Treatment of anti-PLA2R autoantibody-mediated membranous nephropathy

Abstract

The present disclosure relates to the treatment of anti-PLA2R positive membranous nephropathy. MOR202, an anti-CD38 antibody, is effective when administered to patients in a specific dosing regimen.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating anti-PLA2R autoantibody-mediated membranous nephropathy using antibodies that bind to the CD38 protein. In particular, it relates to improved dosing regimens of anti-CD38 antibodies, such as felzalutamab (MOR202), that are safe and effective for treating patients with anti-PLA2R autoantibody-mediated disorders. [Background technology]

[0002] Anti-PLA2R autoantibody-mediated membranous nephropathy (aMN), an autoimmune kidney disease, is a primary membranous nephropathy (MN) and the leading cause of nephrotic syndrome in adults worldwide (Ronco P, Debiec H Lancet. 2015 May 16; 385(9981): 1983-92). In the United States, the incidence of MN is about 1.2 per 100,000 people. Approximately 3,000 adults are newly diagnosed each year. People aged 50-60 years are usually affected (Couser WG. Clinical Journal of the American Society of Nephrology. 2017; 12(6): 983-97). 40-50% of MN patients progress to end-stage kidney disease (ESKD) within 10-15 years of diagnosis (Passerini P,et al. Front Immunol 2019;10(JUN):1-9; Lai WL,et al. J Formos Med Assoc 2015;114(2):102-11). Even in the absence of ESKD, patients with long-term nephrotic syndrome are at risk for severe and life-threatening thromboembolic and cardiovascular disease. Approximately 80% of MN cases are primary disease mediated by autoantibodies and 20% are secondary disease caused by other diseases. Approximately 75% of primary MN cases occur due to autoantibodies against the phospholipase A2 receptor (PLA2R), which targets PLA2R on podocytes (Bomback AS,et al. Am J Nephrol 2018;47(suppl 1):30-42). The binding of these autoantibodies induces complement activation and inflammation, thickening the glomerular membrane and impairing renal function (Zhang P,et al.J Immunol Res 2021;1-12). Nephrotic syndrome primarily refers to the presence of severe proteinuria (loss of more than 3.5 g of protein per day), low serum albumin, and significant edema. While 30-40% of patients may experience spontaneous remission, 30% of patients will experience persistent proteinuria with long-term preserved renal function, and another 30%-50% will progress to renal failure within 10-15 years (Trujillo H et al.Portuguese Journal of Nephrology & Hypertension.2019;33(1):19-27).Even if patients with nephrotic syndrome do not progress to renal failure, they are at increased risk of life-threatening thromboembolic and cardiovascular events and are more susceptible to infections.

[0003] The M-type phospholipase A2 receptor (PLA2R) is a transmembrane protein expressed in podocytes and defines it as the major autoantigen in MN (Beck LH Jr et al.N Engl J Med.2009 Jul 2;361(1):11-21). Autoantibodies binding to the PLA2R antigen are highly specific for primary MN. Recent studies have revealed the presence of anti-PLA2R autoantibodies in approximately 75% of MN patients that correlate considerably with disease activity (Bomback AS,Clin J Am Soc Nephrol.2018 May 7;13(5):784-786). The fact that the glomerular basal changes that define the disease include both PLA2R protein and antibody 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, thrombospondin type 1 domain containing 7A (THSD7A) (Tomas NM et al. N Engl J Med 2014;371:2277-2287). Symptoms of MN include, but are not limited to, leg and ankle swelling, proteinuria, edema, hypoalbuminemia, and elevated serum lipids, especially hypercholesterol. Thus, aMN is an immune-mediated glomerular disease characterized by the presence of anti-PLA2R and / or anti-THSD7A autoantibodies.

[0004] The main source of anti-PLA2R antibodies are CD38+ / CD20- plasma cells and plasmablasts (Halliley JL,et al.Immunity 2015;43(1):132-45). Higher anti-PLA2R autoantibody titers are associated with more severe disease, longer time to disease remission, and poorer response to anti-CD20 rituximab treatment (Pozdzik A,et al.Biomed Res Int 2018;6281054; Bech AP,et al.Clin J Am Soc Nephrol 2014;9(8):1386-925). Therefore, lowering anti-PLA2R antibody levels and / or preventing their rise may prove to be an effective treatment option. However, to date, there is no approved standard of care for MN. The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends using criteria such as anti-PLA2R antibody titers and proteinuria to risk stratify patients and determine treatment course (kdigo.org / wp-content / uploads / 2017 / 02 / KDIGO-GN-GLPublic-Review-Draft_1-June-2020.pdfAccessed September 2021). Current treatment plans consist primarily of a variety of non-immunosuppressive drugs (e.g., ACE inhibitors or angiotensin receptor blockers, statins, diuretics), conventional immunosuppressive therapy (IST) (e.g., combinations of cyclophosphamide and steroids, calcineurin inhibitors (CNIs), and mycophenolate mofetil), and off-label use of targeted immunosuppressants (e.g., anti-CD20 antibodies such as rituximab) (KDIGO 2020; Ronco P, et al. Journal of Clinical Medicine. 2021;10(4):607).

[0005] However, these treatments are not effective for all patients, and traditional IST in particular is associated with a high risk of toxicity (Couser WG. Clin J Am Soc Nephrol 2017;12(6):983-97). The drawback of most immunosuppressants is that they exhibit a significant degree of toxicity, with significant side effects and high relapse rates. Adverse events include infections, infertility, hematologic toxicity, and late-stage malignancies. For example, the drawbacks of CNIs include long-term nephrotoxicity, the need for careful monitoring of drug levels, and an increased risk of hypertension and diabetes.

[0006] In MN, a correlation between the clinical course of the disease and anti-PLA2R autoantibody titers is reported. Patients with higher anti-PLA2R autoantibody titers have more severe disease and longer time to disease remission (Pozdzik A, et al. BioMed Research International. 2018:1-19). High titers and persistent or recurrent positivity of anti-PLA2R antibody titers during treatment emerge as negative predictors of outcome (Bomback AS, et al. American Journal of Nephrology. 2018;47(1):30-42). In contrast, a decrease in anti-PLA2R autoantibody levels predicts the likelihood of future remission of proteinuria (Ruggenenti P, et al. Journal of the American Society of Nephrology. 2015;26(10):2545-58).

[0007] Mounting evidence that anti-PLA2R antibodies correlate with disease activity is changing previously established treatment algorithms.

[0008] Patients who present with high autoantibody titers receive off-label therapy with anti-CD20 therapeutic antibodies (e.g., rituximab), which allows for more specific IST by depleting the B cell populations involved as precursors of the plasma cells that produce the causative anti-PLA2R autoantibodies. Rituximab response rates appear to be similar to alkylating agents and CNIs, but side effects appear to be less than other agents used in IST. However, CD20, the target of rituximab, is absent on mature, long-lived antibody-secreting plasma cells (which are the main source of endogenous immunoglobulins). Compared to CD20 expression on mature B cells, only faint CD20 expression remains on early plasmablasts. This may explain the suboptimal efficacy of rituximab therapy in MN patients with high anti-PLA2R antibody titers. As a result, up to 40% of patients did not respond to anti-CD20 therapy (Bomback, 2018, Couser 2017).

[0009] In this regard, direct targeting of plasma cells as well as plasmablasts should generally result in a more pronounced reduction in immunoglobulins and therefore in autoantibodies. A significant portion of anti-PLA2R antibodies in aMNs may be produced by a pool of long-lived plasma cells with a CD20-negative but CD38-positive immunophenotype that are not dependent on the continuous replenishment of differentiating B cells. Thus, strategies that directly target plasma cells may have a greater effect on suppressing pathogenic autoantibodies. In particular, this is important for patients with high levels of autoantibody titers, such as those with poor responses to rituximab (anti-CD20) therapy, who maintain high levels of autoantibody titers despite B cell depletion.

[0010] Current treatments for aMN are often associated with adverse events and severe side effects, so new therapeutic options and dosing regimens are needed to treat aMN.

[0011] Felzalutamab offers a novel mechanism of action that may emerge as an important treatment option for patients with aMN compared to current (off-label) treatment options such as calcineurin inhibitors (CNIs), alkylating cytotoxic agents (cyclophosphamide), and anti-CD20 antibodies. Felzalutamab is an investigational fully human IgG1 monoclonal anti-CD38 antibody that depletes plasmablasts and plasma cells. Felzalutamab specifically binds to the cell surface antigen CD38. When felzalutamab binds to CD38-positive plasma cells, it promotes the depletion of such cells by two mechanisms of action: i) antibody-dependent cell-mediated cytotoxicity (ADCC), in which plasma cells are lysed by natural killer (NK) cells, and ii) antibody-dependent cell-mediated phagocytosis (ADCP), in which macrophages clear plasma cells (Endell J,et al. Blood.2012;120(21):4018-4018; Raab MS,et al. The Lancet Haematology.2020;7(5):e381-e394) (Figure 10). Its mechanism of action does not involve complement-dependent cytotoxicity, which is associated with infusion-related reactions (IRR).

[0012] Most therapeutic antibodies are administered as a fixed dose or a size-based dose. In size-based dosing regimens, mAbs are administered based on body weight or body surface area to ensure equal mAb exposure between patients.

[0013] The results of a first-in-human clinical trial of felzalutamab MOR202C101 (NCT01421186) defined the recommended dose as 16 mg / kg in patients with multiple myeloma (Raab MS, et al. The Lancet Haematology. 2020;7(5):e381-e394). Based on the pharmacokinetic and pharmacodynamic results of this clinical trial, we used a modeling and simulation approach to identify the appropriate dose and dosing regimen for the treatment of patients with aMN. The applied model was a minimal physiological PK model (mPBPK model) that implements i) previously published drug distribution concepts (Niederalt C, et al. J Pharmacokinet Pharmacodyn 2018;45(2):235-57; Cao Y, et al. J Pharmacokinet Pharmacodyn 2014;41(4):375-87), ii) the consideration that CD38-high expressing plasma cells as the main target cells are mainly located in a narrow compartment (e.g., bone marrow) with limited drug distribution. By assuming a specific time range for CD38 turnover, the established mPBPK was able to predict target occupancy, which could be compared with in vitro results predicting effective cell killing and thus clinical efficacy.

[0014] Surprisingly, a hybrid fixed dose regimen with dose levels similar to 16mg / kg and corresponding to a defined weight range predicted the best target occupancy (Example 2). This finding was unexpected. Compared to MM patients, aMN patients are devoid of tumor cells, and therefore, the amount of CD38pos cells present in aMN patients is significantly lower. Nevertheless, dose levels remain similar due to limited drug distribution to narrow compartments (such as bone marrow). The predicted drug levels were best achieved by using fixed dose levels corresponding to a defined weight range.

[0015] Furthermore, the applied treatment interval is particularly suitable for the treatment of aMN, since the higher drug exposure in the first 4 weeks (weekly or biweekly dosing) is expected to effectively reduce the number of target cells at the start of treatment. After that, the reduction in plasma cells is expected to be maintained over time, even with no further dosing or with a much reduced drug exposure. As described in Example 3, the two different exposure periods and potential retreatment after 3 or 5 months are selected to best characterize the interindividual variability of the exposure / efficacy relationship, taking into account long-term effects and potential effects after retreatment.

[0016] Felzalutamab is currently being studied in anti-PLA2R-positive aMN in a Phase Ib / IIa trial (M-PLACE, NCT04145440) and a Phase IIa trial (New-PLACE, NCT04733040).

[0017] Preliminary data indicate that felzartamab is effective in treating anti-PLA2R-positive aMN by eliminating cells that produce anti-PLA2R autoantibodies. Therefore, felzartamab results in a reduction of pathological anti-PLA2R autoantibodies in these patients (e.g., Figures 4, 5, 8, 9A, B). Felzartamab shows effective responses in patients with unmet medical need who do not or respond poorly to conventional therapies. Summary of the Invention

[0018] The present invention relates to an improved and effective dosing regimen with the anti-CD38 monoclonal antibody MOR202 (also known as felzalutamab) in patients with anti-PLA2R membranous nephropathy.

[0019] In one aspect, an antibody specific for CD38 is provided for use in treating a subject with autoantibody-mediated membranous nephropathy, comprising an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 of sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6), wherein the antibody is administered at a fixed dose level. In some embodiments, the autoantibody-mediated membranous nephropathy is anti-PLA2R positive membranous nephropathy. In some embodiments, the antibody is administered at a fixed dose corresponding to a weight range of the subject. In some embodiments, the antibody is administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg, corresponding to body weight ranges of <50 kg, 50.5-70 kg, 70.5-90 kg, and >90.5 kg, respectively. In some embodiments, the antibody is administered at a fixed dose level of 16 mg / kg. In some embodiments, the antibody is administered once a week (QW) for the first three weeks. In some embodiments, the antibody is administered once every two weeks (q2w). In some embodiments, the antibody is administered at intervals of i) days 1, 8, 15, 29, and 57, representing a three month treatment period, or ii) days 1 and 15, representing a one month treatment period. In some embodiments, the antibody for use further comprises a re-treatment 3 or 5 months after the end of the previous treatment period. In some embodiments, the antibody is administered at intervals of days 1, 8, 15, and 22, followed by administration on days 29, 57, 85, 113, and 141 during a 24 week treatment period. In some embodiments, the antibody is administered twice with an 85 day treatment interval. In some embodiments, the antibody is administered five times with an 85 day treatment interval. In some embodiments, the antibody is administered nine times with a 24 week treatment interval. In some embodiments, the antibody is administered nine times with a 141 day treatment interval. In some embodiments, the antibody is administered once a week for the first month of treatment, then once every four weeks thereafter.In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered intravenously over 2 hours. In some embodiments, the subject has a serum level of anti-PLA2R antibody at screening of ≧50 RU / mL, ≧100 RU / mL, ≧150 RU / mL, ≧200 RU / mL, ≧250 RU / mL, ≧300 RU / mL. In some embodiments, the subject has a serum level of anti-PLA2R antibody of ≧150 RU / mL. In some embodiments, the subject has a urinary protein-to-creatinine ratio (UCPR, g / g) of ≧3.0 g / g, ≧4.0 g / g, ≧5.0 g / g, ≧6.0 g / g, or ≧7.0 g / g. In some embodiments, in a 24-hour urine screen, the subject has proteinuria of ≧3.5 g / 24 hours, ≧4.0 g / 24 hours, ≧4.5 g / 24 hours, or ≧5.0 g / 24 hours. In some embodiments, the antibody results in a change of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% from baseline anti-PLA2R titer. In some embodiments, the subject has serum anti-PLA2R antibodies of ≧50 RU / mL and has a reduction in anti-PLA2R autoantibody titer of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% compared to baseline on day 8 of cycle 1. In some embodiments, the antibody provides a >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% change from baseline anti-PLA2R titer at day 8 of cycle 1. In some embodiments, the antibody provides a 25%-80% change from baseline anti-PLA2R titer. In some embodiments, the antibody provides a 25%-80% change from baseline anti-PLA2R titer over a 4 week treatment period.In some embodiments, the antibody results in a >80% change from baseline anti-PLA2R titer. In some embodiments, the antibody results in a >80% change from baseline anti-PLA2R titer over a 4 week treatment period. In some embodiments, the antibody does not increase anti-PLA2R titer over a 4 week treatment period. In some embodiments, the antibody comprises a variable heavy chain of sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of sequence DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8). In some embodiments, the antibody comprises an IgG1 Fc region. In some embodiments, the antibody is formulated for administration in combination with 650 mg to 1,000 mg of oral paracetamol. In some embodiments, the antibody is formulated for administration in combination with 25 mg to 50 mg of oral or intravenous diphenhydramine. In some embodiments, the antibody is formulated for administration in combination with 100 mg intravenous methylprednisolone, or the equivalent.

[0020] In another aspect, the present invention relates to a method of treating anti-PLA2R-mediated membranous nephropathy in a patient, comprising administering to the patient an anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a fixed dose. Preferably, the anti-CD38 antibody is felzalutamab. The antibody is administered at 16 mg / kg once a week (i.e., a total of four doses in cycle 1). In treatment cycles 2-6, felzalutamab is administered at 16 mg / kg once every four weeks on the first day of each cycle (i.e., C2D1, C3D1, ..., a total of five doses in cycles 2-6).

[0021] In another aspect, the invention provides felzalutamab or a biosimilar thereof for use in the treatment of a subject with anti-PLA2R-mediated membranous nephropathy, wherein felzalutamab or a biosimilar thereof is administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg, corresponding to body weight ranges of <50 kg, 50.5-70 kg, 70.5-90 kg, >90.5 kg, respectively, and felzalutamab or a biosimilar thereof is administered at intervals of i) days 1, 8, 15, 29, and 57 representing a three month treatment period, or ii) days 1 and 15 representing a one month treatment period, with optional re-treatment 3 or 5 months after the end of the previous treatment period, and wherein felzalutamab or a biosimilar thereof is administered intravenously.

[0022] In another aspect, the present invention provides a method for treating autoantibody-mediated membranous nephropathy, comprising administering to a subject in need of treatment a therapeutically effective amount of an antibody specific for CD38, comprising an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 region of sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6), wherein the antibody is administered at a fixed dose level. In some embodiments, the autoantibody-mediated membranous nephropathy is anti-PLA2R positive membranous nephropathy. In some embodiments, the antibody is administered at a fixed dose corresponding to a weight range of the subject. In some embodiments, the antibody is administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg, corresponding to body weight ranges of <50 kg, 50.5-70 kg, 70.5-90 kg, and >90.5 kg, respectively. In some embodiments, the antibody is administered at a fixed dose level of 16 mg / kg. In some embodiments, the antibody is administered once a week (QW) for the first three weeks. In some embodiments, the antibody is administered once every two weeks (q2w). In some embodiments, the antibody is administered at intervals of i) days 1, 8, 15, 29, and 57, representing a three month treatment period, or ii) days 1 and 15, representing a one month treatment period. In some embodiments, the method further comprises re-treating 3 or 5 months after the end of the previous treatment period. In some embodiments, the antibody is administered at intervals of days 1, 8, 15, and 22, followed by administration on days 29, 57, 85, 113, and 141 during a 24 week treatment period. In some embodiments, the antibody is administered twice with an 85 day treatment interval. In some embodiments, the antibody is administered five times with an 85 day treatment interval. In some embodiments, the antibody is administered nine times with a 24 week treatment interval. In some embodiments, the antibody is administered nine times with a 141 day treatment interval.In some embodiments, the antibody is administered once a week for the first month of treatment and once every four weeks after the first month. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered intravenously over two hours. In some embodiments, the subject has a serum level of anti-PLA2R antibody at screening of ≧50 RU / mL, ≧100 RU / mL, ≧150 RU / mL, ≧200 RU / mL, ≧250 RU / mL, ≧300 RU / mL. In some embodiments, the subject has a serum level of anti-PLA2R antibody of ≧150 RU / mL. In some embodiments, the subject has a urinary protein to creatinine ratio (UCPR, g / g) of ≧3.0 g / g, ≧4.0 g / g, ≧5.0 g / g, ≧6.0 g / g, or ≧7.0 g / g. In some embodiments, in a 24 hour urine screen, the subject has proteinuria of > 3.5g / 24 hr, > 4.0g / 24 hr, > 4.5g / 24 hr, or > 5.0g / 24 hr. In some embodiments, the antibody results in a change of > 10%, > 15%, > 20%, > 25%, > 30%, > 35%, > 40%, > 45%, > 50%, > 55%, > 60%, > 65%, > 70%, > 75%, > 80%, > 85%, > 90%, > 95% or 100% from baseline anti-PLA2R titer. In some embodiments, the subject has serum anti-PLA2R antibodies of ≧50 RU / mL and has a reduction in anti-PLA2R autoantibody titer of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% compared to baseline on day 8 of cycle 1. In some embodiments, the antibody provides a >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% change from baseline anti-PLA2R titer on day 8 of cycle 1. In some embodiments, the antibody provides a 25%-80% change from baseline anti-PLA2R titer.In some embodiments, the antibody provides a 25%-80% change from baseline anti-PLA2R titer over a 4 week treatment period. In some embodiments, the antibody provides a >80% change from baseline anti-PLA2R titer. In some embodiments, the antibody provides a >80% change from baseline anti-PLA2R titer over a 4 week treatment period. In some embodiments, the antibody does not increase anti-PLA2R titer over a 4 week treatment period. In some embodiments, the antibody comprises a variable heavy chain of sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of sequence DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8). In some embodiments, the antibody comprises an IgG1 Fc region. In some embodiments, the antibody is administered in combination with 650 mg to 1,000 mg of oral paracetamol. In some embodiments, the antibody is administered in combination with 25 mg to 50 mg of oral or intravenous diphenhydramine. In some embodiments, the antibody is administered in combination with 100 mg of intravenous methylprednisolone, or its equivalent.

[0023] In another aspect, the present invention provides a method of treating anti-PLA2R mediated membranous nephropathy, the method comprising administering a therapeutically effective amount of felzalutamab or a biosimilar of felzalutamab to a subject in need of treatment, wherein felzalutamab or a biosimilar of felzalutamab is administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg, corresponding to a body weight range of <50 kg, 50.5-70 kg, 70.5-90 kg, >90.5 kg, respectively, wherein felzalutamab or a biosimilar of felzalutamab is administered at intervals of i) days 1, 8, 15, 29, and 57 representing a three month treatment period, or ii) days 1 and 15 representing a one month treatment period, optionally with re-treatment 3 or 5 months after the end of the previous treatment period, and wherein felzalutamab or a biosimilar of felzalutamab is administered intravenously. [Brief description of the drawings]

[0024] [Figure 1] Figure 1 shows a schematic of the major cell types of B cell differentiation and their CD19, CD20, and CD38 expression levels. The main antibody-secreting cell types targeted by anti-CD38 antibody therapy (such as treatment with MOR202) are shown. [Diagram 2] Figure 2 shows the dosing schedule for the treatment of anti-PLA2R-mediated membranous nephropathy (New-PLACE trial, NCT04733040). If no immune response is obtained or only partial, the initial 3-month treatment phase may be followed by additional treatment phases at the same or similar dosing intervals. [Diagram 3] Figure 3 shows the simulation results of CD38 target occupancy after 5 or 2 doses of felzalutamab. Predicted CD38 receptor occupancy results after fixed doses of felzalutamab. Example of an 85 kg aMN patient receiving a dose of 1300 mg. (A) 5 doses, (B) 2 doses. Best scenario: CD38 half-life is 800 min, drug partition coefficient is 0.85, worst scenario: CD38 half-life is 80 min, drug partition coefficient is 0.95. [Figure 4]FIG. 4 shows the relative change in anti-PLA2R antibody titers from baseline 8 weeks after initiation of treatment (Cohort 1 (5-dose schedule) (based on preliminary data from the ongoing New-PLACE study NCT04733040)). [Diagram 5] FIG. 5 shows the relative change in anti-PLA2R antibody titers from baseline 8 weeks after initiation of treatment (Cohort 2 (2-dose schedule) (based on preliminary data from the ongoing New-PLACE trial NCT04733040)). [Figure 6] Figure 6 shows the study design of the M-PLACE trial (9-dose schedule) NCT04145440. Anti-PLA2R+: anti-phospholipase A2 receptor positive, C: cycle, EOT: end of treatment, FU: observation, IST: immunosuppressive treatment, IV: intravenous, MN: membranous nephropathy, TEAE: treatment-emergent adverse events. [Figure 7] Figure 7 shows serum concentrations of felzalutamab pre-dose and weeks 1-4 post-dose based on preliminary data from the M-PLACE study (9-dose schedule), NCT04145440. After evaluation of felzalutamab serum levels over the first month of treatment, all patients demonstrated drug exposure within the expected concentration range. [Figure 8] Figure 8 shows the relative change from baseline in anti-PLA2R antibody titers in C1D8 based on preliminary data from the M-PLACE study (9-dose schedule) NCT04145440. Of the 31 patients analyzed, 25 showed a decrease in anti-PLA2R antibody levels after 1 week of treatment, 3 had an increase, and 3 had no visit or early discontinuation, resulting in unavailable data for day 8 of cycle 1. Ab: antibody, anti-PLA2R: anti-phospholipase A2 receptor, C: cycle, D: day, IgG: immunoglobulin G, IPR: immunological partial response. [Figure 9A]Figure 9A shows a preliminary phenotypic subgroup analysis based on anti-PLA2R response (≥4 weeks post-treatment) based on preliminary data from the M-PLACE study (9-dose schedule) NCT04145440. A significant reduction in anti-PLA2R antibody titers (>80% reduction in change from baseline at last available visit or absolute values ​​<20 U / mL). A surprising finding is that felzalutamab can induce a rapid and sustained reduction in anti-PLA2R autoantibody titers, independent of cohort or initial anti-PLA2R titers, thereby providing mechanistic evidence. [Figure 9B] Figure 9B shows a preliminary phenotypic subgroup analysis based on anti-PLA2R response (≥ 4 weeks post-treatment) based on preliminary data from the M-PLACE study (9-dose schedule) NCT04145440. Intermediate reductions in anti-PLA2R antibody titers (changes between 25-80% reduction from baseline at last available visit (inclusive of lower and upper limits)). A surprising finding is that felzalutamab can induce a rapid and sustained reduction in anti-PLA2R autoantibody titers, independent of cohort or initial anti-PLA2R titers, thereby providing mechanistic evidence. [Figure 9C] Figure 9C shows a preliminary phenotypic subgroup analysis based on anti-PLA2R response (≥ 4 weeks post-treatment) based on preliminary data from the M-PLACE study (9-dose schedule) NCT04145440. Variable anti-PLA2R antibody titers (patients not meeting criteria for deep or intermediate decline). If patients met criteria for multiple categories, they were classified into higher categories (variable < intermediate, decline < deep decline). A surprising finding was that felzalutamab was able to induce a rapid and sustained decline in anti-PLA2R autoantibody titers, independent of cohort or initial anti-PLA2R titers, thereby providing mechanistic evidence. [Figure 10]Figure 10 shows the mechanism of action of felzalutamab in MN. Plasmablasts and short- and long-lived plasma cells are CD38 positive cells. The anti-CD38 antibody felzalutamab causes the destruction of plasmablasts and plasma cells via ADCC and ADCP, thereby reducing the secretion of destructive anti-PLA2R autoantibodies. ADCC: antibody-dependent cell-mediated cytotoxicity, ADCP: antibody-dependent cell-mediated phagocytosis, CD: cluster of differentiation, FcγR: Fc-gamma receptor, NK: natural killer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] definition The term "CD38" refers to the protein known as CD38, which has the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1, T10.

[0026] Human CD38 (UniProt P28907) has the following amino acid sequence: MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI (SEQ ID NO: 9)

[0027] CD38 is a type II transmembrane glycoprotein and is an example of an antigen highly expressed on antibody-secreting cells (including autoantibody-secreting plasmablasts and plasma cells). Functions ascribed to CD38 include both receptor-mediated adhesion, signaling events, and (ecto)enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as a substrate for the formation of cyclic ADP-ribose (cADPR) and ADPR as well as nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to function as second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 controls the extracellular NAD+ concentration and thereby cell survival by regulating NAD-induced cell death (NCID). In addition to signaling via Ca2+, CD38 signaling occurs via crosstalk with antigen receptor complexes on T and B cells, or with other types of receptor complexes (such as MHC molecules), and thus is involved in several cellular responses as well as in IgG antibody switching and secretion.

[0028] The term "antibody" refers to a monoclonal antibody, including all isotypes, such as IgG, IgM, IgA, IgD, and IgE. The preferred isotype of antibody for use in the present invention is IgG. IgG antibodies are composed of two identical heavy chains and two identical light chains linked by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called "complementarity determining regions" ("CDRs") or "hypervariable regions" and are primarily responsible for binding to an epitope of an antigen. These are referred to, from the N-terminus, as CDR1, CDR2, and CDR3. The more highly conserved portions of the variable regions outside the CDRs are referred to as "framework regions." An "antibody fragment" refers to an Fv, scFv, dsFv, Fab, Fab'F(ab')2 fragment, or other fragments that contain at least one variable heavy chain or variable light chain, each of which contains a CDR and a framework region. Such antibodies or antibody fragments can be of any type, such as murine, rat, chimeric, humanized or human antibodies or antibody fragments.

[0029] "VH" refers to the variable region of the immunoglobulin heavy chain of an antibody or antibody fragment. "VL" refers to the variable region of the immunoglobulin light chain of an antibody or antibody fragment.

[0030] As used herein, the term "anti-CD38 antibody" includes an anti-CD38 binding molecule in the broadest sense and any molecule that specifically binds to CD38, inhibits the activity or function of CD38, or otherwise affects CD38.

[0031] Antibodies specific for CD38 are described, for example, in WO199962526 (Mayo Foundation), WO200206347 (Crucell Holland), US2002164788 (Jonathan Ellis), WO2005103083, WO2006125640 and WO2007042309 (MorphoSys AG), WO2006099875 (Genmab), and WO2008047242 (Sanofi-Aventis). Combinations of antibodies specific for CD38 with other agents are described, for example, in WO200040265 (Research Development Foundation), WO2006099875 and WO2008037257 (Genmab), as well as WO2010061360, WO2010061359, WO2010061358 and WO2010061357 (Sanofi Aventis), all of which are incorporated by reference in their entirety.

[0032] As used herein, a "human antibody" or "human antibody fragment" is an antibody or antibody fragment having variable regions in which the framework and CDR regions are derived from sequences of human origin. If the antibody contains a constant region, the constant region is also derived from such sequences. Human origin includes, but is not limited to, antibodies that contain human germline sequences, mutated versions of human germline sequences, or consensus framework sequences derived from human framework sequence analysis, e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86). Human antibodies can be isolated, for example, from synthetic libraries or transgenic mice (e.g., Xenomouse). An antibody or antibody fragment is human if its sequences are human, regardless of the species from which the antibody is physically derived, isolated, or produced.

[0033] The structures and positions of immunoglobulin hypervariable domains, e.g., CDRs, can be defined using well-known numbering schemes, such as the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (e.g., Interest, USDepartment 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 USDepartment of Health and 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. al., (1997) J. Mol. Biol. 273:927-948).

[0034] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition that displays a unique binding site having a unique binding specificity and affinity for a particular epitope.

[0035] The present disclosure provides a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of the disclosed anti-CD38 antibody. As used herein, a "therapeutically effective amount" or "effective amount" refers to the amount of an antibody specific for CD38 required to induce a desired biological response. According to the present disclosure, a therapeutically effective amount is the amount of an antibody specific for CD38 required to treat and / or prevent autoantibody-mediated membranous nephropathy and symptoms associated with said disorder.

[0036] The amount effective for a particular therapeutic purpose depends on the severity of the disease or injury, as well as the weight and general condition of the subject. The effective amount for a particular individual may vary depending on factors such as the condition being treated, the overall health of the patient, the 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; Dent (2001) Good Laboratory and Good Clinical Practice, London, UK).

[0037] As used herein, the terms "treatment," "treating," and the like mean alleviating the symptoms, removing the cause of the symptoms, either temporarily or permanently, or preventing or delaying the appearance of symptoms of the specified disorder or condition.

[0038] "Prevent" or "prevention" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of a disease from developing in a subject who may be exposed to a disease-causing agent or who is predisposed to a disease prior to the onset of the disease). "Prevention" refers to a method aimed at preventing the onset of a disease or its symptoms or a method aimed at delaying the onset of a disease or its symptoms.

[0039] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure that is intended to prevent, rather than treat or cure, a disease. Non-limiting examples of prophylactic measures include administration of a vaccine, administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis, for example, due to immobilization, and administration of an antimalarial drug such as chloroquine before visiting an area where malaria is prevalent or where there is a high risk of acquiring malaria.

[0040] "Administered" or "administration" includes, but is not limited to, delivery of the drug by an injectable form, such as an intravenous, intramuscular, intradermal or subcutaneous route or a mucosal route, as a nasal spray or aerosol for inhalation, or as an ingestible solution, capsule or tablet. Preferably, administration is by an injectable form. The antibodies of the present disclosure can be administered at different times and the treatment cycles can have different lengths. The antibodies can be administered daily, every other day, three times a week, weekly, or every other week. The antibodies can also be administered for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks.

[0041] As used herein, the terms "subject", "subject in need of treatment" and the like refer to a human or non-human animal that exhibits one or more symptoms or signs of autoantibody-mediated membranous nephropathy and / or a human or non-human animal that has been diagnosed with autoantibody-mediated membranous nephropathy.Preferably, the subject is a primate, and most preferably a human patient that has been diagnosed with autoantibody-mediated membranous nephropathy.Preferably, the autoantibody-mediated membranous nephropathy is anti-PLA2R positive membranous nephropathy.

[0042] As used in this context, "subject" or "species" refers to any mammal, including rodents, such as mice or rats, and primates, such as cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), or humans (Homo sapiens). Preferably, the subject is a primate, and most preferably a human.

[0043] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, as used herein, the phrase "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0044] As used herein, "pharmacokinetics" or "PK" refers to how the body affects a particular drug after administration through mechanisms such as absorption and distribution, changes in the body's metabolism of the drug, and the effects and excretion routes of the drug's metabolites. The pharmacokinetic properties of a drug can be affected by the route of administration and the dose of the drug administered.

[0045] "Pharmaceutically acceptable" means approved or approvable by a federal or state regulatory authority or a corresponding authority in a country other than the United States, or as set forth in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, especially humans.

[0046] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which an antibody or antibody fragment is administered.

[0047] 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", are understood to imply the inclusion of particular elements or integers, or groups of elements or integers, but not to exclude other elements or integers, or groups of elements or integers.

[0048] "MOR202" is an anti-CD38 antibody also known as "MOR03087" or "MOR3087" or "Ferzalutamab." These terms are used interchangeably in this disclosure. MOR202 has an IgG1 Fc region.

[0049] According to Kabat, the amino acid sequence of MOR202 HCDR1 is as follows: SYYMN (SEQ ID NO: 1)

[0050] According to Kabat, the amino acid sequence of MOR202 HCDR2 is as follows: GISGDPSNTYYADSVKG (SEQ ID NO:2)

[0051] According to Kabat, the amino acid sequence of MOR202 HCDR3 is as follows: DLPLVYTGFAY (SEQ ID NO: 3)

[0052] According to Kabat, the amino acid sequence of MOR202 LCDR1 is as follows: SGDNLRHYYVY (SEQ ID NO: 4)

[0053] According to Kabat, the amino acid sequence of MOR202 LCDR2 is as follows: GDSKRPS (SEQ ID NO:5)

[0054] The amino acid sequence of MOR202 LCDR3 is as follows: QTYTGGASL (SEQ ID NO:6)

[0055] The amino acid sequence of the MOR202 variable heavy domain is as follows: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7)

[0056] The amino acid sequence of the MOR202 variable light domain is as follows: DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8)

[0057] The DNA sequence encoding the MOR202 variable heavy domain is as follows: CAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACCTATTATGCGG ATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA (SEQ ID NO: 10)

[0058] The DNA sequence encoding the MOR202 variable light domain is as follows: GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGG CATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGCGGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 11)

[0059] The amino acid sequence of MOR202 HCDR1 by HuCAL is as follows: GFTFSSYYMN (SEQ ID NO: 12)

[0060] The term "biosimilar" is used herein in a manner consistent with the working definition promulgated by the FDA, which defines a biosimilar product as one that is "highly similar" to a reference product (despite minor differences in clinically inactive ingredients). In practice, there are no clinically meaningful differences between the reference and biosimilar products in terms of safety, purity, or potency (PHS Act § 262). "Reference product" refers, for example, to commercially available felzalutamab.

[0061] Embodiment The present disclosure relates to improved dosing regimens for MOR202, an antibody specific for CD38, useful for the prevention and / or treatment of autoantibody-mediated membranous nephropathy, preferably anti-PLA2R-mediated membranous nephropathy or glomerulonephritis.

[0062] An antibody specific for CD38 for use in treating a subject with autoantibody-mediated membranous nephropathy is provided, comprising an HCDR1 region of the sequence GFTFSSYYMN (sequence number 12) or SYYMN (sequence number 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (sequence number 2), an HCDR3 of the sequence DLPLVYTGFAY (sequence number 3), an LCDR1 region of the sequence SGDNLRHYYVY (sequence number 4), an LCDR2 region of the sequence GDSKRPS (sequence number 5), and an LCDR3 region of the sequence QTYTGGASL (sequence number 6).

[0063] The present disclosure also provides pharmaceutical compositions comprising the above antibodies, and methods for preventing and / or treating autoantibody-positive membranous nephropathy, preferably anti-PLA2R-positive membranous nephropathy or glomerulonephritis, by administering the above antibodies to a patient under the dosing regimen provided by the present invention.

[0064] One aspect of the present disclosure provides an antibody specific for CD38 for use in the treatment of autoantibody-mediated membranous nephropathy, comprising an HCDR1 region of the sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 of the sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of the sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of the sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of the sequence QTYTGGASL (SEQ ID NO: 6), wherein the antibody is administered at a fixed dose level.

[0065] In a preferred embodiment, the antibody is for use in treating anti-PLA2R positive membranous nephropathy, and said antibody is administered in a fixed dose corresponding to a weight range.

[0066] In further aspects, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered at a fixed dose of 650 mg, 975 mg, 1300 mg or 1625 mg, corresponding to body weight ranges of <50 kg, 50.5-70 kg, 70.5-90 kg, and >90.5 kg, respectively.

[0067] In another embodiment, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered at the above fixed dose levels once weekly (QW) or once every two weeks (q2w) for the first three weeks.

[0068] In another embodiment, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered on i) days 1, 8, 15, 29, and 57, or ii) days 1 and 15, during an 85 day treatment interval following the initial administration at the fixed dose level described above.

[0069] The antibody for use in treating anti-PLA2R-positive membranous nephropathy is administered at intervals of i) days 1, 8, 15, 29, and 57, representing a three month treatment period, or ii) days 1 and 15, representing a one month treatment period.

[0070] The antibody for use in treating anti-PLA2R-positive membranous nephropathy is administered at intervals of i) days 1, 8, 15, 29, and 57, representing a three month treatment period, or ii) days 1 and 15, representing a one month treatment period, with re-treatment occurring three or five months after the end of the previous treatment period.

[0071] In another embodiment, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered intravenously.

[0072] One aspect of the disclosure includes a method of treating anti-PLA2R positive membranous nephropathy in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antibody specific for CD38, the antibody having the sequence The antibody comprises an HCDR1 region of GFTFSSYYMN (sequence number 12) or SYYMN (sequence number 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (sequence number 2), an HCDR3 of the sequence DLPLVYTGFAY (sequence number 3), an LCDR1 region of the sequence SGDNLRHYYVY (sequence number 4), an LCDR2 region of the sequence GDSKRPS (sequence number 5), and an LCDR3 region of the sequence QTYTGGASL (sequence number 6), and is administered at a dose of about 16 mg / kg or more.

[0073] One aspect of the disclosure includes a method of treating anti-PLA2R positive membranous nephropathy in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antibody specific for CD38, the antibody having the sequence The antibody comprises an HCDR1 region of GFTFSSYYMN (sequence number 12) or SYYMN (sequence number 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (sequence number 2), an HCDR3 of the sequence DLPLVYTGFAY (sequence number 3), an LCDR1 region of the sequence SGDNLRHYYVY (sequence number 4), an LCDR2 region of the sequence GDSKRPS (sequence number 5), and an LCDR3 region of the sequence QTYTGGASL (sequence number 6), and the antibody is administered at a fixed dose corresponding to a weight range.

[0074] One aspect of the disclosure includes a method of treating anti-PLA2R positive membranous nephropathy in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of an antibody specific for CD38, the antibody comprising an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 of sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6), the antibody being administered at a fixed dose corresponding to a body weight range, the antibody being administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg, corresponding to a body weight range of <50 kg, 50.5-70 kg, 70.5-90 kg, and >90.5 kg, respectively.

[0075] A further embodiment includes the use of an antibody specific for CD38 in the preparation of a medicament for the treatment of anti-PLA2R positive membranous nephropathy, the antibody comprising an HCDR1 region of the sequence GFTFSSYYMN (sequence number 12) or SYYMN (sequence number 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (sequence number 2), an HCDR3 of the sequence DLPLVYTGFAY (sequence number 3), an LCDR1 region of the sequence SGDNLRHYYVY (sequence number 4), an LCDR2 region of the sequence GDSKRPS (sequence number 5), and an LCDR3 region of the sequence QTYTGGASL (sequence number 6), the antibody being administered at a dose of about 16 mg / kg or more.

[0076] A further embodiment includes the use of an antibody specific for CD38 in the preparation of a medicament for the treatment of anti-PLA2R positive membranous nephropathy, the antibody comprising an HCDR1 region of the sequence GFTFSSYYMN (sequence number 12) or SYYMN (sequence number 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (sequence number 2), an HCDR3 of the sequence DLPLVYTGFAY (sequence number 3), an LCDR1 region of the sequence SGDNLRHYYVY (sequence number 4), an LCDR2 region of the sequence GDSKRPS (sequence number 5), and an LCDR3 region of the sequence QTYTGGASL (sequence number 6), the antibody being administered in fixed doses corresponding to a body weight range.

[0077] A further embodiment includes the use of an antibody specific for CD38 in the preparation of a medicament for the treatment of anti-PLA2R positive membranous nephropathy, said antibody comprising an HCDR1 region of the sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 of the sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of the sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of the sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of the sequence QTYTGGASL (SEQ ID NO: 6), said antibody being administered at a fixed dose corresponding to a weight range, said antibody being administered at a fixed dose of 650 mg, 975 mg, 1300 mg or 1625 mg, corresponding to a weight range of <50 kg, 50.5-70 kg, 70.5-90 kg, >90.5 kg, respectively.

[0078] In a particular aspect, the present disclosure relates to an antibody specific to CD38 for use in treating anti-PLA2R positive membranous nephropathy, the antibody comprising an HCDR1 region of the sequence GFTFSSYYMN (SEQ ID NO: 12) or SYYMN (SEQ ID NO: 1), an HCDR2 region of the sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 of the sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of the sequence SGDNLRHYYVY (SEQ ID NO: 4), an LCDR2 region of the sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of the sequence QTYTGGASL (SEQ ID NO: 6), the antibody being administered at a dose of 16 mg / kg or more.

[0079] In one embodiment, the antibody comprises an HCDR1 region of the sequence GFTFSSYYMN (SEQ ID NO: 12). In one embodiment, the antibody comprises an HCDR1 region of the sequence SYYMN (SEQ ID NO: 1).

[0080] In certain embodiments, the disclosed antibodies specific for CD38 are administered at a dose of 16 mg / kg or greater.

[0081] In a preferred embodiment, the antibody is for use in treating anti-PLA2R positive membranous nephropathy and the antibody is administered at 16 mg / kg.

[0082] In certain embodiments, the antibody is administered twice (ie, twice) with an 85 day treatment interval.

[0083] In a specific embodiment, the antibody is administered five times with an 85 day treatment interval (ie, 5 times).

[0084] In certain embodiments, the antibody is administered nine times with a 24 week treatment interval (ie, 9 times).

[0085] In a specific embodiment, the antibody is administered nine times with a treatment interval of 141 days (ie, 9 times).

[0086] In another embodiment, felzaltamab is administered at 16 mg / kg once weekly for the first month of treatment, then once every four weeks at 16 mg / kg.

[0087] In certain embodiments, the antibody is administered intravenously.

[0088] In a specific embodiment, the antibody is administered intravenously over a period of two hours.

[0089] In certain embodiments, the antibody comprises the sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7) and a variable heavy chain of the sequence DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8) and a variable light chain of

[0090] In certain embodiments, the antibody comprises an IgG1 Fc region.

[0091] In a preferred embodiment, the anti-CD38 antibody is felzalutamab. In another embodiment, the antibody is a biosimilar of felzalutamab.

[0092] In another embodiment, the present disclosure provides a method for treating and / or preventing proteinuria associated with anti-PLA2R-positive membranous glomerulonephritis in an individual, the method comprising administration of an effective amount of an antibody or antibody fragment specific for CD38, or one or more pharmaceutical compositions described herein.

[0093] In another embodiment, the present disclosure provides a method for preventing decline in renal function in an individual with anti-PLA2R-positive membranous nephropathy, the method comprising administration of an effective amount of an antibody or antibody fragment specific for CD38, or one or more pharmaceutical compositions described herein.

[0094] In another embodiment, a method for treating anti-PLA2R autoantibody-mediated membranous nephropathy comprises the steps of: i) measuring the weight of a subject having anti-PLA2R-positive membranous glomerulonephritis; ii) determining the dose of anti-CD38 antibody to be administered based on a fixed dose scheme of 650 mg, 975 mg, 1300 mg or 1625 mg, corresponding to weight ranges of 50 kg, 50.5-70 kg, 70.5-90 kg, and >90.5 kg; and iii) administering the determined fixed dose of antibody to the subject.

[0095] In another embodiment, a method of treating anti-PLA2R autoantibody-mediated membranous nephropathy in a subject is provided, the method comprising: i) determining anti-PLA2R titer in a subject with anti-PLA2R-positive membranous glomerulonephritis prior to administration of an anti-CD38 antibody; and ii) administering the anti-CD38 antibody felzalutamab at a dose of 16 mg / kg to the subject on days 1, 8, 15, 22, 29, 57, 85, 113, and 141, wherein the subject has serum anti-PLA2R antibodies ≧50 RU / mL, ≧100 RU / mL, ≧150 RU / mL, ≧200 RU / mL, ≧250 RU / mL, ≧300 RU / mL (detected by serum ELISA) at screening.

[0096] In one embodiment, anti-PLA2R titers are determined by serum ELISA.

[0097] In another embodiment, felzalutamab (MOR202) or a biosimilar of felzalutamab is used to reduce anti-PLA2R autoantibody titers in patients with anti-PLA2R-positive aMN.

[0098] In one embodiment, the determined fixed dose of antibody is administered once a week (QW) or once every two weeks (q2w) for the first three weeks.

[0099] In another embodiment, the antibody is administered at intervals of i) days 1, 8, 15, 29, and 57; or ii) days 1 and 15.

[0100] In another embodiment, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered at intervals of days 1, 8, 15, and 22, followed by administration on days 29, 57, 85, 113, and 141 during a 24 week treatment period.

[0101] In another embodiment, the antibody for use in treating anti-PLA2R positive membranous nephropathy is administered at 16 mg / kg at intervals of 1, 8, 15, and 22, followed by 29, 57, 85, 113, and 141 days during a 24 week treatment period.

[0102] In one embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, the antibody is administered at 16 mg / kg, and the antibody results in a change of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% from baseline anti-PLA2R titer.

[0103] In one embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, the antibody is administered at 16 mg / kg, and the antibody results in a change of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% from baseline anti-PLA2R titer on day 8 of cycle 1.

[0104] In another embodiment, felzalutamab (MOR202) or a biosimilar of felzalutamab is used to reduce anti-PLA2R autoantibody titers in patients with anti-PLA2R-positive aMN, resulting in a reduction in anti-PLA2R autoantibody titers compared to baseline of >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% on Day 1 of Cycle 8.

[0105] In another embodiment, felzalutamab (MOR202) or a biosimilar of felzalutamab is used to reduce anti-PLA2R autoantibody titers in a subject with anti-PLA2R-positive aMN, where the subject has serum anti-PLA2R antibodies ≧50 RU / mL and the reduction in anti-PLA2R autoantibody titers compared to baseline is >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95% or 100% on Day 1 of Cycle 8.

[0106] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, wherein the antibody is administered at 16 mg / kg, and the antibody results in a 25-80% change from baseline anti-PLA2R titer.

[0107] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, wherein the antibody is administered at 16 mg / kg, and the antibody results in a 25-80% change from baseline anti-PLA2R titer over 4 weeks of treatment.

[0108] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, wherein the antibody is administered at 16 mg / kg, and the antibody results in a >80% change from baseline anti-PLA2R titer.

[0109] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, wherein the antibody is administered at 16 mg / kg, and the antibody results in a >80% change from baseline anti-PLA2R titer over 4 weeks of treatment.

[0110] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, the antibody is administered at 16 mg / kg, and the antibody stabilizes or maintains anti-PLA2R titers over 4 weeks of treatment.

[0111] In another embodiment, the antibody is used to treat anti-PLA2R positive membranous nephropathy, the antibody is administered at 16 mg / kg, and the antibody does not increase anti-PLA2R titers over a 4 week treatment period.

[0112] In one embodiment, felzalutamab (MOR202) or a biosimilar of felzalutamab is used as the anti-PLA2R antibody reduction agent.

[0113] In one embodiment, felzalutamab (MOR202) or a biosimilar of felzalutamab is used as the anti-PLA2R antibody titer stabilizing agent.

[0114] In one embodiment, a subject with anti-PLA2R positive aMN has a urinary protein to creatinine ratio (UPCR, (g / g)) of ≧3.0 g / g, ≧4.0 g / g, ≧5.0 g / g, ≧6.0 g / g, or ≧7.0 g / g.

[0115] In another embodiment, subjects with anti-PLA2R positive aMN on a 24 hour urine screen have proteinuria of ≧3.5 g / 24 hr, ≧4.0 g / 24 hr, ≧4.5 g / 24 hr, or ≧5.0 g / 24 hr. EXAMPLES

[0116] Example 1: Study Population - NewPLACE Study (NCT04733040) NewPLACE is a two-arm, multicenter, open-label, parallel-group Phase II study evaluating the efficacy, safety, and pharmacokinetics / pharmacodynamics of the human antibody MOR202 in subjects with anti-PLA2R antibody-positive membranous nephropathy who are candidates for immunosuppressive therapy.

[0117] ClinicalTrials.gov identifier: NCT04733040-NewPLACE study

[0118] Patients were eligible to participate in the study if they met the following criteria:

[0119] Study Inclusion Criteria The subjects' age was ≥18 to ≤80 years (as of the date of signing the informed consent). · Urinary protein-to-creatinine ratio (UPCR) ≥ 3.0 g / g (measured from a 24-hour urine collection) at screening or proteinuria ≥ 3.5 g / 24 hours from a 24-hour urine collection. Estimated glomerular filtration rate (eGFR) ≥ 50 ml / min / 1.73 m 2 It is. (If the renal biopsy reveals an interstitial fibrosis and tubular atrophy (IFTA) score of <25%, then eGFR >30 and <50 ml / min / 1.73 m 2 (may include). - Failure to achieve spontaneous remission despite adequate treatment (sufficient dose and duration) with angiotensin-converting enzyme inhibitors (ACEIs) and / or angiotensin receptor blockers (ARBs) in accordance with clinical practice and scientific guidelines. If a subject is intolerant to ACEIs and / or ARBs, the reasons must be documented and approval for enrollment must be obtained from the medical monitor. · Systolic blood pressure (BP) < 150mmHg and diastolic blood pressure < 100mmHg after 5 minutes of rest. Serum anti-PLA2R antibodies measured by Euroimmun ELISA are ≥ 50.0RU / mL. For female subjects, women were eligible to participate if they were not pregnant, not breastfeeding, and met at least one of the following criteria: a. Not a female of childbearing potential (FCBP), or b. FCBP who agree to follow contraception instructions during treatment and for at least 3 months after the last dose of MOR202.

[0120] Main Exclusion Criteria Hemoglobin <80g / L (4.96mmol / L) · Thrombocytopenia: Platelets<100.0x10 9 / L ·Neutropenia: Neutrophils <1.5x10 9 / L ·Leukopenia: white blood cells <3.0x10 9 / L Hypogammaglobulinemia: Serum immunoglobulin ≦4.0g / L ·B cells<5x10 6 / L Type 2 diabetes: Subjects with type 2 diabetes must have a renal biopsy performed within 6 months prior to screening that shows MN without evidence of diabetic nephropathy. - Glycated hemoglobin (HbA1c) < 8.0% or 64mmol / mol; - No known diabetic retinopathy, - No known peripheral neuropathy, Patients may only participate in clinical trials if their diabetes is controlled as indicated by Total bilirubin, aspartate aminotransferase or alanine aminotransferase >1.5xULN, alkaline phosphatase >3.0xULN.

[0121] Main outcome measures The primary objective of this study is to evaluate the efficacy of two different dosing regimens of MOR202 in patients with anti-PLA2R antibody-positive membranous nephropathy, characterized by changes in anti-PLA2R antibody levels after 3 months compared to baseline.

[0122] Secondary outcome measures To evaluate the efficacy of two different dosing regimens of MOR202 in terms of complete immunological response (ICR) rates after 3, 6, 12, and 24 months, characterized by anti-PLA2R antibody levels.

[0123] The efficacy of two different dosing regimens of MOR202 will be evaluated in terms of total proteinuric response (OPR) rates at 6, 12, and 24 months.

[0124] To evaluate the safety of MOR202, we will assess the frequency, incidence, and severity of treatment-emergent adverse events (TEAEs) from the end of treatment (average 3 months per treatment period).

[0125] To evaluate the PK profile of MOR202 as determined by serum concentrations over time.

[0126] The potential immunogenicity of MOR202, as determined by the formation of anti-drug antibodies (ie, the number of subjects expressing anti-MOR202 antibodies), will be investigated.

[0127] Example 2: Dose modeling Previously, a population PK (POP-PK) model for felzartamab was established based on the results of the first-in-human clinical trial MOR202C101 in MM patients (NCT01421186; Raab MS, et al. The Lancet Haematology. 2020; 7(5): e381-e394). To predict the appropriate dose and dosing regimen for the treatment of aMN patients, the existing Pop-PK model was adapted to aMN patients, taking into account the difference in total CD38 levels between both populations. aMN subjects were assumed to have similar CD38 expression levels as healthy volunteers (HV) (expression level = number of CD38 molecules per cell type × number of cells). For MM patients, we assumed the same amount of CD38 expression plus the MM tumor cell population. Values ​​for total CD38 expression were obtained from various publications.(Brooimans RA et al. Cytometry.Part B,Clinical cytometry 76(1),S.18-26;Donohue DM,et al.The Journal of clinical investigation 37(11),S.1564-1570;Terstappen LW et al..Blood 76(9),S.1739-1747;Muschler GF et al. al.J.Orthop.Res.19(1),S.117-125;Hernigou P et al.International orthopaedics 37(11),S.2279-2287;Fennema EM,et al.Acta orthopaedica 80(5),S.618-621;Halliley JL,Tipton C,Liesveld J,et al.Immunity 43(1),S.132-145;Loken MR,et al.Cytometry.Part B,Clinical cytometry 76(1),S.27-36;Mei HE,et al.Blood 125(11),S.1739-1748;Sambuceti G,et al. European journal of nuclear medicine and molecular imaging 39(8),S.1326-1338;Trepel F(1974)Klinische Wochenschrift 52(11),S.511-515;Hassan et al.Journal of the Royal Society of Medicine 97(10),S.465-471).

[0128] Based on this evaluation, the following values ​​were used for total CD38 expression, resulting in 4.54-fold higher target expression in MM patients compared to aMN patients:

[0129] The average CD38 expression level in MM patients is approximately 3.5x10^16 molecules.

[0130] The average CD38 expression level in IgAN patients is approximately 7.7x10^15 molecules.

[0131] This coefficient was implemented into the existing POP-PK model of FiH study MOR202C101 by adjusting the Michaelis-Menten-like nonlinear clearance term part of the model.

[0132] In step 2, the above Pop-PK model for aMN subjects was combined with a minimal physiological PK model (mPBPK model). This combination provided a PK / PD modeling approach that allowed prediction of felzalutamab levels in various organs. Step 2 was important because the main target cells of felzalutamab (i.e., CD38-high expressing plasma cells) are primarily located in compartments where monoclonal antibodies show limited distribution (e.g., immune niches in the bone marrow).

[0133] Considering the main mechanisms of action of MOR202 (i.e., ADCC and ADCP), CD38 occupancy was identified as a relevant PD parameter for evaluating clinical efficacy. As shown in in vitro experiments, felzalutamab-induced cell killing depended on the number of CD38 molecules expressed on the cell surface of target cells and the number of felzalutamab molecules bound per cell (Boxhammer R (2015). MOR202, a Human Anti-CD38 Monoclonal Antibody, Mediates Potent Tumoricidal Activity In Vivo and Shows Synergistic Efficacy in Combination with Different Antineoplastic Compounds. Poster Publication ASH). Assuming the presence of sufficient and active NK cells or macrophages as effector cells, high cell killing was observed with approximately ≥ 150,000 antibody binding (ABC) per cell for both mechanisms of action. A decrease in ABC levels resulted in a decrease in cell killing efficacy. Considering that the average CD38 expression rate is about 430,000 molecules per plasma cell in bone marrow, a target occupancy rate of about 35% needs to be achieved to induce adequate cell killing. Nevertheless, a higher target occupancy rate seems preferable, especially at the beginning of treatment, taking into account differences in CD38 expression on plasma cells (ranging from about 220,000 to 780,000 ABC) and interindividual variability such as differences in the number and cellular activity of NK / macrophage cells.

[0134] To assess which felzalutamab dose would ensure such target occupancy, an established PK / PD model was used for simulations, assuming the following: The primary target cells of felzaltamab (i.e., CD38-high plasma cells) are located primarily in compartments where monoclonal antibodies have limited distribution (e.g., bone marrow); and By considering a specific time range of CD38 turnover.

[0135] The results of simulating CD38 occupancy in an 85 kg aMN patient receiving a fixed dose of 1300 mg felzalutamab, considering the 5th and 2nd dose schedule, are summarized in Figure 3. With 5 doses of felzalutamab, a target occupancy of 81%-92% was predicted during the first month of treatment in the best case simulation scenario (CD38 half-life of 800 min, drug partition coefficient of 0.85). With the worst case simulation scenario, a target occupancy of 37%-54% was predicted during the first month of treatment (CD38 half-life of 80 min, drug partition coefficient of 0.95). With 2 doses of felzalutamab, the target occupancy was predicted to be 81%-88% in the best scenario and 24%-52% in the worst scenario. Similar results were observed for other weight ranges, as shown in Example 3.

[0136] Example 3: NewPLACE-Administration MOR202 is dosed according to the patient's weight, which should be measured the day before, or preferably the day of, injection. Four fixed dose levels are used, corresponding to four weight ranges. TIFF2024525870000001.tif29170

[0137] M1 group: Five doses of MOR202 were administered on days 1, 8, 15, 29, and 57.

[0138] M2 group: Two doses of MOR202 were administered on days 1 and 15.

[0139] Subjects in the M1 group who have no ICR on anti-PLA2R antibody levels after 6 months (day 183) will receive the same course of treatment (5 doses) starting on day 204. Subjects in the M2 group who have an immunological partial response (IPR) will receive the same course of treatment (2 doses) starting on day 204. Subjects in the M2 group who have no ICR or IPR on anti-PLA2R antibody levels after 6 months (day 183) will receive a 5-dose regimen starting on day 204 (5 doses). Thus, subjects will receive 650 mg to 1625 mg of MOR202 per dose (intravenously, IV) in 5 doses administered on days 1, 8, 15, 29, and 57, or 2 doses administered on days 1 and 15.

[0140] Medications to reduce the risk of infusion-related reactions (IRR) due to MOR202 should be administered 30 to 60 minutes prior to infusion. Oral paracetamol 650-1,000mg Oral or intravenous diphenhydramine 25-50 mg or equivalent Methylprednisolone 100 mg or equivalent given intravenously The first infusion of MOR202 lasts approximately 90 minutes. If no infusion reactions occur, the infusion time may be shortened to 1 hour for the second dose, or even shorter for subsequent infusions. The infusion time must be at least 30 minutes. TIFF2024525870000002.tif48170

[0141] If a complete response in anti-PLA2R antibody levels is not observed at the 6 month visit (ie, day 183), the subject may be treated again on day 204.

[0142] Example 4: Preliminary Results New-PLACE (NCT04733040) A preliminary evaluation of anti-PLA2R antibody levels 8 weeks after the start of treatment with felzalutamab is shown in Figure 4 (cohort M1, 5-dose schedule) and Figure 5 (cohort M2, 2-dose schedule). In most patients, a decrease in anti-PLA2R antibody levels was observed after 8 weeks of treatment. In a few patients in cohort M1 (5-dose schedule) (Figure 4), no decrease in anti-PLA2R antibody levels was observed after 8 weeks of treatment and there was no strong increase in autoantibody levels. Most patients in cohort M2 (2-dose schedule) (Figure 5) responded with a significant decrease in anti-PLA2R antibody levels after 8 weeks of treatment. The increase in autoantibody levels in the few patients in cohort M2 (2-dose schedule) in which no decrease in autoantibodies occurred appeared to be more pronounced than in the corresponding patients in cohort M1 (5-dose schedule).

[0143] Overall, the observed decrease in anti-PLA2R antibody titers after 8 weeks of treatment was independent of cohort, suggesting successful depletion of CD38+ plasma cells in most patients treated with felzalutamab.

[0144] Example 5: Preliminary Results M-PLACE (NCT04145440) According to the site investigator, enrolled patients were aged 18–80 years with biopsy-proven anti-PLA2R-positive MN requiring IST. Other key inclusion criteria were: - Urinary protein to creatinine ratio (UPCR) ≥ 3.0 g / g by 24-hour urine screen, or proteinuria ≥ 3.5 g / 24 hours - Estimated glomerular filtration rate (eGFR) ≥ 50 mL / min / 1.73 m 2 or eGFR ≥ 30 and < 50 mL / min / 1.73 m 2 and renal biopsy interstitial fibrosis and tubular atrophy score <25%.

[0145] A total of 31 patients were enrolled in one of the two cohorts. Cohort 1: Newly diagnosed patients (Cohort 1A) and patients who relapsed on previous treatment (Cohort 1B), with serum anti-PLA2R antibodies ≥ 50RU / mL (central laboratory, Euroimmun ELISA) - Cohort 2: Patients with anti-PLA2R positive MN who are refractory to previous IST and require another IST

[0146] Patients received 16 mg / kg felzalutamab intravenously (IV) for nine doses, once weekly for the first month of treatment and then once every four weeks (Figure 6). After completion of treatment, patients continued to be followed up for up to 28 weeks.

[0147] The primary outcome was the incidence and severity of treatment-emergent adverse events (TEAEs). TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

[0148] Key secondary endpoints were best immune response, complete immunological response (ICR) rate, and partial immunological response (IPR) based on reduction in serum anti-PLA2R antibody titers. -ICR was defined as a decrease in anti-PLA2R antibody titer to <14 RU / mL. -IPR was defined as a >50% decrease in anti-PLA2R antibody titers from baseline.

[0149] Pharmacokinetics (PK, felzalutamab serum levels) and immunogenicity (anti-drug antibodies) were assessed at selected time points in all patients during the study. Model-based prediction of PK was performed prior to study initiation, based on PK data from the first-in-human study (NCT01421186) and expected total CD38 expression in MN patients.

[0150] In the treatment period, the first three patients were treated and observed until day 1 of cycle 2 or until toxicity leading to treatment discontinuation. Treatment initiation in further patients was paused until the end of the treatment period, and patients who entered the treatment period continued on the study per protocol.

[0151] Preliminary results (M-PLACE): Thirty-one patients were enrolled (cohort 1A: 15 patients, cohort 1B: 3 patients, cohort 2: 13 patients). TIFF2024525870000003.tif176170TIFF2024525870000004.tif106170

[0152] safety Treatment-emergent adverse events (AEs) were mostly mild in severity, and the study was able to continue according to protocol. The safety profile was consistent with felzalutamab's mechanism of action, and AEs were manageable. Of the 31 patients, 26 (84%) experienced 164 TEAEs. Five (16%) of the 31 patients experienced five treatment-emergent serious AEs (SAEs), with two events considered related to felzalutamab (one type I hypersensitivity, one IRR), and three events not related to felzalutamab. No events had a fatal outcome. Seven (23%) of the 31 patients experienced 10 treatment-emergent special adverse events (AESIs), the majority of which were allergic reactions to felzalutamab (seven in four patients). Other AESIs included one grade 3 neutropenia, one grade 3 IRR, and one grade 4 COVID-19 (not considered related to felzalutamab). Four of 31 patients (13%) discontinued felzalutamab treatment due to AEs: one grade 3 chest pain, one grade 3 type I hypersensitivity, one grade 4 COVID-19, and one grade 3 IRR. All events were considered related to felzalutamab, except for COVID-19.

[0153] Pharmacokinetics and immunogenicity After evaluation of felzalutamab serum levels over the first month of treatment, all patients showed drug exposure in the expected concentration range (Figure 7). Anti-drug antibodies (ADA) were analyzed in 21 of 31 patients. Two patients had pre-existing ADA, but no effect on the PK of felzalutamab was observed after the first dose. No treatment-induced or new ADAs were detected.

[0154] Immune response Of the 31 patients enrolled, 25 showed an initial decrease in anti-PLA2R antibody levels after 1 week of treatment, 3 had an increase, and 3 had no clinic visit or early discontinuation, making data unavailable for day 8 of cycle 1 (Figure 8). Nearly all patients experienced an immune response by day 8 of cycle 1, and felzalutamab rapidly and substantially reduced anti-PLA2R antibody titers in patients with anti-PLA2R-positive MN.

[0155] Based on long-term (≥4 weeks) anti-PLA2R antibody kinetics, three subgroups were identified across both cohorts (Figure 9). - Patients with a sustained and significant decrease in anti-PLA2R titers: >80% decrease from baseline or absolute value <20 U / mL at last visit (n=6) - Patients with moderate decline in anti-PLA2R titers: 25-80% decrease from baseline at last visit (n=9) - Patients with variable anti-PLA2R titers: did not meet the criteria for a large or intermediate decrease (n=14). These patients' titers appear to be within a consistent range over time and do not show a sustained increase in autoantibody levels.

[0156] Although the data are preliminary, an initial rapid decline in anti-PLA2R antibody titers was observed in most patients one week after the first felzalutamab dose, and the overall degree of response was heterogeneous, as expected in patients with MN (Gu Y, et al. Biomolecules 2021;11(4):513). The observed decline in anti-PLA2R antibody titers was independent of cohort, suggesting successful depletion of CD38+ plasma cells.

[0157] In early evaluation 6 months after initiation of treatment, the decrease in anti-PLA2R antibody titers was associated with a decline in UPCR in the majority of patients, further supporting the potential role of anti-PLA2R antibody levels on clinical response.

Claims

1. An antibody specific for CD38 for use in the treatment of a subject having autoimmune-mediated membranous nephropathy, comprising an HCDR1 region of the sequence GFTFSSYYMN (SEQ ID NO: 12) or SY YMN (SEQ ID NO: 1), an HCDR2 region of the sequence GISGDPSTYYADS VK G (SEQ ID NO: 2), an HCDR3 of the sequence DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of the sequence SGD NLRHYYYVY (SEQ ID NO: 4), an LCDR2 region of the sequence GDSKRPS (SEQ ID NO: 5), and an LCDR3 region of the sequence QTYTGGASL (SEQ ID NO: 6), wherein the antibody is administered at a fixed dose level of 650 mg, 975 mg, 1300 mg or 1625 mg corresponding to body weight ranges of <50 kg, 50.5 - 70 kg, 70.5 - 90 kg, >90.5 kg, respectively.

2. The antibody according to claim 1, wherein the autoimmune-mediated membranous nephropathy is anti-PLA2R positive membranous nephropathy.

3. The antibody according to claim 1, wherein the antibody is administered once a week (QW) for the first 3 weeks.

4. The antibody according to claim 1, wherein the antibody is administered once every two weeks (q2w).

5. The antibody according to claim 1, wherein the antibody is administered at intervals of day 1, day 8, day 15, day 29, and day 57, which represent a 3-month treatment period, or i) between day 1 and day 15, which represent a 1-month treatment period.

6. The antibody according to claim 5, further comprising retreatment 3 or 5 months after the end of the previous treatment period.

7. The antibody according to claim 1, wherein the antibody is administered at intervals of day 1, day 8, day 15, and day 22 during a 24-week treatment period, and subsequently at day 29, day 57, day 85, day 113, and day 141.

8. The antibody according to claim 1, wherein the antibody is administered twice at an 85-day treatment interval.

9. The antibody according to claim 1, wherein the antibody is administered five times at an 85-day treatment interval.

10. The antibody according to claim 1, wherein the antibody is administered nine times at a 24-week treatment interval.

11. The antibody according to claim 1, wherein the antibody is administered nine times at a 141-day treatment interval.

12. The antibody according to claim 3, wherein the antibody is administered once a week during the first month of treatment and once every 4 weeks after the first month of treatment.

13. The antibody according to claim 1, wherein the antibody is administered intravenously.

14. The antibody according to claim 13, which is intravenously administered over 2 hours.

15. The antibody according to claim 1, wherein the serum level of the subject's anti-PLA2R antibody at the time of screening is ≧50 RU / mL.

16. The antibody according to claim 15, wherein the serum level at the time of screening is ≧100 RU / mL.

17. The antibody according to claim 16, wherein the serum level at the time of screening is ≧200 RU / mL.

18. The antibody according to claim 17, wherein the serum level at the time of screening is ≧250 RU / mL.

19. The antibody according to claim 18, wherein the serum level at the time of screening is ≧300 RU / mL.

20. The antibody according to claim 19, wherein the serum level is ≧150 RU / mL.

21. The antibody according to claim 1, wherein the urine protein to creatinine ratio (UPCR) of the subject is ≧3.0 g / g.

22. The antibody according to claim 21, wherein the UPCR is ≧4.0 g / g.

23. The antibody according to claim 22, wherein the UPCR is ≧5.0 g / g.

24. The antibody according to claim 23, wherein the UPCR is ≧6.0 g / g.

25. The antibody according to claim 24, wherein the UPCR is ≧7.0 g / g.

26. The antibody according to claim 1, wherein in a 24-hour urine screening, the subject has proteinuria of ≧3.5 g / 24 hours.

27. The antibody according to claim 26, wherein the proteinuria is ≧4.0 g / 24 hours.

28. The antibody according to claim 27, wherein the proteinuria is ≧4.5 g / 24 hours.

29. The antibody according to claim 28, wherein the proteinuria is ≧5.0 g / 24 hours.

30. The antibody has a variable heavy chain of the sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSSGISGDPSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7) and a sequence of DIELTQPPSVSVAPGQTA RISCSGD NLRHYYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAED EADYYCQTYTGGASLVFGGG TKLT VLGQ (SEQ ID NO: 8) The antibody according to any one of claims 1 to 29, comprising a variable light chain thereof.

31. The antibody according to claim 30, wherein the antibody comprises an IgG1 Fc region.

32. The antibody according to claim 1, wherein the antibody is formulated for administration in combination with 650 mg to 1,000 mg of oral paracetamol.

33. The antibody according to claim 1, wherein the antibody is formulated for administration in combination with 25 mg to 50 mg of oral or intravenous diphenhydramine.

34. The antibody according to claim 1, wherein the antibody is formulated for administration in combination with 100 mg of intravenous methylprednisolone or its equivalent.

35. A belimumab or a biosimilar of belimumab for use in the treatment of a subject having anti-PLA2R-mediated membranous nephropathy, wherein the belimumab or the biosimilar of belimumab is administered at a fixed dose of 650 mg, 975 mg, 1300 mg, or 1625 mg corresponding to body weight ranges of <50 kg, 50.5 to 70 kg, 70.5 to 90 kg, >90.5 kg, respectively, and the belimumab or the biosimilar of belimumab is administered at intervals of i) day 1, day 8, day 15, day 29, and day 57 representing a 3-month treatment period, or ii) day 1 and day 15 representing a 1-month treatment period, and if necessary, retreatment is performed 3 months or 5 months after the end of the previous treatment period, and The belimumab or the biosimilar of belimumab, wherein the belimumab or the biosimilar of belimumab is administered intravenously.

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