome, the presence of lesions are associated with chronic inflammatory infiltrates with release of autoantibodies against the salivary glandular epithelial cells. Other autoantibodies in Sjogren’s syndrome are directed against ribonucleoprotein autoantigens Ro / SS-A and La / SS-B, coiled-coil-containing molecules, members of golgin family, poly (ADP) ribose polymerase (PARP) and type 3 muscarinic receptor. At present, a targeted treatment of Sjogren’s syndrome is not available and current therapeutic approaches are only symptomatic by treating the sicca and fatigue symptoms, for example with pilocarpine, bromhexine and hydroxychloroquine, respectively.Anti-NMDA encephalitis

[0018] The most common antibody-mediated acute autoimmune encephalitis is the anti-N- methyl-D-aspartate-receptor (NMDAR) encephalitis (Granerod et al. (2010) Lancet Infect Dis 10:835-44). Its incidence is estimated at 3-5 per 1.000.000 population and year. Anti-NMDA encephalitis represents a model disease for a group of syndromes characterized by detection of autoantibodies targeting synaptic structures. Anti-NMDAR antibodies are most common, followed by antibodies against leucine-rich glioma inactivated-1 (LGI1 ) The contactin-associated protein like 2 (Caspr2), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA)-A and -B receptors, dipeptidyl-peptidase-like protein-6 (DPPX), and glycine receptor (GlyR) antibodies are other examples of neuronal cell-surface antibodies. Anti-NMDAR encephalitis preferentially occurs in young adults and children, predominantly women (80%). Approximately 70% of the patients develop prodromal symptoms (e.g. headache, fever, rapid change of behavior, anxiety, hallucinations, and psychosis).Atty. Docket No. 2790B-1 18WO1 Abnormal movements (e.g. orofacial dyskinesias, chorea, and stereotyped movements) and decrease of consciousness, coma, and severe global autonomic dysregulation (sometimes leading to hypoventilation and asystolia) ensue. Seizures and status epilepticus may occur at any stage of the disease. Approximately, 50% of patients respond well to IVIGs, steroids, or plasma exchange and the other 50% require rituximab alone or in combination with cyclophosphamide. However, in some patients, recovery is incomplete, may take years, and mortality due to intensive care complications can be as high as 7%

[0019] The presence of pathogenic autoantibodies in the autoantibody-mediated autoimmune diseases exemplified above is a consequence of a failure or breakdown of central and / or peripheral B cell tolerance toward the corresponding self-antigens.Summary of the Invention

[0020] The present disclosure provides a method of treating a subject suffering from IgA nephropathy, the method comprising administering to the subject a regimen of at least five doses of felzartamab over six months, and measuring a level of CD19+CD27hiCD38hi plasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hi plasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months.

[0021] In some aspects, a method according to the present disclosure includes measuring a baseline level of CD19+ B lymphocytes of the subject before the administering step, comparing the level of CD19+ B lymphocytes in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level of CD19+ B lymphocytes in the blood sample is not more than 10% less than the baseline level.

[0022] In some aspects, a method according to the present disclosure includes measuring a baseline level of CD19+CD27hiCD38hiplasmablasts of the subject before the administering step, comparing the level of CD19+CD27hiCD38hi plasmablasts in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level of CD19+CD27hiCD38hiplasmablasts in the blood sample is at least 10% less than the baseline level.

[0023] The present disclosure provides a method of preserving vaccine response in a subject having primary membranous nephropathy and having received a vaccine by administering 650 mg to 1625 mg felzartamab to the subject.

[0024] The present disclosure provides a method of treating a subject suffering from antibody- mediated rejection, the method comprising administering to the subject a regimen of at least five doses of felzartamab over six months, and measuring a level of donor-specific antibody, a level of CD16bright NK-cells, donor-derived cell-free DNA, levels of torque teno virus (TTV) Viremia, or any combination thereof, in a blood sample taken from the subject after the six months.

[0025] The present disclosure provides a method of reducing glomerulitis in a subject having received a kidney transplant, the method comprising administering at least five doses ofAtty. Docket No. 2790B-1 18WO1 felzartamab over six months, wherein each of the doses is 650 mg to 1625 mg felzartamab. In some aspects, the method includes obtaining a biological sample from the subject and measuring inflammation of glomeruli in the biological sample. In some aspects, the method includes measuring a level of CD19+CD27hiCD38hiplasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hiplasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months.

[0026] The present disclosure provides a method of reducing peritubular capillaritis in a subject having received a kidney transplant, the method comprising administering at least five doses of felzartamab over six months, wherein each of the doses is 650 mg to 1625 mg felzartamab. In some aspects, the method includes obtaining a biological sample from the subject and measuring lesions in peritubular capillaries in the biological sample. In some aspects, the method includes measuring a level of CD19+CD27hiCD38hiplasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hiplasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months.Detailed Description of the Invention

[0027] Figure 1 shows a schematic of the IGNAZ trial study design. Each dose is shown as an arrow.

[0028] Figure 2 shows a schematic of the days in the IGNAZ trial on which samples were taken from the trial participants.

[0029] Figure 3A shows plasmablasts per microliter in the samples taken from IGNAZ trial participants six months after the first dose was administered, i.e. , at the end-of-trial (EOT). Figure 3B shows CD19+B cells per microliter in the samples taken from IGNAZ trial participants at EOT. Figure 3C shows anti-tetanus toxoid titers in the samples taken from IGNAZ trial participants at EOT. Figure 3D shows anti-tetanus toxoid titers in the samples taken from IGNAZ trial participants twenty four months after the first dose was administered, i.e., at the end-of-study (EOS). Figure 3E shows anti-SARS-CoV2 titers before and after vaccination. Figure 3F shows anti-SARS-CoV2 titers before and after SARS-CoV2 infection.

[0030] Figure 4A shows antibody titers over time in the placebo arm of the IGNAZ trial. Figure 4B shows antibody titers over time, including galactose deficient immunoglobin A1 (Gd-lgA1 ) titers, in the M3 arm of the IGNAZ trial. Figure 4C also shows antibody titers over time in the M3 arm of the IGNAZ trial, but with IgM titers instead of Gd-lgA1 titers.

[0031] Figure 5A shows the change (per protocol) in urine proteimcreatine ratios (UPGR) over time in IGNAZ trial participants. Figure 5B shows the change (per protocol) in glomerular filtration rate (eGFR) over time in IGNAZ trial participants. Figure 5C shows the change (full analysis set) in UPCR over time in IGNAZ trial participants. Figure 5D shows the change (full analysis set) in eGFR over time in IGNAZ trial participants.Atty. Docket No. 2790B-118WO1

[0032] Figure 6A shows the correlation between patient response and decrease in Gd-lgA1 titers at the end of the trial. Figure 6B shows the correlation over time. Figure 6C presents a table listing counts of patient recovery over time.

[0033] Figure 7A shows a schematic of the M-PLACE trial study design. Figure 7B shows a schematic of the New PLACE trial study design. Each trial dose is shown as an arrow.

[0034] Figure 8A shows plasmablasts per microliter in the samples taken from New Place arm 2 trial participants at EOT. Figure 8B shows plasmablasts per microliter in the samples taken from New Place arm 1 trial participants at EOT. Figure 8C shows plasmablasts per microliter in the samples taken from M-Place trial participants at EOT. Figure 8D shows CD19+B cells per microliter in the samples taken from New Place arm 2 trial participants at EOT. Figure 8E shows CD19+B cells per microliter in the samples taken from New Place arm 1 trial participants at EOT. Figure 8F shows CD19+B cells per microliter in the samples taken from M-Place trial participants at EOT.

[0035] Figure 9A shows longitudinal changes (Median %CFB + IQR) in anti-PLA2R titers across three dose regimens in PMN patients. M-PLACE C1 patients who completed 9 dose regimen (n=14) and NewPLACE patients who did not receive prohibited conmeds prior to 6 months (2 dose arm n = 9 , 5 dose arm n = 6) were included in analysis. Figure 9B boxplots show median %CFB + IQR overlaid with individual data at month 6. Figure 9C shows anti-PLA2R serum levels (median anti-PLA2R RU / mL + IQR) baseline (black) and 1 week after the first dose and prior to re-treatment dosing (gray) and 1 week after the first re-treatment dose.

[0036] Figure 10A shows anti-PLA2R titer (RU / mL) at baseline, week 1 post-treatment, and at end of treatment (month 6) for patients that received at least 2 doses of felzartamab. Figure 10B shows median reductions in pathogenic anti-PLA2R titers at week 1 . Figure 10C shows median reductions in pathogenic anti-PLA2R titers at end of treatment. Figures 10B and 10C relate to data in patients with <150 RU / mL and >150 RU / mL anti-PLA2R at baseline. Boxplots show median + IQR overlaid with individual data.

[0037] Figure 11A shows median %change from baseline + IQR of evaluable circulating antibody titers in M-PLACE cohort 1 patients who received all 9 doses of felzartamab (n = 14). Figure 11 B shows EOT (6mo) polyclonal IgG versus EOT %CFB anti-PLA2R of individual patients. Figure 11C shows EOT (6mo) anti-TT %CFB versus EOT %CFB anti-PLA2R of individual patients. In both Figures 11 B and 11C the median + IQR is marked (n=17, n=16 respectively) and the dashed line represents equivalent % change.

[0038] Figure 12 shows a trial Scheme. AMR = antibody-mediated rejection; dd-cfDNA = donor- derived cell-free DNA; DSA = donor-specific antibody; eGFR = estimated glomerular filtration rate; NK cell = natural killer cell; TTV = Torque Teno virus.

[0039] Figure 13A shows Sankey plots of the dynamics of morphologic antibody-mediated rejection (active or chronic active) as compared with no activity (chronic inactive or no rejection)Atty. Docket No. 2790B-1 18WO1 in the placebo groups across biopsy samples obtained at baseline, week 24, and week 52. Figure 13B shows Sankey plots of the dynamics of morphologic antibody-mediated rejection (active or chronic active) as compared with no activity (chronic inactive or no rejection) in the felzartamab groups across biopsy samples obtained at baseline, week 24, and week 52. Vertical stacks represent biopsy time points and include the numbers of biopsies that were performed. The bands indicate the movement of biopsy results between groups from baseline to week 52. The width of the bands is proportional to the number of cases.

[0040] Figure 14A shows the microvascular inflammation score (a sum score of glomerulitis and peritubular capillaritis) in biopsy samples according to the Banff classification at baseline, week 24, and week 52. The horizontal lines indicate medians. At 24 weeks, 7 of 1 1 patients who had received felzartamab had a microvascular inflammation score of 0 as compared with 1 of 10 patients in the placebo group. At 52 weeks, 4 of 11 patients in the felzartamab group maintained a microvascular inflammation score of 0 as compared with 0 of 10 in the placebo group. The lefthand series of dots represents placebo, while the right-hand series represents felzartamab. Figure 14B shows a molecular score reflecting the probability of antibody-mediated rejection in biopsy samples obtained at baseline, week 24, and week 52. The horizontal line in each box represent the median, the tops and bottoms of the boxes represent the upper and lower limits of the interquartile range, and the I bars represent 1.5 times the interquartile range. One patient in the placebo group had allograft loss after 14 weeks, so biopsy samples at week 24 and week 52 were not available. In addition, microvascular inflammation was not calculated for one patient at baseline and for another at week 52 in the placebo group (no grading of peritubular capillaritis because of interstitial infiltrates). Week 24 molecular data were missing for one patient in the felzartamab group. Mean differences and 95% confidence intervals between the felzartamab and placebo groups are provided for biopsy results obtained at weeks 24 and 52. For every box pair, the left-hand box represents placebo, while the right-hand box represents felzartamab.

[0041] Figure 15A shows Banff Lesion Scores (BLS) for glomerulitis. Figure 15B shows BLS for peritubular capilliaritis. Figure 15C shows BLS for glomerular double contours. Figure 15D shows BLS for chronic vasculopathy. Figure 15E shows BLS for tubular atrophy. Figure 15F shows BLS for interstitial fibrosis. Dot plots (horizontal bars indicate the medians) of BLS. Numbers of biopsies included in the analysis are indicated for each treatment arm and time point, respectively.

[0042] Figure 16A shows molecular biopsy results scores related to ‘All rejection’ (RejProb). Figure 16B shows molecular biopsy results scores related to TCMR (TCMRProb). Figure 16C shows scores reflecting injury-repair (IRRAT). Figure 16D shows scores reflecting chronic injury (ciprob). Figure 16E shows individual pathogenesis-based transcript sets reflecting NK cell burden (NKB). Figure 16F shows individual pathogenesis-based transcript sets reflecting y- interferon associated (GRIT1 ). Figure 16G shows individual pathogenesis-based transcript setsAtty. Docket No. 2790B-1 18WO1 reflecting donor-specific antibody selective transcripts (DSAST). Figure 16H shows individual pathogenesis-based transcript sets reflecting T cell associated transcripts (QCAT).

[0043] Figure 17A shows the percent change in the mean fluorescence intensity of donorspecific antibody in the two trial groups. Line plots show medians, and I bars indicate interquartile ranges. Figure 17B shows box plots of peripheral-blood CD16bright NK-cell counts. Figure 17C shows the fraction of donor-derived cell-free DNA. Figure 17D shows the number of copies of torque teno virus (TTV) (Panel D). In Panels B-D, the horizontal line in each box represents the median, the tops and bottoms of boxes represent the upper and lower limits of the interquartile range, and the I bars represent 1 .5 times the interquartile range; outliers are indicated by circles. One patient in the placebo group had allograft loss after 14 weeks, so week 24 and 52 biomarker results were unavailable. Levels of donor-specific antibody were undetectable at day 0 in three patients (two in the felzartamab group and one in the placebo group) despite detectable levels of donor-specific antibody at screening, and no TTV DNA was detected in four patients (one in the felzartamab group and three in the placebo group); no data were imputed in these analyses. For NK-cell counts and donor-derived cell-free DNA, mean differences and 95% confidence intervals between the felzartamab and placebo groups are provided for selected time points. For every box pair, the left-hand box represents placebo, while the right-hand box represents felzartamab.

[0044] Figure 18A shows renal function. Individual (thin lines) and mean eGFR slopes (thick lines) in placebo (light grey) and felzartamab arms (dark grey). Shaded areas represent 95% confidence intervals. Figure 18B shows median eGFR (placebo [n=11 ]; felzartamab [n=11 ]).

[0045] Figure 19A shows the median (IQR) percentage change from baseline in polyclonal IgA during the treatment period and follow-up of Part 1 and Part 2. Figure 19B shows the shows the median (IQR) percentage change from baseline in polyclonal IgG during the treatment period and follow-up of Part 1 and Part 2. Figure 19C shows the median (IQR) percentage change from baseline in polyclonal IgM during the treatment period and follow-up of Part 1 and Part 2. Figure 19D shows the median (IQR) percentage change from baseline in serum IgA, IgG, and IgM in the felzartamab 9-dose arm in Part 1 .

[0046] Figure 20 shows the median (IQR) percentage change from baseline in serum Gd-lgA1 during the treatment period and follow-up of Part 1 and Part 2.

[0047] Figure 21 shows the change from baseline in 24-hour urine proteimcreatinine (UPCR) in the per protocol set (PPS). *P<0.05 for LS mean difference versus placebo.

[0048] Figure 22A shows the change from baseline (as g / g) in 24-hour UPCR in the full analysis set (FAS). Figure 22B shows the change from baseline (as percentage) in 24-hour UPCR in the FAS.

[0049] Figure 23 shows the change from baseline in estimated glomerular filtration rate (eGFR) in the PPS.Atty. Docket No. 2790B-1 18WO1

[0050] Figure 24A shows the change from baseline (as g / g) in eGFR in the full analysis set (FAS). Figure 24B shows the change from baseline (as percentage) in eGFR in the FAS.

[0051] Figure 25A shows the probability of recovery to baseline in Gd-lgA1 during the study. Figure 25B shows the probability of recovery to baseline in IgA during the study. Figure 25C shows the probability of recovery to baseline in IgG during the study. Figure 25D shows the probability of recovery to baseline in IgM during the study.

[0052] Figure 26A shows the genome-wide effect of felzartamab treatment on gene expression (AAlogFC) from baseline to week 24. Figure 26B shows the genome-wide effect of felzartamab treatment on gene expression (AAlogFC) from week 24 to week 52. Figure 26C shows the genome-wide effect of felzartamab treatment on gene expression (AAlogFC) from baseline to week 52. The dots to the right of the vertical, dashed line in Figures 26A-26C represent genes significantly increased and decreased in felzartamab vs. placebo arms (p < 0.05). The dark gray circles to the left of the vertical, dashed line in Figures 26A-26C denote genes having p-value > 0.05. Functional enrichment by differentially expressed genes are included in Figures 26A-26C. Gene labels represent the top 10 genes by representation across all enrichment terms in Figures 26A-26C. Figure 26D shows the effect of felzartamab on interferon gamma (IFNG)-inducible antibody-mediated rejection (ABMR) activity genes. Figure 26E shows the effect of felzartamab on natural killer (NK) cell-expressed ABMR activity genes. Figure 26F shows the effect of felzartamab on ABMR-associated endothelial genes. In Figures 26D-26F, the whiskers represent empirical Bayes moderate standard errors in fold change.

[0053] Figure 27 shows the dd-cfDNA levels in individual patients in the trial.

[0054] Figure 28 shows CD38 mf concentration reported in the ImmuNexUT database for the indicated cell types.

[0055] Figure 29 shows CD38 protein expression on the indicated cells types. Floating bars (min to max) of CD38 antigen density are shown for specified immune populations from bone marrow or peripheral blood of healthy donors. Each symbol represents a unique donor, and the line represents the median.

[0056] Figure 30A shows CD38 upregulation with loss of CD19 and CD20 expression on pan B cells as B cells differentiate into antibody-secreting cells. Figure 30B shows the same on plasmablasts. Figure 30C shows the same on plasma cells. Each dot represents a single PBMC donor, and horizontal lines represent the median.

[0057] Figure 31 A shows that depletion of in vitro differentiated pan B cells following treatment with rituximab (rtx), obinutuzumab (obi), tafasitamab (tafa) daratumumab (dara), and felzartamab (felza). Figure 31 B shows the same on plasmablasts. Figure 31 C shows the same on plasma cells. Each symbol represents a separate NK cell donor and bars represent the median. Statistical significance was determined using paired t-tests. *p < 0.05, **p < 0.01 , ***p < 0.001 .Atty. Docket No. 2790B-1 18WO1

[0058] Figure 32 shows felzartamab-mediated depletion of plasmablasts differentiated from peripheral blood mononuclear cells (PBMCs) of patients with membranous nephropathy (MN) or IgA nephropathy (IgAN). ADCC activity was assessed on in vitro differentiated plasmablasts generated from PBMCs of patients with MN or IgAN after incubation with felzartamab and allogeneic NK cells from healthy donors. Each symbol represents a unique donor with MN or IgAN, and bars represent the median. Statistical significance was determined using paired t-tests. **p < 0.01 .

[0059] Figure 33 shows that felzartamab treatment decreased human plasmablasts in engrafted huCD34+NSG-SGM3 mice in vivo. The number of CD38br'9htor CD38dimplasmablasts (CD45+CD3 / CD33 CD16 CD56 CD20 CD19+CD27+CD38+) per pL of sample is shown. Each symbol represents an individual mouse, with the shape of the symbol representing a unique huCD34+donor. Statistical significance was determined using an unpaired, non-parametric Mann- Whitney test. ***p < 0.001 , ****p < 0.0001 .

[0060] Figure 34A shows change in Ig-K chain titers from beginning to end of the study in vehicle-treated mice. Figure 34B shows change in Ig-K chain titers from beginning to end of the study in felzartamab-treated mice. Each symbol represents an individual animal. Statistical significance was determined using a non-parametric Wilcoxon matched-pairs signed rank test. **p < 0.01 .

[0061] Figure 35 shows a table of concomitant medications being taken by patients enrolled in the IgA nephropathy trial.

[0062] Figure 36 illustrates a five-compartment model to capture felzartamab related treatment effects on cellular subsets and immunoglobulins. Five physiological compartments are encoded in the model: central, peripheral, immunological, bone marrow, and gut.

[0063] Figure 37 is a table summarizing clinical trial data used for model calibration.

[0064] Figure 38 summarizes the percentage change from baseline of a variety of pharmacodynamic markers over time according to the number of felzartamab doses delivered to a patient.

[0065] Figures 39A-39C show the model’s predictions of NK cell dynamics following felzartamab administration.

[0066] Figures 40A-40C show the model’s predictions of plasma cell dynamics following felzartamab administration.

[0067] Figures 41 A & 41 B show model predicted percent change in circulating immunoglobulins following 9 doses of felzartamab.Atty. Docket No. 2790B-1 18WO1Definitions

[0068] The term “CD38” refers to a protein known as CD38, having the following synonyms: ADP-ribosyl cyclase 1 , cADPr hydrolase 1 , Cyclic ADP-ribose hydrolase 1 , T10. Human CD38 (UniProt P28907) has the following amino acid sequence:

[0069] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTK RFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCN KILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNN PVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHG GREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI (SEQ ID NO: 9)

[0070] CD38 is a type II transmembrane glycoprotein and an example of an antigen that is highly expressed on antibody-secreting cells (including autoantibody-secreting plasmablasts and plasma cells). Functions ascribed to CD38 include both receptor-mediated adhesion and signaling events and (ecto-) enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as substrate for the formation of cyclic ADP-ribose (cADPR) and ADPR, but also of nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to act as second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 regulates the extracellular NAD+ concentration and hence cell survival by modulation of NAD-induced cell death (NCID). In addition to signaling via Ca2+, CD38 signaling occurs via cross-talk with antigenreceptor complexes on T and B cells or other types of receptor complexes, e.g. MHC molecules, and is in this way involved in several cellular responses, but also in switching and secretion of IgG antibodies.

[0071] A “human antibody” or “human antibody fragment”, as used herein, is an antibody or antibody fragment having variable regions in which the framework and CDR regions are from sequences of human origin. If the antibody contains a constant region, the constant region also is from such sequences. Human origin includes, but is not limited to human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296:57-86). Human antibodies can be isolated e.g. from synthetic libraries or from transgenic mice (e.g. Xenomouse). An antibody or antibody fragment is human if its sequence is human, irrespective of the species from which the antibody is physically derived, isolated, or manufactured.

[0072] The structures and locations of immunoglobulin variable domains, e.g., CDRs, may be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (see, e.g. Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991 ), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabat et al., (1991 ) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91 -3242 U.S. Department of Health andAtty. Docket No. 2790B-1 18WO1 Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948.

[0073] A “humanized antibody” or “humanized antibody fragment” is defined herein as an antibody molecule, which has constant antibody regions derived from sequences of human origin and the variable antibody regions or parts thereof or only the CDRs are derived from another species. For example, a humanized antibody can be CDR-grafted, wherein the CDRs of the variable domain are from a non-human origin, while one or more frameworks of the variable domain are of human origin and the constant domain (if any) is of human origin.

[0074] The term "chimeric antibody" or “chimeric antibody fragment” is defined herein as an antibody molecule, which has constant antibody regions derived from, or corresponding to, sequences found in one species and variable antibody regions derived from another species. Preferably, the constant antibody regions are derived from, or corresponding to, sequences found in humans, and the variable antibody regions (e.g. VH, VL, CDR or FR regions) are derived from sequences found in a non-human animal, e.g. a mouse, rat, rabbit or hamster.

[0075] The term "isolated antibody” refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments having different antigenic specificities. Moreover, an isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemicals. Thus, in some aspects, antibodies provided are isolated antibodies, which have been separated from antibodies with a different specificity. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. An isolated antibody that specifically binds to an epitope, isoform or variant of a target may, however, have cross-reactivity to other related antigens, e.g., from other species (e.g., species homologs).

[0076] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a unique binding site having a unique binding specificity and affinity for particular epitopes.

[0077] In addition, as used herein, an “immunoglobulin” (Ig) hereby is defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), and includes all conventionally known antibodies and functional fragments thereof.

[0078] The phrase “antibody fragment”, as used herein, refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen. Examples of binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment, which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separateAtty. Docket No. 2790B-1 18WO1 genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as “single chain Fragment (scFv)”). Such single chain antibodies are to be encompassed within the term “antibody fragment”. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv. Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1 -VH-CH1 ) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites).

[0079] The present disclosure provides therapeutic methods comprising the administration of a therapeutically effective amount of an anti-CD38 antibody as disclosed to a subject in need of such treatment. A "therapeutically effective amount ' or ..effective amount”, as used herein, refers to the amount of an antibody specific for CD38, necessary to elicit the desired biological response. In accordance with the present disclosure, the therapeutic effective amount is the amount of an antibody specific for CD38 necessary to treat and / or prevent immune complex mediated diseases and symptoms associated with said diseases. An effective amount for a particular individual may vary, depending on factors such as the condition being treated, the overall health of the patient, the method route and dose of administration and the severity of side effects (Maynard, et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001 ) Good Laboratory and Good Clinical Practice, London, UK).

[0080] As used herein, the terms "treat", "treating", or the like, mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

[0081] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset. “Prevention” refers to methods which aim to prevent the onset of a disease or its symptoms or which delay the onset of a disease or its symptoms.

[0082] "Administered" or “administration” includes but is not limited to delivery of a drug by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet. Preferably, the administration is by an injectable form.

[0083] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times. The therapies (e.g., prophylactic or therapeuticAtty. Docket No. 2790B-1 18WO1 agents) of the combination therapies of the present disclosure can be administered concomitantly or sequentially to a subject. The therapy (e.g., prophylactic or therapeutic agents) of the combination therapies of the present disclosure can also be cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one of the therapies (e.g., agents) to avoid or reduce the side effects of one of the therapies (e.g., agents), and / or to improve, the efficacy of the therapies.

[0084] The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the disclosure can be administered to a subject concurrently. The term "concurrently" is not limited to the administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather it is meant that a pharmaceutical composition comprising antibodies or antibody fragments of the disclosure are administered to a subject in a sequence and within a time interval such that the antibodies of the disclosure can act together with the other therapy(ies) to provide an increased benefit than if they were administered otherwise.

[0085] “Subject” or “species”, as used herein refers to any mammal, including rodents, such as mouse or rat, and primates, such as cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta) or humans (Homo sapiens). Preferably, the subject is a primate, most preferably a human.

[0086] As used herein, the term "a subject in need thereof" or the like, mean a human or a non-human animal patient that exhibits one or more symptoms or indicia of immune complex- mediated disease, and / or who has been diagnosed with an immune complex mediated disease (e.g. IgA nephropathy). Preferably, the subject is a primate, most preferably a human patient who has been diagnosed with IgA nephropathy or lupus nephritis.

[0087] As used herein, the term “immune mediated diseases” refers to a group of diseases that are characterized by an attack of antibodies or T cells on a subject’s own tissues.

[0088] As used herein, the term "about" when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1 %. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1 , 99.2, 99.3, 99.4, etc.).

[0089] “Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0090] “Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which an antibody or antibody fragment is administered.Atty. Docket No. 2790B-1 18WO1

[0091] Throughout this specification, unless the context requires otherwise, the words "comprise", “have” and “include” and their respective variations such as "comprises", "comprising", “has”, “having”, “includes” and “including” will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0092] “Felzartamab” is an anti-CD38 antibody, also known as “MOR202”, “MOR03087” or “MOR3087”. The terms are used interchangeable in the present disclosure. MOR202 has an I gG 1 Fc region.

[0093] The amino acid sequence of the MOR202 HCDR1 according to Kabat is:

[0094] SYYMN (SEQ ID NO: 1 )

[0095] The amino acid sequence of the MOR202 HCDR2 according to Kabat is:

[0096] GISGDPSNTYYADSVKG (SEQ ID NO: 2)

[0097] The amino acid sequence of the MOR202 HCDR3 according to Kabat is:

[0098] DLPLVYTGFAY (SEQ ID NO: 3)

[0099] The amino acid sequence of the MOR202 LCDR1 according to Kabat is:

[0100] SGDNLRHYYVY (SEQ ID NO: 4)

[0101] The amino acid sequence of the MOR202 LCDR2 according to Kabat is:

[0102] GDSKRPS (SEQ ID NO: 5)

[0103] The amino acid sequence of the MOR202 LCDR3 is: QTYTGGASL (SEQ ID NO: 6)

[0104] The amino acid sequence of the MOR202 Variable Heavy Domain is:

[0105] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDP SNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTV SS (SEQ ID NO: 7)

[0106] The amino acid sequence of the MOR202 Variable Light Domain is:

[0107] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIP ERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8)

[0108] The DNA sequence encoding the MOR202 Variable Heavy Domain is:

[0109] CAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGCCT GCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGC CAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACC TATTATGCGGATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCT GTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGA TCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGC TCA (SEQ ID NO: 10).

[0110] The DNA sequence encoding the MOR202 Variable Light Domain is:[01 1 1] GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCG CGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCAtty. Docket No. 2790B-1 18WO1 CGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGGCATCCCGGA ACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGC GGAAGACGAAGCGGATTATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGC GGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 1 1).

[0112] In one embodiment, the present disclosure provides felzartamab or a pharmaceutical composition comprising felzartamab or an antibody fragment thereof, for use in the treatment of immune mediated disease in a subject, such as kidney disease. The methods presently disclosed include the following steps: 1 ) administering to the subject a regimen of at least five doses of felzartamab over six months, and 2) measuring a level of CD19+CD27hiCD38hi plasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hi plasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months. Additionally or alternatively, methods are disclosed herein for reducing antibody titers (e.g., immunoglobulin kappa chain titers) in a patient by administering an effective dose of felzartamab to a patient in need thereof, and optionally measuring antibody titers (e.g., kappa chain titers) following felzartamab administration.

[0113] In some embodiments, the subject is administered six doses, seven doses, eight doses, nine doses, or even more doses of felzartamab over the six months. In some embodiments, felzartamab is administered at a dose of 16 mg per kilogram of subject body mass. In some embodiments, felzartamab is administered as a fixed dose according to the following schedule:

[0114] In one embodiment, the immune mediated disease is selected from anti-PLA2R membranous nephropathy (aMN) or IgA nephropathy (IgAN). If the population of CD19+ B lymphocytes is adversely affected, felzartamab treatment may be discontinued. In such circumstances, where the disease is aMN, a course of cyclophosphamide, rituximab, a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), and / or a corticosteroid (e.g., prednisone) may be started after felzartamab is discontinued. For example, alternating months of cyclophosphamide and corticosteroids for a total of 6 months (Ponticelli protocol) may be instituted. Where felzartamab is discontinued and the disease is IgAN, a course of cyclophosphamide, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blockers (ARB), a diuretic, and / or corticosteroids (e.g., prednisone or budesonide) may be started after felzartamab is discontinued.

[0115] In some aspects, the subject experiences proteinuria of up to 6.0 g / day (total protein based on 24-hour urine collection). In some aspects, the subject with IgAN has persistent proteinuria. In some embodiments, said persistent proteinuria is a persistent proteinuria with UPCR > 1 mg / mg based on 24-hour urine collection or said persistent proteinuria is a persistentAtty. Docket No. 2790B-1 18WO1 proteinuria with UPCR > 0.75 mg / mg based on 24-hour urine collection, wherein at least once within 12 months prior to the administration of felzartamab said subject with IgAN has been determined to have a UPCR > 1 mg / mg based on 24-hour urine collection. In some embodiments, said proteinuria is characterized by a urine-protein creatinine ratio (UPCR), based on 24-hour urine collection, of at least 0.75 mg / mg. In some embodiments, said proteinuria is characterized by a 24-hour urine-protein creatinine ratio (UPCR), based on 24-hour urine collection, of up to 6.0 mg / mg.Numbered Aspects

[0116] Aspect 1 . A method of treating a subject suffering from an immune-mediated disease (e.g., IgA nephropathy, primary membranous nephropathy, an antibody-mediated rejection, lupus nephritis, systemic lupus erythematosus (SLE), Graves’ Disease, Myasthenia Gravis, Anti-PLA2R positive Membranous Glomerulonephritis (aMN), Pemphigus, Sjogren's syndrome, and / or Anti- NMDA encephalitis), the method comprising administering to the subject a regimen of at least five doses of felzartamab over six months, and measuring a level of CD19+CD27h'CD38hiplasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27h'CD38hiplasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months.

[0117] Aspect 2. The method of aspect 1 , wherein each of the doses is 650 mg to 1625 mg felzartamab.

[0118] Aspect 3. The method of aspect 1 or 2, wherein nine doses of felzartamab are administered over the six months.

[0119] Aspect 4. The method of aspect 3, wherein the doses are administered on days 1 , 8, 15, 22, 29, 57, 85, 1 13, and 141 of the regimen.

[0120] Aspect 5. The method of any one of aspects 1 -4, wherein the measuring comprises performing flow cytometry on the blood sample.

[0121] Aspect 6. The method of any one of aspects 1 -5, further comprising measuring a galactose-deficient immunoglobin A1 (Gd-lgA1 ) titer in the blood samples.

[0122] Aspect 7. The method of any one of aspects 1 -6, further comprising administering a further regimen of felzartamab to the subject after the measuring.

[0123] Aspect 8. The method of any one of aspects 1 -6, further comprising measuring a baseline level of CD19+ B lymphocytes of the subject before the administering step, comparing the level of CD19+ B lymphocytes in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level of CD19+ B lymphocytes in the blood sample is not more than 10% less than the baseline level.

[0124] Aspect 9. The method of any one of aspects 1 -6 and 8, further comprising measuring a baseline level of CD19+CD27hiCD38hiplasmablasts of the subject before the administering step, comparing the level of CD19+CD27hiCD38hi plasmablasts in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level ofAtty. Docket No. 2790B-118WO1 CD19+CD27hiCD38hiplasmablasts in the blood sample is at least 10% less than the baseline level.

[0125] Aspect 10. The method of any of the preceding aspects, wherein the antibody or antibody fragment is dosed depending on subject body weight, optionally wherein the dosage is 650 mg for a subject weighing <50 kg; 975 mg for a subject weighing >50-70 kg; 1300 mg for a subject weighing >70-90 kg; 1625 mg for a subject weighing >90 kg.

[0126] Aspect 11. A method of treating a subject suffering from IgA nephropathy comprising administering acetaminophen, diphenhydramine, famotidine, and / or methylprednisolone to the subject, then performing three infusions of felzartamab at a dosage of 650 mg if the subject weighs <50 kg; 975 mg if the subject weighs >50-70 kg; or 1300 mg if the subject weighs >70-90 kg; 1625 mg if the subject weighs >90 kg.

[0127] Aspect 12. The method of any preceding aspect, comprising administering to the subject 650-1000 mg acetaminophen, about 50 mg diphenhydramine, about 20 mg famotidine intravenously, and / or 50-100 mg methylprednisolone.

[0128] Aspect 13. The method of any preceding aspect, wherein the subject has persistent proteinuria despite treatment with an angiotensin-converting enzyme inhibitor (ACEi) and / or an angiotensin receptor blocker (ARB) before treatment with felzartamab, and the method comprising administering the felzartamab to the subject for at least three months, and reducing proteinuria in the subject within three months of administration of felzartamab.

[0129] Aspect 14. The method of any preceding aspect, wherein the subject has persistent proteinuria despite treatment with an angiotensin-converting enzyme inhibitor (ACEi) and / or an angiotensin receptor blocker (ARB) before treatment with felzartamab, and the method comprising administering the felzartamab to the subject for at least six months, reducing proteinuria in the subject within three months of administration of felzartamab, and maintaning reduction in proteinuria in the subject for at least eighteen months.

[0130] Aspect 15. The method of any preceding aspect, comprising reducing proteinuria in the subject by at least 30%, 35%, 40%, or 45% after three months, six months, 12 months, or 18 months after treatment with felzartamab.

[0131] Aspect 16. The method of any preceding aspect, comprising administering 9 doses of felzartmab to the subject and maintaining reduction in proteinuria in the subject for at least eighteen months.

[0132] Aspect 17. The method of any preceding aspect, comprising maintaning a reduction of eGFR in the subject of at least 10% at 18 months after treatment with felzartamab.

[0133] Aspect 18. A method of preserving vaccine response in a subject having primary membranous nephropathy and having received a vaccine, comprising administering 650 mg to 1625 mg felzartamab to the subject.Atty. Docket No. 2790B-118WO1

[0134] Aspect 19. The method of aspect 18, wherein the antibody or antibody fragment will be dosed in at least 2 doses, at least 5 doses, or at least 9 doses.

[0135] Aspect 20. The method of aspect 18 or 19, wherein the vaccine is a COVID19 vaccine.

[0136] Aspect 21 . The method of any of the preceding aspects, wherein the subject to be treated is characterized by proteinuria at screening of > 1 .0 g / day.Working ExamplesExample 1 : Evaluation of efficacy and safety of the human anti-CD38 antibody felzartamab (MOR202) in subjects with IgA nephropathy (IgAN)1.1 Study Design

[0137] The study’s aim was to evaluate the efficacy and safety of the human anti-CD38 antibody felzartamab (MOR202) in patients with IgA nephropathy (IgAN). Study objectives and endpoints are summarized in Table 2. The study design is summarized in FIGs. 1 and 2.Table 2. Study objectives and endpointsAtty. Docket No. 2790B-118WO1Atty. Docket No. 2790B-118WO11.2 Study populationBaseline values of study participants are shown in Table 3 below. Inclusion criteria of the study were as follow:1 . Patients of age > 18 to < 80 years.2. Biopsy confirmed diagnosis of IgAN.3. Proteinuria at screening visit > 1 .0 g / d.4. Treatment with an angiotensin-converting enzyme inhibitor and / or angiotensin receptor blocker at maximum doses or maximally tolerated doses for > 3 months and adequate blood pressure (recommended is < 125 mm Hg systolic and < 75 mm Hg diastolic).5. A female was only eligible to participate if she was not pregnant, not breast feeding, and agreed to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of felzartamab.6. A table of concomitant medications for the patients enrolled in the trial is shown in FIG. 35.Table 3. Baseline characteristics (all enrolled patients)Atty. Docket No. 2790B-118WO1Kidney biopsies were performed as per institutional practice and analyzed according the MEST- C score for IgAN (see Table 4).Table 4. Pathological variables used in MEST-C Score for IgAN (Trimarchi et al. 2017).Exclusion criteria

[0138] Patients were excluded from the study if any of the following criteria applied:1 . Secondary forms of IgAN, indicated by the presence of any other systemic disease potentially leading to IgA deposits (e.g. Lupus nephritis, Schonlein-Henoch purpura, ankylosingAtty. Docket No. 2790B-1 18WO1 spondylitis, dermatitis herpetiformis, chronic liver disease, inflammatory bowel disease, celiac disease). Severe renal impairment as defined by estimated GFR < 30 mL / min (using chronic kidney disease-epidemiology collaboration [CKD-EPI] formula) or the need for dialysis or renal transplant. Rapidly progressive variant of IgAN, defined as eGFR loss by more than 30% per 3 months and not explained by changes in renin angiotensin system (RAS) blockade. Minimal change variant of IgAN. Concomitant other progressive glomerulonephritis or non-immunologic glomerular disease such as diabetic nephropathy. Recipients of a kidney transplant. Systemic immunosuppression (e.g. mycophenolate mofetil [MMF], cyclophosphamide, biologies like rituximab [RTX]), in particular corticosteroid therapy exceeding 20 mg / day prednisone-equivalent for more than 7 consecutive days. Any previous treatment with an anti-CD38 antibody. Body mass index (BMI) > 35 kg / m2. Hemoglobin < 70 g / L (4.9 mmol / L). Thrombocytopenia: Platelets < 100.0 x 109 / L. Neutropenia: Neutrophils < 1.5 x 109 / L. Leukopenia: Leukocytes < 3.0 x 109 / L. Diabetes mellitus type 1 . Diabetes mellitus type 2: Patients with type 2 diabetes mellitus may only enter the clinical trial if a kidney biopsy shows IgAN without evidence of diabetic nephropathy and their disease is controlled, such as: a. Glycated hemoglobin (HbA1 c) < 8.0% or < 64 mmoL / mol. b. No diabetic retinopathy known. c. No peripheral neuropathy known. Significant uncontrolled cardiovascular disease (including arterial or venous thrombotic or embolic events) or cardiac insufficiency (New York Heart Association [NYHA] class IV). Clinically relevant findings on a 12-lead electrocardiogram (ECG) as determined by the investigator at screening. History of significant cerebrovascular disease or sensory or motor neuropathy of toxicity > grade 3. Aspartate aminotransferase or alanine aminotransferase >1 .5 x ULN, alkaline phosphatase >3.0 x ULN. Known or suspected hypersensitivity to felzartamab and its excipients (L-histidine, sucrose, polysorbate 20).Atty. Docket No. 2790B-118WO121 . Serologic or virologic markers positive for HIV, hepatitis C (patients with positive anti-hepatitis C virus [anti-HCV] antibody but negative HCV RNA-PCR can enroll) or active or latent hepatitis B (patients with positive hepatitis B surface antigen [HBsAg] are excluded). For patients with isolated positive hepatitis B core antibody [anti-HBc], hepatitis B virus (HBV) DNA test by PCR must be non-detectable to enroll).22. Any malignancy within 5 years prior to screening start, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or other non-melanomatous skin cancer.23. Any active infection (viral, fungal, bacterial) requiring systemic therapy.1.3 Dosing

[0103] Patients received nine infusions of either felzartamab or placebo on Day 1 , 8, 15, 22, 29, 57, 85, 113 and 141 according to Table 5 and FIG. 1 .Table 5. Dosing arms

[0104] Felzartamab was dosed depending on patient body weight (Table 6). The absolute dose to be administered intravenously (i.v.) was determined according to the following information: Table 6. Felzartamab (MOR202) dose by body weight

[0105] Each patient received 650 mg to 1625 mg felzartamab per dose i.v. depending on their individual body weight. Within 4 specified body weight ranges, a fixed dosing concept was employed to simplify the dosing procedure. The 4 dose levels for the 4 body weight ranges wereAtty. Docket No. 2790B-1 18WO1 chosen to be similar to a 16 mg / kg dose (i.e., the recommended dose in the FIR study MOR202C101 ) as shown in Table 7.Table 7: Felzartamab fixed dosing in comparison to body weight dosing

[0106] The patients were infused with felzartamab in 0.9% saline or placebo (0.9% saline only). Premedication to reduce the risk of IRRs was administered 2 hours to 30 minutes prior to each infusion:• Oral paracetamol (acetaminophene) 650 to 1000 mg.• Oral or i.v. diphenhydramine 25 to 50 mg or equivalent drug and dose.• i.v. corticosteroid according to Table 8.

[0107] If no IRRs occurred, then infusion speed was increased and glucocorticoid premedication reduced according to Table 7. For patients who did not experience > Grade 2 IRRs / > Grade 1 cytokine release syndrome to felzartamab / placebo during the first three cycles, premedication was optional for subsequent infusions. Otherwise, the premedication was continued for subsequent administrations.Table 8. Felzartamab / placebo infusion speed and i.v. corticoid premedication1.4 Efficacy assessment

[0108] Time points for all efficacy assessments are provided in Example 1.1 and efficacy objectives and endpoints are shown in Table 2. Times of sample collection are shown in FIG. 2. Efficacy parameters are defined in Table 9.Atty. Docket No. 2790B-1 18WO1Table 9. Efficacy parametersProteinuria and UPCR were determined from 24-hour urine samples. If the collected urine did not contain at least 5 mg creatinine / kg / day for females and 6 mg creatinine / kg / day for males, urine collection was repeated immediately without undue delay.

[0109] Flow cytometry was used to quantify B lineage cell populations (whole blood) from the EOT samples. Total B cells were identified based on CD19 staining. Circulating CD38+ plasmablasts were identified based on staining for CD19, CD27, and CD38. Polyclonal immunoglobulins (IgA, IgG, and IgM) were also assayed by turbidimetry to monitor total antibody production, while Gd-lgA1 was assayed by ECLIA to monitor disease-relevant antibody production. Samples from seven study participants were excluded from analyses because these participants had received three or fewer blinded infusions. Baseline biomarker values from theseAtty. Docket No. 2790B-118WO1 samples are shown in Table 10 below. Additionally antibody titers from EOT and EOS blood samples were analyzed using the Elecsys® Anti-SARS-CoV-2 S Assay (Roche Diagnostics) and VaccZyme™ Anti-Tetanus Toxoid (TT) IgG Enzyme Immunoassay (MK010).Table 10. Baseline biomarker values

[0110] Results from the flow cytometry assay are shown in FIG. 3A (plasmablasts) and FIG. 3B (total B cells). These data show that felzartamab targets CD27hiCD38hiplasmablasts while preserving total CD19+B cells. Immunoglobin titer results are shown in FIGs. 4A-4C. These data show that 9 doses of felzartamab durably reduce Gd-lgA1 and total IgA antibodies off-treatment while total IgG and IgM recovers rapidly. The anti-tetanus toxoid results are shown in FIG. 3C (EOT) and FIG. 3D (EOS). Anti-SARS-CoV2 and anti-tetanus toxoid titers over time are shown in Table 11 .Table 11. Antibody Titers Throughout the StudyAtty. Docket No. 2790B-118WO1Part 2Open-lab felzartam9-dosePrior vaccination (within 12 months of baseliivaccine type_ 615,681(6727-32,2 Participants negative for anti-SARS-CoV-2 at baseline (<0.8 U / mL) Number I i T iLowest observed levels of anti-SARS-CoV-2 (U / mL) post-baseline65939 (17410599)Participants who become negative for anti-SARS-CoV-2 on study (<0.8 U Number I 6 I 6 who COVID-19 infection onAtty. Docket No. 2790B-118WO1_

[0111] Regarding antibody titers, of 54 IGNAZ participants, 53 had blood samples that made it possible to measure antibody titers. Of those 53, 47 had protective anti-tetanus toxoid (TT) titers at baseline (Table 11). Baseline anti-TT immunity was maintained throughout the study in the majority of participants, with 48 participants maintaining protective titers (<0.1 lU / mL) on study There was no need for booster vaccination on study and only 1 case of prophylactic vaccination during the off-treatment period.

[0112] Four participants had titers decrease to below protective levels during the study. However, all of those four had low baseline titers, and reductions were minimal with titers staying >0.08 lU / mL Modest reductions in anti-TT titers over time were comparable between participants who received felzartamab and those who received placebo (FIGs. 3C and 3D).

[0113] Similarly, 45 participants with available data had positive anti-SARS-CoV-2 titers at baseline (Table 11), and participants maintained positive baseline titers of anti-SARS-CoV-2 during the study (Table 11). Across arms, 16 participants received >1 SARS-CoV-2 vaccination on study and 17 participants experienced acute SARS-CoV-2 infections during the treatment period. Seven of eight participants with data pre- and post-vaccination titers mounted a vaccine response regardless of treatment arm, suggesting vaccine immunity is preserved (Figure 3E). Similarly, five of six participants generated antibody responses to SARS-CoV-2 infection while receiving treatment, suggesting humoral antibody response to acute infection is preserved with felzartamab treatment (Figure 3F).

[0114] Finally, the samples were also assayed to measure urine protein :creatine ratio and glomerular filtration rate over time. These results are shown in FIG. 5A (UPCR) and FIG. 5B (eGFR). FIG. 5A shows a 50% reduction in UPCR over 18 months after last dose, with ongoing reduction at Month 24. FIG. 5B shows stabilization of eGFR across treated arms vs placebo, which has rapid progression consistent with high-risk IgAN. Taken together, these data show a prolonged durability in response observed in UPCR and eGFR over 18 months after the last dose of felzartamab.

[0115] FIG. 6B shows the correlation between the magnitude of the decrease in Gd-lgA1 titers over the course of felzartamab treatment and the likelihood that a patient will experience a complete response, defined as a UPCR value of <0.5 g / g, a reduction in UPCR of 50% or more, and stable eGFR, as defined by a decrease of 25% or less.Atty. Docket No. 2790B-118WO1Example 2: M-PLACE: A Phase Ib / lla multicenter open-label study for treatment of two cohorts of aMN patients with MOR202 (NCT04145440)

[0116] A phase Ib / lla, open-label, multicenter clinical trial (M-PLACE) to assess safety and efficacy of the human anti-CD38 antibody MOR202 in anti-PLA2R antibody positive membranous nephropathy (aMN) was initiated in the US and Europe. ClinicalTrials.gov identifier (NCT number): NCT04145440. A second trial (New-PLACE, NCT04733040) was also initiated.

[0117] 2.1 . Study Design

[0118] Objectives of the study were to evaluate the safety, tolerability and efficacy of the human anti-CD38 antibody MOR202 in patients with anti-PLA2R positive membranous nephropathy (aMN) and to assess the effect of felzartamab on serum anti-PLA2R antibodies levels. The M- PLACE dosing regime is summarized in FIG. 7A. The New PLACE dosing regime is summarized in FIG. 7B.

[0119] The main treatment rationale was the reduction of membranous nephropathy (MN) disease specific anti-PLA2R antibodies through targeted depletion of autoantibody producing plasma cells by felzartamab.

[0120] The patient population included adult subjects with biopsy-proven MN positive for anti- PLA2R antibodies. Ages eligible for study were 18 to 80 years (adults, older adults). All sexes were eligible for study.

[0121] Key Inclusion Criteria:• Urine protein to creatinine ratio of > 3.0 g / g (as measured from a 24 h urine collection)• Estimated glomerular filtration rate > 50 mL / min / 1 ,73m2or >30 and <50 mL / min / 1 ,73m2, and interstitial fibrosis and tubular atrophy score of less than 25% on a renal biopsy obtained within the last 6 months prior to start of screening.• on supportive treatment with an Angiotensin Converting Enzyme Inhibitor or an Angiotensin II Receptor Blocker for at least 4 weeks prior to Screening, having reached a stable dose.• Systolic BP < 150 mmHg and diastolic BP < 100 mmHg• Vaccinated against Pneumococcus within the last 3 years prior to date of signing informed consent (some subjects were vaccinated during screening to meet this criterion; interval to first dose of felzartamab must be at least 14 days).• Cohort 1 a (newly diagnosed patients): Serum anti-PLA2R antibodies > 150.0 Response Units (RU) / mL determined at screening by Euroimmun ELISA.• Cohort 1 b, relapse subjects: Must have had complete immunological and / or clinical remission according to judgement of the investigator and serum anti-PLA2R antibodies > 50.0 RU / mL determined at screening by Euroimmun ELISA.• Cohort 2: Failure of previous therapy, i.e. subject never achieved a complete immunological and / or clinical remission according to judgement of the investigator during or afterAtty. Docket No. 2790B-1 18WO1 completion of a recognized 1ST containing cyclosporine A, tacrolimus, mycophenolate-mofetil, ACTH or alkylating agents (e.g. cyclophosphamide), or rituximab. Serum anti-PLA2R antibodies > 20.0 RU / mL determined at screening by the Euroimmun ELISA.Key Exclusion Criteria:• Hemoglobin < 90 g / L.• Thrombocytopenia: Platelets < 100.0x109 / L.• Neutropenia: Neutrophils < 1 .5x109 / L.• Leukopenia: Leukocytes < 3.0x109 / L.• Hypogammaglobulinemia: Serum immunoglobulins < 5.0 g / L.• Secondary cause of MN (e.g. systemic lupus erythematosus, medications, malignancies)• Concomitant renal disease other than MN (e.g., diabetic renal disease, lupus nephritis, IgA nephropathy).• NewPLACE patients with prior 1ST within 180 days of baseline were excluded from the analysis.

[0122] M-PLACE Cohort 1 had approximately 20 aMN patients stable on supportive care treatment with ACEI / ARB at screening with unfavorable prognostic features such as proteinuria (>5g / 24h) and high and stable serum titers of anti-PLA2R antibodies (>150.00 response units (RU) / mL, Euroimmun ELISA) eligible for 1ST, or subjects relapsing after complete or partial proteinuria response including a serum anti-PLA2R antibody titer less than 20 RU / mL for at least 6 months. Some subjects were newly diagnosed (Cohort 1 a) or relapsing (Cohort 1 b) after a prior proteinuria and immunological response to 1ST.

[0123] M-PLACE Cohort 2 had approximately 10 aMN patients requiring 2nd or 3rd line 1ST who did not respond immunologically to their last prior line of therapy and thus were considered refractory.

[0124] Failure of previous therapy, i.e. subject never achieved a reduction of serum anti-PLA2R antibody titers to below 20 RU / mL during or after completion of a recognized 1ST containing CSA, tacrolimus, MMF, ACTH or alkylating agents (e.g. cyclophosphamide), or rituximab determined after at least 6 months after start of therapy.

[0125] Exclusion criteria were active infection, secondary cause of MN (e.g. SLE, medications, malignancies), Type 1 or 2 diabetes mellitus, pregnancy or breast feeding, known or suspected hypersensitivity to the study drugs and its excipients.

[0126] MOR202 monotherapy treatment of the two cohorts was administered over a 24-week treatment phase followed by a 28-week observational follow-up phase (FIG. 7A).

[0127] 2.2. Administration of MOR2Q2 (MQR03087)

[0128] MOR202 was supplied as a lyophilized powder for reconstitution in labelled glass vials. MOR202 must be stored at 2-8°C until use. For drug preparation each vial was reconstituted with 4.8 mL water for injection (WFI). After reconstitution each vial contained 325 mg of MOR202 inAtty. Docket No. 2790B-1 18WO1 an extractable volume of 5 mL (65 mg / mL). For infusion it was diluted in 250 ml_ 0.9% sodium chloride solution.

[0129] The first MOR202 i.v. infusion was administered over approximately 90 minutes (about 3mL / min). If no infusion reactions occurred, the infusion time was shortened to 1 hour or shorter in subsequent infusions but limited to the shortening steps outlined in Table 5. Infusion time was not shorter than 30 minutes. Premedication of subjects with antihistamines and antipyretic drugs (e.g. paracetamol / acetaminophen) as prophylaxis of infusion related reactions (IRRs) was recommended. Co-medication for prevention of IRRs with i.v. dexamethasone (or equivalent glucocorticoids administered i.v.) approximately 30 minutes before start of MOR202 infusion was mandatory for the first 3 applications as outlined in Table 1 1 .Table 11: MOR202 infusion guideline2.3. Assessment of safety, immunogenicity and pharmacokinetics

[0130] Safety was assessed in terms of physical examination, vital signs, oxygen saturation, electrocardiograms, hematological and biochemical tests, adverse events and immunogenicity. Adverse events were graded according to NCI CTCAE, version 4.03. To monitor for immunogenicity and pharmacokinetics the presence of anti-MOR202 antibodies (anti-drug antibodies) and serum concentrations of MOR202, blood samples were drawn at selected time points. Urine samples were also collected.2.4. Efficacy Assessments

[0131] Major efficacy assessments included: (i) Serum anti-PLA2R antibody levels measured by ELISA to track the course of immunological response before, during and after MOR202 therapy, (ii) Proteinuria based on UPGR from 24h urine / spot urine measured during and after MOR202 therapy, (iii) Kidney function was determined before, during, and after MOR202 therapy by estimating glomerular filtration rate (eGFR) based on the CKD-epi equation. (iV) Urinary Sodium excretion was determined from 24h urine. All M-PLACE cohort 1 and NewPLACE patients that received at least two doses and had baseline measurements were included in analysis.2.5. Biomarker

[0132] Presence and titer of anti-PLA2R antibodies at selected time points (i.e. kinetics of anti- PLA2R antibody titers) were determined for all subjects during the course of the study. Serum concentrations of total IgG, IgA, and IgM were assessed by ELISA. Quantitative NK cell, B cell, T cell (incl. regulatory T cell), plasma blast, plasma cell numbers at selected time points were determined by peripheral blood flow cytometry or ELISPOT assays.Atty. Docket No. 2790B-1 18WO1

[0133] Table 12 shows dose-dependent decreases in anti-PLA2R levels, with only modest decreases in total IgG and anti-Tetanus Toxoid. Preservation of protective immunoglobulins including polyclonal IgG and anti-TT, is consistent with previous findings (data not shown) demonstrating effective COVID19 vaccine responses in M-PLACE. Together these data suggest felzartamab preserves humoral immunity.Table 12. Titers of anti-PLA3R autoantibodies, anti-TT antibodies, and total IgG

[0134] Felzartamab treatment selectively depleted detectable circulating plasmablasts without impacting earlier B cell lineages (FIGs. 8A-8F). The 9-dose arm of the M-PLACE study showed greater durability of immunological response compared to the 2 or 5 dose regimens of the New PLACE trial (FIGs. 9A-9C). Baseline anti-PLA2R levels were not predictive for felzartamab immunological response in M-PLACE cohort 1 PMN patients (FIGs. 10A-10C). Felzartamab reduced pathogenic anti-PLA2R autoantibodies to a greater extent than protective immunoglobulins in M-PLACE cohort 1 (FIGs. 11A-1 1 C).2.6. KDQOL-36

[0135] The Kidney Disease Quality of Life (KDQOL-36™) survey was used for the assessment of the Quality of Life (QoL) defined as score change from baseline in patients with autoimmune membranous nephropathy treated with MQR202.Example 3: Clinical evaluation of felzartamab (MOR202) in kidney transplant recipients3.1 Patient Population

[0136] 22 kidney-transplant recipients with antibody-mediated rejection were randomly assigned to receive felzartamab or placebo (Fig. 12). The trial treatment was completed by 21 of the patients after 1 patient in the placebo group had graft loss caused by rejection at week 14. The median time until trial inclusion was 9 years (interquartile range, 5 to 18) after transplantation.Atty. Docket No. 2790B-1 18WO1

[0137] Baseline characteristics were generally well balanced between the two groups (Table 13), except that the median age was older in the placebo group and the median eGFR was higher in the felzartamab group. Overall, 7 of 22 patients (32%) had active antibody-mediated rejection, and 15 of 22 patients (68%) had chronic active antibody-mediated rejection. The presence of human leukocyte antigen (HLA) class II donor-specific antibody was observed in 13 of 22 patients (59%), and a mean fluorescence intensity of donor-specific antibody of more than 10,000 was observed in 8 of 22 patients (36%). The median eGFR was 37 ml per minute per 1.73 m2 (interquartile range, 33 to 64). The median ratio of spot urine protein to creatinine was 993 (interquartile range, 178 to 1510), with urinary protein measured in milligrams and creatinine measured in grams. Molecular analysis revealed fully developed antibody-mediated rejection in most patients. Triple immunosuppression was being administered to 18 of 22 patients (82%).Atty. Docket No. 2790B-118WO1Atty. Docket No. 2790B-1 18WO13.2 Safety

[0138] Adverse events were reported in all the patients and were predominantly mild or moderate in severity (Table 14). A greater incidence of adverse events was reported in the felzartamab group than in the placebo group (119 vs. 81 events), as were adverse events that were deemed by the trial investigators to be related to felzartamab or placebo (27 vs. 11 events). No patients discontinued treatment because of adverse events, and there were no fatal adverse events. The frequency of serious adverse events, which were primarily infection-related, was lower in the felzartamab group than in the placebo group (in 1 patient [9%] vs. 4 patients [36%]). During the first infusion, mild or moderate infusion-related reactions were reported in 8 patients (73%) in the felzartamab group and in no patients in the placebo group (P = 0.001 ). The most frequent adverse events were infections, which occurred in 17 of 22 patients (77%) and were more frequent in the felzartamab group than in the placebo group (in 10 patients [91 %] vs. 7 patients [64%] ; P = 0.31 ). The frequency of nasopharyngitis was greater in the felzartamab group than in the placebo group (in 9 patients [82%] vs. 3 patients [27%]; P = 0.03), as was the frequency of coronavirus disease 2019 (in 7 patients [64%] vs. 3 patients [27%]; P = 0.20). Cytomegalovirus viremia was reported in 1 patient in the felzartamab group. Laboratory analyses did not reveal meaningful changes in safety laboratory measures (FIGs. 15A-15F).Table 14. Adverse Events.Atty. Docket No. 2790B-118WO13.3 Biopsy Results

[0139] Biopsy procedures were performed at 24 weeks and 52 weeks in 11 patients in the felzartamab group and in 10 patients in the placebo group. A patient in the placebo group who had graft loss at week 14 was not included in the analysis. In this patient, biopsy that had been performed shortly before graft loss showed persistent chronic active antibody-mediated rejection. At week 24, resolution of antibody-mediated rejection — which included either chronic (inactive) rejection or no rejection — had occurred in 9 of 11 patients (82%) in the felzartamab group and in 2 of 10 patients (20%) in the placebo group, for a between-group difference of 62 percentage points (95% confidence interval [Cl], 19 to 100) and a risk ratio of 0.23 (95% Cl, 0.06 to 0.83) (Figs. 13A-13B). The effect of felzartamab on rejection activity was characterized by a reduction in the microvascular inflammation score, with a median score of 0 (interquartile range, 0 to 1 ) in the felzartamab group and 2.5 (interquartile range, 2 to 3) in the placebo group at week 24, for a mean between-group difference of -1 .95 (95% Cl, -2.97 to -0.92) (Figs. 14A). A score of 0 was reported in 7 of 11 patients (64%) with felzartamab and in 1 of 10 patients (10%) with placebo, for a between-group difference of 54 percentage points (95% Cl, 11 to 98) and a risk ratio of 0.40 (95% Cl, 0.18 to 0.91). The dynamics of Banff lesion scores through week 52 are shown in Figs. 15A-F. Changes in the morphologic characteristics of allografts were accompanied by a substantially lower molecular score reflecting the probability of antibody-mediated rejection in the felzartamab group than in the placebo group. At 24 weeks, the median score was 0.17 (interquartile range, 0.09 to 0.51 ) in the felzartamab group and 0.77 (interquartile range, 0.37 to 0.86) in the placebo group, for a mean difference of -0.39 (95% Cl, -0.64 to -0.14) (Fig. 14B). Patients in the felzartamab group also had lower scores for any type of rejection and pathogenesis-based transcript sets reflecting the NK-cell burden, gamma interferon effects, cytotoxic T cells, and transcripts selective for donor specific antibody (Figs. 16A-16H). At 24 weeks, subclinical T-cell-mediated rejection that was graded as Banff type IA developed in a patient in the felzartamab group. Three months later, biopsy revealed spontaneous resolution of tubulointerstitial infiltrates. Consistent values for a molecular score of less than 0.2 for T- cell-mediated rejection were observed in biopsy samples in the felzartamab group. MorphologicAtty. Docket No. 2790B-118WO1 and molecular scores that indicate chronic transplant injury were unaffected by treatment. Biopsies at week 52 (6 months after completion of treatment) indicated recurrence of rejection in 3 of the 9 patients in the felzartamab group who had a response to treatment. Median scores for microvascular inflammation remained lower in the felzartamab group than in the placebo group (1 [interquartile range, 0 to 2] vs. 2 [interquartile range, 2 to 3.5]), for a mean difference between groups of -1.58 (95% Cl, -2.70 to -0.45). Among the patients who received felzartamab, six patients still had either chronic (inactive) or no rejection. However, molecular scores related to rejection and NK-cell burden increased toward baseline levels.3.4 Blood Biomarkers

[0140] At 24 weeks, the median CD16br'9htNK-cell count in peripheral blood was lower in the felzartamab group than in the placebo group (16 cells per microliter [interquartile range, 8 to 41] vs. 54 cells per microliter [interquartile range, 38 to 170]), for a mean difference of -87 cells per microliter (95% Cl, -177 to 4) (Fig. 17B). At 12 weeks, the median fraction of donor-derived cell- free DNA was 0.33% (interquartile range, 0.25 to 0.40) in the felzartamab group and 0.95% (interquartile range, 0.37 to 1 .63) in the placebo group, for a mean difference of -0.75 percentage points; 95% Cl, -1 .41 to -0.09); at week 24, the median fraction of donor-derived cell-free DNA was 0.31% (interquartile range, 0.21 to 0.49) in the felzartamab group and 0.82% (interquartile range, 0.34 to 2.90) in the placebo group, for a mean between-group difference of -0.58 percentage points (95% Cl, -1 .90 to 0.73), with increases toward baseline levels by week 52 (Fig. 17C). There was evidence of modestly lower values for the mean fluorescence intensity of the peak donor-specific antibody, total IgG, and IgM with felzartamab treatment (Fig. 17A). As reflected by the TTV viral load, the level of overall immunosuppression did not increase in either trial group (Fig. 17D); the numbers of T cells, B cells, and CD138+ antibody-secreting cells in peripheral blood remained unaffected.3.5 Clinical Outcomes

[0141] At 1 year, survival was 100% in the two trial groups. One graft loss in the placebo group had occurred because of persistent chronic active antibody-mediated rejection. The 1-year eGFR slope was -0.39 ml per minute per 1.73 m2(95% Cl, -5.47 to 4.69) in the felzartamab group and -4.53 ml per minute per 1 .73 m2(95% Cl, -9.83 to 0.77) in the placebo group (difference, 4.14 ml per minute per 1 .73 m2; 95% Cl, -3.20 to 11.48) (Figs. 18A-18B). In the two groups, the ratio of spot urinary protein to creatinine did not change over time.Atty. Docket No. 2790B-118WO1Example 4: Randomized, double-blind, placebo-controlled phase 2a study assessing the efficacy and safety of felzartamab for IgA nephropathy4.1 Study design and oversight

[0142] A randomized, double-blind, multicenter, placebo-controlled phase 2a study was conducted in two parts, each with a screening period, 6-month treatment period, and follow-up period (Part 1 , 18 months; Part 2, 6 months).4.2 Randomization and treatment

[0143] In Part 1 , patients were randomized 1 :1 :1 :1 : by interactive response technology to receive nine intravenous infusions of placebo or felzartamab 16 mg / kg in one of three arms (2- dose, 5-dose, or 9-dose) by body weight (<50 kg, 650 mg; >50-70 kg, 975 mg; >70-90 kg, 1300 mg; >90 kg, 1625 mg) on days on days 1 , 8, 15, 22, 29, 57, 85, 113, and 141 . Planned enrollment in Part 1 was 44 patients (11 per arm). After 48 patients were randomized in Part 1 , six Japanese patients were enrolled in Part 2 and received the felzartamab 9-dose schedule open-label. Patients received standard of care with an ACEi and / or ARB throughout the study. Sodiumglucose co-transporter-2 inhibitors could be continued but not initiated. Immunosuppressive therapies were prohibited.

[0144] Patients were monitored for infusion-related reactions (IRRs) for >2 hours after the first three infusions and >1 hour after all infusions that followed an IRR. Oral paracetamol (acetaminophen) 650-1000 mg, oral / intravenous diphenhydramine 50 mg (or equivalent), histamine type-2 receptor antagonists (e.g., intravenous famotidine 20 mg or equivalent), and methylprednisolone 50-100 mg (or equivalent) were required before the first three infusions. If no IRRs occurred during the first infusion, the infusion speed could be increased from 2 mL / min (first infusion) to 4 mL / min (second infusion) or 8 mL / min (subsequent infusions).4.3 Participants

[0145] Eligible patients were aged 18-80 years and had IgAN confirmed by biopsy <8 years before informed consent; proteinuria >1.0 g / d (Part 1 ) or >0.5 g / d (Part 2); treatment with maximally-tolerated ACEi and / or ARB >3 months before informed consent; systolic blood pressure <125 mmHg; and diastolic blood pressure <75 mmHg. Exclusion criteria included secondary IgAN (eg, resulting from lupus nephritis or chronic liver disease); estimated glomerular filtration rate (eGFR) <30 mL / min / 1 .73 m2(CKD-EPI) or need of dialysis or kidney transplant; rapidly progressive variant of IgAN (eGFR loss of >30% within 3 months); minimal change variant of IgAN; other progressive glomerulonephritis or nonimmunologic glomerular disease (eg, diabetic nephropathy); systemic immunosuppressive therapy, particularly corticosteroid therapy >20 mg / day prednisone-equivalent for >7 consecutive days with 180 days of informed consent; or prior anti-CD38 treatment.Atty. Docket No. 2790B-1 18WO14.4 Endpoints and assessments

[0146] The primary endpoint was the change from baseline in 24-hour urine proteimcreatinine ratio (UPCR) at 9 months. Secondary endpoints included change in eGFR and the incidence and severity of treatment-emergent AEs (TEAEs). Exploratory endpoints included change from baseline in Gd-lgA1 and polyclonal IgA, IgG, and IgM. Proteinuria (24-hour UPCR) and eGFR were assessed at screening, pre-dose at baseline and at months 3, 6 (end of treatment [EOT]), 9, 12, 15, 18, 21 , and 24 (end of study [EOS]). Serum levels of Gd-lgA1 were measured using a validated EOLIA (MorphoSys AG) at baseline; on days 8, 15, 22, 29, 57, 85 (3 months), 113, 141 , 169 (6 months; EOT), 267 (9 months), 366 (12 months), 457 (15 months), 548 (18 months), 639 (21 months), and 730 (24 months; EOS). Serum levels of IgM, IgG, and IgA were measured using immunoturbidimetric assays (Roche) at screening and baseline; on days 8, 15, 22, 29, 57, 85 (3 months), 1 13, 141 , 169 (6 months; EOT), 267 (9 months), 366 (12 months), 457 (15 months), 548 (18 months), 639 (21 months), and 730 (24 months; EOS). Safety monitoring included vital signs, physical examinations, electrocardiograms, hematology and chemistry, coagulation, and urinalysis. All AEs were recorded and graded using CTCAE, version 5.0.4.5 Statistical analysis

[0147] Efficacy analyses were performed using the per protocol set (PPS; all patients who received >1 study treatment and met the below PPS criteria; Part 1 , n=41 ; Part 2, n=6). Seven patients in Part 1 (2-dose, n=1 ; 5-dose, n=3; 9-dose, n=3) were excluded from the PPS for receiving <3 infusions of blinded study drug. Three additional patients received prohibited therapy and remained in the PPS until the time of prohibited medication. Safety analyses included patients who received >1 dose of study treatment (full analysis set [FAS]; n=54) based on actual treatment. Pharmacodynamic analyses included patients in the PPS with >1 available sample.

[0148] Continuous variables were summarized using means, standard deviations (SD), medians, and interquartile ranges (IQR). Categorical variables were summarized using the numbers and proportions of patients. Time to serum immunoglobulin recovery (the first measurement within 10% of baseline following on-treatment nadir) was estimated using Kaplan- Meier time-to-event analysis. Patients were right-censored at the time of study discontinuation and initiation of prohibited therapy. The primary endpoint (decrease in 24-hour UPCR) was estimated using a mixed-effects model with repeated measures (MMRM), in which the percentage change from baseline in UPCR was the response variable and baseline UPCR, treatment, visit, treatment by visit interaction were fixed-effect covariates. The model made no assumptions for correlation of UPCR between visits within a patient. Within-group treatment comparisons were summarized using least-squares (LS) means and standard error (SE) derived from the MMRM. Change from baseline in eGFR was assessed using an MMRM on the additive scale.Atty. Docket No. 2790B-1 18WO14.6 Study participants

[0149] 97 patients were screened, of whom 48 were randomized in Part 1 (placebo, n=12; felzartamab 2-dose, n=12; felzartamab 5-dose, n=1 1 ; felzartamab 9-dose, n=13), and six Japanese patients were enrolled in Part 2 (open-label felzartamab 9-dose). Overall, patients were predominantly men (66.7%) and White (61.1 %) or Asian (37.0%; Table 15). The mean (SD) age was 41 .6 (12.3) years overall (n=54) and varied between treatment arms in Part 1 (placebo, 39.6 [11 .8] years; felzartamab 2-dose, 47.4 [10.4] years; felzartamab 5-dose, 35.1 [14.3] years; felzartamab 9-dose, 39.2 [7.2] years) and Part 2 (felzartamab 9-dose open-label; 51 .7 [14.2] years).Atty. Docket No. 2790B-118WO1Atty. Docket No. 2790B-1 18WO1

[0150] Median (IQR) baseline 24-hour UPCR was 1 .4 (0.9-2.3) g / g overall and varied between treatment arms in Part 1 (placebo, 1 .8 [1 .3-2.9] g / g; felzartamab 2-dose, 1 .4 [1 .0-2.2] g / g; felzartamab 5-dose, 1.8 [1 .1 -2.3] g / g; felzartamab 9-dose, 1.1 [0.6-2.7] g / g) and Part 2 (1 .0 [0.7-1 .2] g / g). Median (IQR) baseline eGFR for was 69.2 (48.3-100.7) mL / min / 1.73 m2overall and varied between treatment arms in Part 1 (placebo, 73.8 [49.6-110.2] mL / min / 1 .73 m2; felzartamab 2-dose, 55.0 [43.2-64.5] mL / min / 1.73 m2; felzartamab 5-dose, 83.7 [58.4-1 18.0] mL / min / 1.73 m2; felzartamab 9-dose, 62.3 [48.5-85.0] mL / min / 1 .73 m2) and Part 2 (85.3 [66.5-105.6] mL / min / 1.73 m2).

[0151] The six-month treatment phase was completed by 46 of 54 (85.2%) patients overall, including 40 of 48 (83.3%) in Part 1 and all six (100.0%) patients in Part 2 (FIGs. 19A-19C). Eight (16.7%) patients in Part 1 discontinued treatment due to AEs (n=6), withdrawn consent (n=1 ), and patient request (n=1 ). Exposure is summarized in Table 16. Overall, 48 of 54 (88.9%) patients completed follow-up and two (3.7%) patients discontinued follow-up due to withdrawn consent (n=1 ) and investigator decision (n=1 ). The median (range) follow-up time was 24 months in Part 1 and 12 months in Part 2.Atty. Docket No. 2790B-118WO14.7 Efficacy

[0152] Proteinuria (24-hour UPCR) was reduced in the felzartamab arms versus the placebo arm beginning at month 3 of the treatment period and remained reduced 18 months after EOT (24 months), with the greatest reduction observed in the 9-dose arm (FIGs. 5A, 21 , 22A, 22B). In Part 1 (n=41 ), the LS mean (SE) change from baseline to 9 months (n=39) in 24-hour UPCR was -5.7% (14.4%) in the placebo arm, -12.5% (14.0%) in the felzartamab 2-dose arm (LS mean difference [LSMD] vs placebo, -6.8%; 95% Cl: -47.5%, 33.9%), -12.8% (16.5%) in the felzartamab 5-dose arm (LSMD, -7.1%; 95% Cl: -51.3%, 37.1%), and -29.5% (14.8%) in theAtty. Docket No. 2790B-1 18WO1 felzartamab 9-dose arm (LSMD, -23.8%; 95% Cl: -65.7%, 18.1 %). The LS mean (SE) change from baseline to 24 months (n=34) in 24-hour UPCR was 3.7% (17.2%) in the placebo arm, -1 .9% (16.4%) in the felzartamab 2-dose arm (LSMD vs placebo, -5.6%; 95% Cl: -53.7%, 42.5%), -9.5% (17.9%) in the felzartamab 5-dose arm (LSMD, -13.2%; 95% Cl: -63.6%, 37.2%), and -44.5% (16.7%) in the felzartamab 9-dose arm (LSMD, -48.2%; 95% Cl: -97.0%, 0.6%). In Part 2 (open-label felzartamab 9-dose arm), LS mean (SE) change from baseline in 24-hour UPCR was -44.8% (19.2%) at 9 months (n=6; LSMD, -39.1 %; 95% Cl: -88.1 %, 9.9%) and -48.8% (22.3%) at 12 months (n=6; LSMD, -61.8%; 95% Cl: -1 18.6%, -5.0%; Tables 17 and 18, FIGs. 5A, 21 , 22A, 22B, 35).Atty. Docket No.2790B-118WO1Atty. Docket No. 2790B-1 18WO1SD, standard deviation; UPCR, urine protein:creatinine ratio.

[0153] The decline in eGFR was reduced in the felzartamab arms versus the placebo arm beginning at month 3 of the treatment period and continued to 18 months after EOT (month 24; FIGs. 5B, 23, 24A, 24B). In Part 1 , the LS mean (SE) change from baseline (n=41 ) to 24 months (n=35) in eGFR was -15.2 (4.2) ml_ / min / 1.73 m2in the placebo arm, -7.1 (3.9) mL / min / 1.73 m2in the felzartamab 2-dose arm (LSMD, 8.1 mL / min / 1 .73 m2; 95% Cl: -3.5, 19.7), -4.0 (4.4) mL / min / 1 .73 m2in the felzartamab 5-dose arm (LSMD, 11 .2 mL / min / 1 .73 m2; 95% Cl: -1 .0, 23.4), and -6.4 (4.1) mL / min / 1 .73 m2in the felzartamab 9-dose arm (LSMD, 8.8 mL / min / 1.73 m2; 95% Cl: -3.0, 20.6). In Part 2 (open-label felzartamab 9-dose arm), the LS mean (SE) change from baseline to 12 months (n=6) in eGFR was -9.6 (4.2) mL / min / 1.73 m2(LSMD, 1 .1 mL / min / 1 .73 m2; 95% Cl: -11.8, 9.6; FIGs. 5B, 23, 24A, 24B).4.8 Pharmacodynamic markers

[0154] Maximal reduction of serum total IgA occurred during the six-month treatment period, with greater median decreases from baseline observed in the felzartamab arms than in the placebo arm (-32.6% to -35.8% vs -7.2%; FIG. 19A). During the off-treatment follow-up, median total IgA gradually increased in the 2-dose and 5-dose arms but remained reduced in the 9-dose arms. At 24 months, the reductions in median total IgA were greater in the Part 1 9-dose arm (-19.8%) than in the 2-dose arm (-8.9%) and 5-dose arm (-13.7%). Kaplan-Meier estimated median (95% Cl) time to IgA recovery (i.e., to within 10% of baseline) after EOT increased as the number of felzartamab doses increased (2-dose, 9.2 [0.1 -NR] ; 5-dose, 14.9 [6-NR]; 9-dose, >18 months; 9-dose open-label, >12 months after EOT, FIG. 25A). Most participants who received nine doses of felzartamab (Part 1 , n=7 [70%]; Part 2, n=4 [67%]) had sustained reductions in median total IgA at 24 months without recovery during off-treatment follow-up (FIG. 19D). In contrast, following an initial decrease from baseline to months 3 and 6 of the treatment period, median serum total IgG and IgM recovered to baseline levels in all felzartamab arms within 6 months after EOT (12 months; FIGs. 19B, 19C, 25C, 25D).

[0155] Serum levels of Gd-lgA1 were decreased in the felzartamab arms versus the placebo arm and gradually increased toward baseline during off-treatment follow-up (FIG. 20). Reductions in serum Gd-lgA1 were similar between the felzartamab treatment arms, with maximal median reductions from baseline of -31 .2% to -43.2% compared with -6.8% in the placebo arm. Median time to Gd-lgA1 recovery tended to increase with more felzartamab doses (2-dose, 2.9 [-3.4-NR]; 5-dose, 3.9 [-1.6-NR]; 9-dose, 9.0 [-2.3-NR]; 9-dose open-label, 5.8 [-4.1 -NR] months relative to 6-month EOT; FIG. 25B).

[0156] The phase 2a IGNAZ study is the first to evaluate anti-CD38 plasma cell-directed therapy for IgAN. Treatment with felzartamab led to rapid, durable, and clinically relevant reduction in proteinuria, indicating a disease-modifying effect of plasma cell depletion with theAtty. Docket No. 2790B-118WO1 anti-CD38 monoclonal antibody felzartamab in patients with IgAN and persistent proteinuria despite treatment with stable and maximally tolerated RAS inhibitors. Given that targeting proximal pathogenic events is important for preserving kidney function in IgAN, it is noteworthy that reduction in proteinuria with felzartamab was observed by month 3 of the treatment period, with the greatest mean reductions in the felzartamab 9-dose arms. Furthermore, the reductions in proteinuria with felzartamab were maintained for 18 months after ending treatment in all three arms in Part 1 (2-dose, -1.9%; 5-dose, -5.6%; 9-dose, -44.5%) and for 6 months after ending treatment in Part 2 (-48.8%), indicating that the treatment effects were durable, especially in the 9-dose arms, and that continuous treatment with felzartamab is not needed to maintain clinically meaningful changes in proteinuria. These findings contrast those of a recent phase 3 study, in which proteinuria reductions in patients with IgAN were sustained for only three months after completion of 9-months of daily therapy.

[0157] The reduction of proteinuria in the felzartamab arms was accompanied by evidence of stabilized kidney function, assessed as a reduction in eGFR decline compared with the placebo arm (LSMD of change, 10.7%— 15.6%) at 18 months after ending therapy.

[0158] Consistent with the mechanism of felzartamab depletion of antibody-secreting plasma cells and plasmablasts, serum levels of total IgA, IgG, and IgM and Gd-lgA1 rapidly decreased during treatment with felzartamab compared with placebo, but serum total IgA remained reduced 18 months after ending therapy in the 9-dose arm. Importantly, serum Gd-lgA1 gradually recovered toward baseline after ending therapy in the placebo arm and felzartamab arms, suggesting that the changes in serum Gd-lgA1 may be due, at least in part, to the natural progression of IgAN. Consistent with these findings, recovery of serum Gd-lgA1 toward baseline levels was also observed in patients with IgAN following discontinuation of 12 months of APRIL blockade in a randomized double-blind phase 2 study.

[0159] The IGNAZ study population is representative of the general IgAN population. Patients were predominantly male, White or Asian, had clinically significant proteinuria (median 24-hour UPCR, 1.4 g / g; IQR, 0.9-2.3) and mild kidney dysfunction per KDIGO20 (median eGFR, 69.2 mL / min / 1.73 m2; IQR, 48.3-100.7), were receiving maximally tolerated ACEi or ARB, and were diagnosed a median of 2.4 years before entry. Because the incidence of IgAN appears to be greater among Japanese patients, Part 2 of the study enrolled six additional Japanese patients who received the felzartamab 9-dose regimen open-label. The effects of felzartamab on proteinuria, eGFR, and Gd-lgA1 in the Japanese arm were consistent with those seen with the same regimen in Part 1 .

[0160] Felzartamab was well tolerated and had a safety profile consistent with that in patients with antibody-mediated kidney transplant rejection and primary membranous nephropathy treated with felzartamab. TEAEs were generally mild or moderate in severity and there were no grade 4 or 5 TEAEs or dose-related relationship with safety. Two patients who received felzartamab hadAtty. Docket No. 2790B-1 18WO1 serious AEs that resolved. Six patients had TEAEs resulting in discontinuation of felzartamab, five from treatment-related IRR / hypersensitivity and one from treatment-emergent anxiety. Similar to other reports with felzartamab and anti-CD38 therapy, four patients had grade 3 IRRs or hypersensitivity during the first infusion, all of which resolved with medication or discontinuation of felzartamab. All infections were mild or moderate in severity and did not appear to be dependent on felzartamab dose. Consistent with the observation that humoral immunity to SARS- Cov-2 vaccination remains intact in both primary membranous nephropathy patients and IgA nephropathy patients following treatment with felzartamab, median serum IgG and IgM recovered to above baseline levels.

[0161] The sustained reduction of proteinuria >18 months after EOT in the felzartamab 9-dose arm persisted longer than the suppression of IgG and IgM, indicating a disease-specific effect and that humoral immunity is preserved despite depletion of plasma cells. The tolerable safety profile of felzartamab, the sustained reduction of proteinuria at >18 months after EOT in the felzartamab 9-dose arm, and the reduced decline in kidney function are benefits of felzartamab for patients with IgAN at high risk for loss of kidney function.Atty. Docket No. 2790B-118WO1Atty. Docket No. 2790B-1 18WO1Example 5: Randomized, controlled trial demonstrating that treatment with CD38 monoclonal antibody felzartamab suppresses antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence post-treatment in some patients.5.1 Study Background and Methods

[0162] A randomized, controlled trial demonstrated that treatment with CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence post-treatment in some patients.

[0163] The study examined the molecular effects of 6-months felzartamab treatment on biopsies using genome-wide microarray analysis, comparing pre-treatment, end-of-treatment (24 week) and post-treatment (week 52) biopsies from 10 felzartamab and 10 placebo patients.5.2 Outcomes

[0164] As shown in FIGS. 26A-26E, felzartamab reduced molecular ABMR activity scores in all 9 patients with baseline ABMR activity, selectively suppressing interferon gamma (IFNG)- inducible and natural killer (NK) cell transcripts, with minimal effect on ABMR-induced endothelial transcripts (FIG. 26E) and no effect on T cell transcripts. However, molecular recurrence was nearly universal by week 52 (FIG. 26C). In genome-wide transcriptome analysis, felzartamab impacted 58 genes between baseline and week 24 (FIG. 26A). Ten of the top 20 differentially expressed genes were decreased, including those associated with ABMR activity (FIG. 26A). Functional enrichment analysis confirmed suppression of 12 ABMR-related pathways. Of the top 20 differentially expressed genes, 10 were increased. These genes likely represented normal parenchymal genes, suppressed by ABMR activity, all of which decreased after therapy, mirroring the return of ABMR activity by week 52. Felzartamab suppressed both IFNG-inducible and NK- expressed ABMR activity genes. From baseline to week 52, felzartamab affected 166 genes. 17Atty. Docket No. 2790B-1 18WO1 of the top 20 genes were injury-inducible and decreased by week 52. Lastly, felzartamab slowed the trajectories of molecular injury scores, indicating lasting recovery from ABMR-related parenchymal injury.

[0165] Felzartamab selectively suppressed IFNG-inducible (FIG. 26E) and NK cell (FIG. 26F) transcripts, offering parenchymal benefits and potentially slowing progression to kidney failure despite near-universal molecular recurrence by week 52.Example 6: Sub-study of randomized, double-blind, bi-center, placebo-controlled phase 2 trial, felzartamab, a monoclonal CD38 antibody, reversed morphological and molecular antibody-mediated rejection (AMR) activity after kidney transplantation6.1 Methods

[0166] A randomized, double-blind, bi-center, placebo-controlled phase 2 trial, felzartamab, a monoclonal CD38 antibody, reversed morphological and molecular antibody-mediated rejection (AMR) activity after kidney transplantation (Mayer et al.,NEJM 2024; 391 :122) . The sub-study of the felzartamab trial investigated whether noninvasive biomarkers reflecting plasma cell activity (donor-specific antibody [DSA] characteristics), graft injury (donor-derived cell-free DNA [dd- cfDNA]) and intragraft inflammation (C-X-C motif chemokine ligands [CXCL]9 and 10), could reflect the resolution of AMR activity and / or its recurrence after treatment cessation.

[0167] Twenty-two recipients were randomized 1 :1 to receive felzartamab or placebo for six months, followed by a six-month observational period. Kidney biopsies were performed at 24 and 52 weeks. DSA mean fluorescence intensities (MFI), titers, and C1 q-fixing capability, along with CXCL9 / 10 levels in serum and urine were measured using microbead assays. Dd-cfDNA was quantified at tight intervals using digital droplet PCR in a subset (16 / 22) of patients.6.2 Outcomes

[0168] As shown in FIG. 27, the dd-cfDNA levels decreased in all but one patient within the first four weeks of treatment (median decrease in absolute dd-cfDNA-levels from baseline: -79% [IQR -91 % to -60%]). After treatment cessation, dd-cfDNA began to rise gradually. In contrast, DSA characteristics (MFI values, DSA titers, C1q-fixing), as well as CXCL9 and CXCL10 levels in serum and urine, showed no meaningful changes, with no significant differences between groups. These results suggest that dd-cfDNA is a useful biomarker for monitoring response to felzartamab treatment. Further, dd-cfDNA could be used to indicate the recurrence of rejection after treatment cessation in a timely non-invasive manner.Example 7: Selective and Potent Targeting of CD38+ Antibody-Secreting Cells from Patients with Immune-Mediated Kidney Disease7.1 Methods

[0169] It is known from analysis of data sourced from ImmuNexUT database4 (Immune Cell Gene Expression Atlas from the University of Tokyo) that the CD38 transcript is upregulated in plasmablasts (FIG. 28). Flow cytometry-based CD38 quantification was evaluated in immuneAtty. Docket No. 2790B-118WO1 cells from peripheral blood, bone marrow, and in vitro differentiated antibody-secreting cells (ASCs) from healthy donors and patients with immune-mediated disease (IMD).7.2 Outcomes

[0170] CD38 is highly expressed on ASCs and other cellular drivers of IMD. CD38 protein expression is highest on plasmablasts and plasma cells (FIG. 29). FIGs. 30A-30C show that CD38 increases while CD19 and CD20 expression diminishes as B cells from peripheral blood of healthy donors differentiate into ASCs. ASCs, including plasmablasts and plasma cells, express the highest median levels of CD38 at 70,000-400,000 molecules / cell. FIGs. 31A-31C show antibody dependent cellular cytotoxicity (ADCC) assessed on pan B cells and in vitro differentiated plasmablasts and plasma cells from healthy donors incubated with the indicated B- cell-targeti ng therapies in the presence of allogeneic NK cells from healthy donors. Felzartamab selectively depleted ASCs while sparing earlier B-lineage cells, unlike other B-cell-targeting therapies. In particular, felzartamab mediated depletion of in vitro differentiated plasmablasts from patients with IMDs.7.3 Methods

[0171] Depletion of ASCs after treatment with felzartamab was assessed in NSG-SGM3 mice engrafted with human CD34+cord blood in vivo. NSG-SGM3 mice were injected with human CD34+progenitor cells from cord blood on day zero. On days 0, 1 , 1 .5, 2, and 2.5 the mice were then injected with felzartamab or vehicle. At three weeks post engraftment, blood was drawn and analyzed by flow cytometry.7.4 Outcomes

[0172] FIGs. 32 & 33 show that felzartamab treatment decreased human plasmablasts relative to vehicle treatment in engrafted huCD34+NSG-SGM3 mice in vivo. Felzartamab mediated depletion of CD38br'9htplasmablasts in vivo in this humanized mouse model. FIG. 34A shows the change in Ig-K chain titers over the course of the trial in vehicle-treated mice, while FIG. 34B shows the same in felzartamab-treated mice. Relative to titers observed in vehicle-treated mice, felzartamab treatment led to reduction of human Ig-K titers in vivo.Example 8: A quantitative systems pharmacology model of felzartamab to link immune cell and pharmacodynamic responses in immune mediated diseases8.1 Methods

[0173] A five-compartment model was established that includes a central compartment, a peripheral compartment, and compartments for antibody secreting cell maturation and survival (immunologic, bone marrow, and gut). Plasma cell repopulation was also modeled including in the immunological compartment which represents B cell maturation in secondary lymphoid organs (eg, spleen, lymph nodes). See, FIG. 36.Atty. Docket No. 2790B-1 18WO1

[0174] The model encodes maturation of naive B cells into plasma cells, secretion of immunoglobulin A (IgA) and immunoglobulin G (IgG), and drug-dependent killing of CD38+ plasma cells and NK cells. Felzartamab exposure was modeled using parameters derived from a previously developed population pharmacokinetic model. The PK parameters for felzartamab were derived from population pharmacokinetic (popPK) analysis fitted to exposure data from clinical studies of felzartamab in IMDs. Polyclonal immunoglobulin, circulating plasmablast, and circulating NK cell data was generated from longitudinal samples collected in the IGNAZ, AMR, MPLACE, and NewPLACE studies as listed in FIG. 37.

[0175] The Python language (version 3.12) was used to perform all analysis in this work. The model was implemented using the Applied BioMath (now Certara) QSP Notebook platform version 2.0.0b11 , and the fides-BFGS method (Frohlich et al., 2022) was used for optimization.8.2 Outcomes

[0176] The model was able to capture reduction and repopulation of circulating short-lived plasma cells and NK cells following felzartamab treatment, consistent with observed trends in clinical data (FIG. 38). Target cell half-life appears to be an important determinant of the magnitude of cellular depletion as well as the durability of PD effects. In addition, the model recapitulates the differences observed in serum IgG and IgA dynamics following treatment. FIGs. 39A-39C (NK cells) and FIGs. 40A-40C (plasma cells) show that repopulation rates of impact the depth and durability of felzartamab treatment induced reduction. Longer half-lives or slower cell repopulation results in deeper reductions in cell counts that require longer to recover.

[0177] Serum IgG titers were reduced to a lesser extent than serum IgA titers and recovered to baseline following the last dose of felzartamab (FIGs. 41 A-41 B). In contrast, serum IgA titers remained below baseline and exhibited slower recovery. The biophysical compartment of IgG and IgA secreting cells could contribute to the observed differences in serum IgG and IgA dynamics.

[0178] Taken together, the model identified potential target cell characteristics important to understanding felzartamab drug effects. This quantitative systems pharmacology model links the mechanistic effects of felzartamab on plasma and NK cells to cellular regeneration and PD effects (immunoglobulin secretion).

[0179] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Atty. Docket No. 2790B-1 18WO1Claims1. A method of treating a subject suffering from IgA nephropathy, the method comprising administering to the subject a regimen of at least five doses of felzartamab over six months, and measuring a level of CD19+CD27hiCD38hiplasmablasts, a level of CD19+ B lymphocytes, or levels of CD19+CD27hiCD38hiplasmablasts and CD19+ B lymphocytes in a blood sample taken from the subject after the six months.

2. The method of claim 1 , wherein each of the doses is 650 mg to 1625 mg felzartamab.

3. The method of claim 1 or 2, wherein nine doses of felzartamab are administered over the six months.

4. The method of claim 3, wherein the doses are administered on days 1 , 8, 15, 22, 29, 57, 85, 113, and 141 of the regimen.

5. The method of any one of claims 1 -4, wherein the measuring comprises performing flow cytometry on the blood sample.

6. The method of any one of claims 1 -5, further comprising measuring a galactose-deficient immunoglobin A1 (Gd-lgA1 ) titer in the blood samples.

7. The method of any one of claims 1 -6, further comprising administering a further regimen of felzartamab to the subject after the measuring.

8. The method of any one of claims 1 -6, further comprising measuring a baseline level of CD19+ B lymphocytes of the subject before the administering step, comparing the level of CD19+ B lymphocytes in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level of CD19+ B lymphocytes in the blood sample is not more than 10% less than the baseline level.

9. The method of any one of claims 1 -6 and 8, further comprising measuring a baseline level of CD19+CD27hiCD38hiplasmablasts of the subject before the administering step, comparing the level of CD19+CD27hiCD38hi plasmablasts in the blood sample to the baseline level, and administering a further regimen of felzartamab to the subject if the level of CD19+CD27h'CD38hiplasmablasts in the blood sample is at least 10% less than the baseline level.

10. The method of any of the preceding claims, wherein the antibody or antibody fragment is dosed depending on subject body weight, optionally wherein the dosage is 650 mg for a subject weighing <50 kg; 975 mg for a subject weighing >50-70 kg; 1300 mg for a subject weighing >70-90 kg; 1625 mg for a subject weighing >90 kg.

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