Anti-CD38 antibodies and pharmaceutical compositions thereof for treating autoimmune diseases mediated by autoantibodies

Abstract

The present invention relates to the use of antibodies or antibody fragments specific for CD38 in preventing and / or treating autoimmune diseases mediated by autoantibodies. According to the present invention, anti-CD38 antibodies can effectively treat anti-PLA2R positive membranous glomerulonephropathy.

Description

Technical Field

[0001] The present invention relates to antibodies or antibody fragments specific for CD38, which can be used to treat and / or prevent autoimmune diseases (AD) mediated by autoantibodies. In particular, the present invention provides a method for reducing autoantibody titers by consuming antibody-secreting cells using anti-CD38 antibodies alone or in combination with one or more immunosuppressive drugs. According to the present invention, anti-CD38 antibodies alone or in combination can effectively treat and / or prevent anti-PLA2R positive membranous nephropathy (aMN). Anti-CD38 antibodies include but are not limited to MOR202. Background Art

[0002] Autoimmune diseases and autoantibodies

[0003] Autoimmune diseases (AD) include more than 70 different diseases, affecting about 5% of the population in Western countries (Lleo et al. Autoimmunity Reviews 2010 Mar; 9 (5): A259-66). AD is a clinical state caused by the activation of autoreactive T cells or autoreactive B cells or both. Some ADs are characterized by the production of pathogenic autoantibodies. Autoantibodies are immunoglobulins that react with autoantigens. Such autoantigens can include proteins, nucleic acids, carbohydrates, lipids, or various combinations thereof, and can be present in all cells (e.g., DNA), or highly restricted to specific cell types in one organ of the organism. In autoantibody-mediated humoral AD, autoantibodies usually appear in high titers in patient serum. For many ADs, clear and unequivocal links between autoantibody formation, specificity, and pathogenesis have been demonstrated (Suurmond and Diamond, J Clin Invest. 2015 Jun 1; 125 (6): 2194–2202). Pathogenic autoantibodies affect disease pathways in multiple ways, including deposition of immune complexes (ICs) and inflammation, stimulation or inhibition of receptor function, stimulation or inhibition of enzyme function, promotion of antigen uptake, cell lysis, microthrombosis, and neutrophil activation (Ludwig et al. Front. Immunol. 2017 May;8:603).

[0004] Systemic lupus erythematosus (SLE)

[0005] For example, systemic lupus erythematosus (SLE) is a polygenic autoimmune disease that affects approximately 50 cases per 100,000 people, with a higher prevalence in women than in men. The central immunological disorder in SLE patients is the inappropriate activation and proliferation of autoreactive memory B cells, leading to the expansion of antibody-secreting cells and the production of a variety of autoantibodies. The major autoantigens in SLE are nuclear components, such as DNA or ribonucleoproteins (RNPs), and the autoantibodies reactive with these antigens have high affinity, are somatically mutated, and have the IgG isotype. SLE patients show high levels of serum antinuclear antibodies (ANA). There may also be autoantibodies to cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, nervous system antigens, plasma proteins, matrix proteins, and other antigens ( Fig.12 ). In SLE, many of these autoantibodies lead to the formation of ICs, which appear to be directly pathogenic after deposition in several tissues.

[0006] Treatment options for SLE include antimalarials, steroidal and nonsteroidal anti-inflammatory agents, immunosuppressive drugs (including cyclophosphamide (CTX), azathioprine (AZA), mycophenolic acid (MMF) and methotrexate (MTX)), and therapies targeting immune cells (Yildirim-Toruner C, Allergy Clin Immunol. 2011 Feb; 127 (2): 303-12). These immunosuppressive or cytotoxic drugs and anti-CD20-mediated B cell depletion can induce remission in SLE patients. However, current treatment regimens often fail to prevent relapses (Stichweh, D. Curr. Opin. Rheumatol. 2004 16: 577–587.5).

[0007] Graves' disease Basedow)

[0008] Graves' Disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid gland. Graves' Disease will occur in approximately 0.5% of men and 3% of women (Burch HB, Cooper DS, 2015, JAMA 314(23):2544–54). In the United States, it often leads to hyperthyroidism and is the most common cause of hyperthyroidism (about 50% to 80% of cases). Symptoms of hyperthyroidism can include irritability, muscle weakness, sleep problems, rapid heartbeat, poor tolerance to heat, diarrhea, unintentional weight loss, thickening of the skin on the shins (called pretibial myxedema), and bulging eyes (a condition caused by Graves' ophthalmopathy). The direct cause of Graves' Disease is autoantibodies against the thyroid stimulating hormone receptor (TSHR). Autoantibodies against thyroglobulin and the thyroid hormones T3 and T4 can also be produced. TSHR autoantibodies mimic TSH and activate TSHR in an unregulated manner, causing hyperthyroidism. Treatment options for Graves' disease include antithyroid drugs (thionamide), ablation of the thyroid gland with radioactive iodine, and surgery (thyroidectomy). However, the challenge in treating Graves' disease remains to inhibit the development or continued production of TSHR autoantibodies.

[0009] Myasthenia gravis (MG)

[0010] Myasthenia gravis (MG) affects 50 to 200 people per million. The number of new diagnoses each year is between 3 and 30 per million. MG is a long-term neuromuscular AD that can cause varying degrees of skeletal muscle weakness and abnormal fatigability, and is caused by the presence of autoantibodies that react with components of the postsynaptic muscle endplate located at the myoneural junction (the junction of the nerve and the muscle). In particular, these autoantibodies block or destroy nicotinic acetylcholine receptors, thereby preventing nerve impulses from triggering muscle contraction. Other autoantibodies have also been found to target a related protein called MuSK (a muscle-specific kinase), as well as LRP4, Agrin, and titin. MG is usually treated with drugs called acetylcholinesterase inhibitors such as neostigmine and pyridostigmine. Immunosuppressants such as prednisone or azathioprine are also often used. In some cases, surgical removal of the thymus may improve disease symptoms. During flare-ups, plasmapheresis and high-dose intravenous immunoglobulin (IVIG) may be used to remove presumed autoantibodies from the circulation, or to dilute and bind circulating antibodies, respectively. Both treatments have relatively transient benefits, usually measured in weeks, and are often associated with high costs. If respiratory muscles become significantly weak, mechanical ventilation may be required.

[0011] Anti-PLA2R-positive membranous glomerulonephritis (aMN)

[0012] Anti-PLA2R autoantibody-mediated membranous nephropathy (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 P, Debiec H Lancet. 2015 May 16; 385(9981): 1983-92). About 80% of membranous nephropathy is idiopathic, while 20% is associated with other diseases or exposures. The global total incidence is estimated to be 1.2 per 100,000 people per year. Although the disease usually progresses slowly, approximately 30% to 40% of patients will eventually develop end-stage renal disease. Patients with residual renal disease in MN are at increased risk of thromboembolic and cardiovascular events. However, although not all aspects of the pathogenesis of MN are understood, the disease is no longer considered idiopathic. The M-type phospholipase A2 receptor (PLA2R) is a transmembrane protein expressed on podocytes and has been defined as the main autoantigen of MN (Beck LH Jr et al., N Engl J Med. 2009 Jul 2; 361 (1): 11-21). Autoantibodies that bind to the PLA2R antigen are highly specific for primary MN. Recent studies have shown that anti-PLA2R autoantibodies are present in approximately 75% of IMN patients and are closely associated with disease activity (Bomback AS, Clin J Am Soc Nephrol. 2018 May 7; 13 (5): 784-786). The fact that the disease that defines glomerular basement changes contains both PLA2R protein and antibody complex deposition provides evidence that anti-PLA2R antibodies play a major causal role in MN. In addition, 5% of patients who are negative for anti-PLA2R antibodies have antibodies against the 7A domain of type 1 thrombospondin, another podocyte antigen (Tomas NM et al., N Engl J Med 2014; 371: 2277–2287). In rare cases of neonatal MN, neutral endopeptidase (NEP) located on the podocyte foot process membrane and the brush border of the renal tubule has been identified as a related antigen (Ronco P et al., JAm Soc Nephrol. (2005) 16: 1205–13). In total, approximately 80% of IMN patients have antibodies against specific identifiable podocyte antigens. Symptoms of membranous nephropathy include, but are not limited to, swelling of the legs and ankles, increased protein in the urine, edema, hypoalbuminemia, elevated blood lipids, especially high cholesterol. Therefore, autoimmune membranous nephropathy is an immune-mediated glomerular disease characterized by the presence of anti-PLA2R autoantibodies and / or anti-THSD7A autoantibodies. In neonatal autoimmune MN, the autoantibodies against NEP present are transferred from the mother.

[0013] Currently, there is no approved standard therapy for MN. Current treatment options primarily include the off-label use of various non-immunosuppressive and immunosuppressive medications. Patients diagnosed with MN and proteinuria >3.5 g / day initially receive supportive therapy based on current clinical criteria with a combination of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs), statins, and diuretics. If proteinuria is not significantly reduced within several months, escalation to immunosuppressive therapy (IST) is indicated. Immunosuppressive therapy includes corticosteroids alternating with alkylating agents such as cyclophosphamide, and calcineurin inhibitors (CNIs, such as cyclosporine A, tacrolimus (FK506), mycophenolate-Mofetil (MMF), or rituximab), even though none of these drugs are approved for use in MN. To a lesser extent, adrenocorticotropic hormone (ACTH) has been used. The therapeutic effects of these drug combinations appear to be similar: remission of proteinuria can be expected in approximately 50% to 60% of patients within the first year and in approximately 70% to 80% of patients within 2 to 3 years, compared with a remission rate of approximately 30% in a control group managed with supportive care alone (spontaneous remission).

[0014] Among all patients with primary MN who do not receive IST, 30% to 40% of patients progress to end-stage renal disease within 10 years of onset. IST reduces the progression rate to less than 10%. Recurrence of proteinuria is observed in approximately 25% of patients previously treated with IST. These cases are usually retreated with different combinations of IST. The disadvantages of the above ISTs are that they exhibit considerable toxicity and are associated with significant side effects and a high relapse rate. 25% of patients treated with cyclophosphamide exhibit adverse reactions, including infection, infertility, hematological toxicity, and malignancies later in life. Disadvantages of CNIs include long-term nephrotoxicity, the need for close monitoring of drug levels, and an increased risk of hypertension and diabetes. The relapse rate of calcineurin inhibitors appears to be higher than that of cyclophosphamide (40-50% vs. 25%). The previously established treatment algorithms are changing because of the overwhelming evidence that anti-PLA2R antibodies are associated with disease activity.

[0015] The recent introduction of off-label use of the anti-CD20 therapeutic antibody rituximab allows for a more specific IST approach by depleting the B cell population that is involved as a progenitor cell in the production of pathogenic anti-PLA2R autoantibodies. Response rates to rituximab appear similar to those of alkylating agents and CNIs, while side effects appear to be lower than those of other drugs used in IST. However, CD20, the target of rituximab, is not present on mature, long-lived antibody-secreting plasma cells, the major source of endogenous immunoglobulins. There is only a small residual amount of CD20 expression on early plasmablasts, compared with CD20 expression on mature B cells. This is a possible explanation for the poor efficacy of rituximab therapy in MN patients with high titers of anti-PLA2R antibodies.

[0016] In this regard, direct targeting of plasmablasts, and plasma cells in general, results in a more pronounced reduction in immunoglobulins and, therefore, in autoantibodies. The majority of anti-PLA2R antibodies in aMN are likely produced by a pool of long-lived plasma cells with a CD20-negative but CD38-positive immunophenotype that is independent of the continuous replenishment of differentiated B cells. Therefore, direct plasma cell targeting strategies may have a more profound impact on the suppression of pathogenic autoantibodies. This is particularly important for patients who do not respond adequately to rituximab (anti-CD20) therapy, who maintain high autoantibody titers despite B cell depletion.

[0017] Pemphigus

[0018] Pemphigus vulgaris is an autoimmune, intraepidermal mucocutaneous disease of the skin and oral cavity that results in blister formation. The incidence of lesions increases by 0.5 to 3.2 cases per 100,000 population per year. These lesions occur primarily between the ages of 40 and 60 years with equal gender predilection. Patients with pemphigus have circulating autoantibodies against pemphigus antigens (desmoglein 3, desmoglein 1, desmocollin, plakoglobin) on epithelial keratinocytes. Disruption of these antigens through antigen-autoantibody reactions has a significant impact on the integrity of the epidermis, leading to cellular detachment (acantholysis), suprabasilarclefting, and subsequent bullous formation. Binding of autoantibodies to keratinocytes also results in the release of proteases and plasminogen activators (which convert plasminogen to plasmin) from the cells, further enhancing acantholysis. Treatment options for high-grade lesions include systemic glucocorticoids and combinations of corticosteroids, immunosuppressants, pulse therapy, photophoresis, and plasmapheresis.

[0019] Sjögren's syndrome

[0020] Sjögren's syndrome is a systemic autoimmune disease characterized by focal infiltration of lymphocytes into the exocrine and lacrimal glands, resulting in dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca), respectively. In Sjögren's syndrome, the presence of lesions is associated with a chronic inflammatory infiltrate that releases autoantibodies against salivary gland epithelial cells. Other autoantibodies in Sjögren's syndrome are directed against ribonucleoprotein autoantigens Ro / SS-A and La / SS-B, coiled-coil containing molecules, members of the Golgi protein family, poly (ADP) ribose polymerase (PARP), and type 3 muscarinic receptors. Currently, there is no targeted therapy for Sjögren's syndrome, and current treatment approaches are limited to symptomatic management of dryness and fatigue symptoms, such as with pilocarpine, bromhexine, and hydroxychloroquine, respectively.

[0021] Anti-NMDA encephalitis

[0022] The most common antibody-mediated acute autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (Granerod J et al., Lancet Infect Dis 2010, 10: 835-44). Its incidence is estimated to be 3-5 per 1,000,000 people per year. Anti-NMDA encephalitis represents a model disease of a group of syndromes characterized by the detection of autoantibodies targeting synaptic structures. Anti-NMDAR antibodies are the most common, followed by leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (Caspr2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-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 occurs preferentially in young adults and children, mainly women (80%). Prodromal symptoms (e.g., headache, fever, rapid changes in behavior, anxiety, hallucinations, and psychosis) occur in approximately 70% of patients. Abnormal movements (e.g., orofacial dyskinesia, chorea, and stereotypic movements) follow as well as decreased consciousness, coma, and severe global autonomic instability (sometimes leading to hypoventilation and cardiac arrest). Seizures and status epilepticus may occur at any stage of the disease. Approximately 50% of patients respond well to IVIG, steroids, or plasma exchange, while the other 50% require rituximab alone or in combination with cyclophosphamide. However, in some patients, recovery is incomplete and may take years, and mortality due to complications from intensive care can be as high as 7%.

[0023] The presence of pathogenic autoantibodies in the autoantibody-mediated autoimmune diseases exemplified above is the result of a breakdown or failure of central and / or peripheral B-cell tolerance to the corresponding self-antigens.

[0024] Central and peripheral B cell tolerance

[0025] The development of B cells begins in the bone marrow. There, the new membrane-bound B cell receptor (BCR) library is produced by somatic recombination of immunoglobulin heavy and light chain gene segments. The downside of producing this huge diversity in the early BCR library by random somatic V (D) J recombination is the simultaneous production of autoantibodies that may be pathogenic. There are at least three mechanisms to prevent the development of autoimmunity. First, autoreactive B cells are deleted by apoptosis. Second, autoreactive B cells change the VL domain by secondary Ig light chain recombination, a process called receptor editing, thereby reducing the autoreactive affinity of their BCR. The third mechanism to silence autoreactive B cells is incapacity, which makes such cells unresponsive to antigens. These central tolerance mechanisms occur in the bone marrow. Therefore, in B cells expressing autoreactive antibodies, the autoreactivity of the emerging antibody library is prevented by apoptosis, receptor editing and induction of incapacity (Wardemann and Nussenzweig, Adv Immunol. 2007; 95: 83-110).

[0026] During B cell differentiation, transitional B cells that emerge from the bone marrow continue to mature in peripheral lymphoid organs (e.g., spleen, lymph nodes) where they establish additional peripheral tolerance mechanisms. The exact mechanisms of peripheral tolerance are still under investigation but involve recognition of ligands (antigens) by the BCR, similar to central tolerance checkpoints in the bone marrow. They may also involve controlled migration and limited availability of BAFF, CD22, Siglec-G, miRNAs, and follicular regulatory T cells (Tregs).

[0027] The terminal product of B cell differentiation is antibody secreting plasma cells. After antigen activation, mature initial B cells directly develop (independent of T cells) into antibody secreting cells, or differentiate into fixed non-dividing plasma cells or memory B cells by proliferating pre-plasmablasts and plasmablasts in the germinal center during T cell-dependent immune response. Both plasmablasts and plasma cells produce and secrete antibodies, thereby providing humoral immunity. When they are derived from autoreactive B cells, plasmablasts and plasma cells contribute to the production of autoantibodies (Hiepe and Radbruch, Nat Rev Nephrol.2016Apr; 12 (4): 232-40).

[0028] The failure of one or more central and / or peripheral tolerance mechanisms results in an increase in the number of circulating autoreactive B cells (i.e., B cells expressing autoantibodies) and autoreactive plasmablasts and plasma cells (i.e., cells expressing and secreting autoantibodies), promoting the development of autoantibody-mediated AD. Once the generation of autoantibodies begins, their production levels are maintained by continuous activation of autoreactive B cells (causing the continuous formation of short-lived plasma cells) or by forming long-lived plasma cells or by both (Manz RA et al., Annu Rev Immunol (2005) 23: 367-86).

[0029] Since autoantibodies are usually the root cause of autoimmune pathology, B cells, plasmablasts and plasma cells are promising therapeutic targets in AD. Short-lived plasma cells respond to conventional immunosuppressive drugs, which directly inhibit the plasmablasts and B cells of proliferation. Non-proliferative short-lived plasma cells disappear within a few days after starting these therapies because they are no longer supplemented. Therapies targeting B cells, such as anti-CD20 (rituximab) and anti-BAFF (belimumab) (see, for example, WO2002002641, WO2009052293A1), reduce the B cell levels in patients who need to reduce B cell levels, thereby reducing the production of short-lived plasmablasts and plasma cells, but this therapy will not affect the long-lived memory plasma cell compartment. In the case where autoantibody production is not affected by this treatment strategy, it should be considered that autoantibodies may be secreted by long-lived memory plasma cells. Furthermore, it can be hypothesized that blocking factors or cells that stimulate autoreactive B cells, for example by targeting type I interferon (IFN), TH cells or regulatory T (Treg) cells, would prevent the development of short-lived plasmablasts and plasma cells, but not plasma cell memory.

[0030] In humans, the long-lived bone marrow-derived plasma cell population is phenotypically defined as CD19-, CD38hi, CD138+ (Halliley JL et al., Immunity. 2015 Jul 21; 43(1): 132-45). The well-known common pan-B cell marker CD20 is usually not expressed on human plasmablasts (Ellebedy AH et al., Nat Immunol. 2016 Oct; 17(10): 1226-34) or long-lived human plasma cells (Halliley JL et al., Immunity. 2015 Jul 21; 43(1): 132-45).

[0031] The potential mechanism of maintaining long-term antibody response can generally be divided into memory B cell dependence and memory B cell independence model.In rhesus monkey animal model, it has been shown that after surgical removal of potential B cell pools from solid tissues (such as spleen and lymph nodes), and depletion of all detectable tetanus-specific memory B cells from the circulation using anti-CD20 antibodies, tetanus-specific serum antibody titers continue to remain above the protective threshold of immune host lifespan, and its decay rate kinetics is no different from untreated controls (Hammarlund E et al., Nat Commun.2017; 8: 1781).Therefore, the antibody response after tetanus vaccination is long-term and provides lifelong protective immunity for the disease.Further analysis of tetanus-specific plasma cells shows that, after 10 years of immunity, long-lived vaccine-induced plasma cells are preferentially identified in certain bone marrow compartments.In summary, these studies provide the following framework, in which the maintenance of long-term serum antibody response seems to be maintained by long-lived plasma cells independent of memory B cells.

[0032] As mentioned above, current treatment options for AD include systemic immunosuppression (ie, high doses of corticosteroids such as dexamethasone). The cytotoxic drug cyclophosphamide Cyclophosphamide has been shown to inhibit T helper cell function, where the reduction of B cells is prolonged because B lymphocytes recover more slowly from alkylating agents, thereby inhibiting the activation of B cells. Other immunosuppressive drugs include, but are not limited to, azathioprine, mycophenolic acid, and methotrexate. Proteasome inhibitors such as bortezomib have been shown to deplete both short-lived and long-lived plasma cells, and the first clinical trials using bortezomib to treat SLE and thrombotic thrombocytopenic purpura are promising (Alexander T et al., Ann Rheum Dis (2015) 74: 1474-8; Patriquin et al., Br J Haematol (2016) 173: 779-85).

[0033] WO2012092612 discloses anti-CD38 antibodies and claims their possible therapeutic use for a variety of autoimmune diseases. In fact, WO2012092612 determined anti-tetanus responses in the HuScid mouse model and only showed experiments using alternative mouse anti-CD38 antibodies in collagen-induced arthritis and SLE autoimmune mouse models. WO2012092612 does not mention the determination of antibody titers in human samples after anti-CD38 treatment, and does not mention or show any data on anti-PLA2R positive membranous nephropathy treated with anti-CD38 antibodies.

[0034] Schuetz C et al. (Blood Adv. 2018; 2(19): 2550-2553) described the use of the anti-CD38 antibody daratumumab in the treatment of autoimmune hemolytic anemia. Cole S et al., Arthritis Res Ther. 2018; 20(1): 85 evaluated the therapeutic potential of daratumumab in patients with RA and SLE.

[0035] Beck LH et al. (J Am Soc Nephrol. 2011; 22(8): 1543-50) disclose the use of the anti-CD20 antibody rituximab to deplete B cells in patients with idiopathic membranous nephropathy. The disclosure does not teach or suggest the use of anti-CD38 antibodies to deplete plasma cells in these patients.

[0036] However, AD patients still suffer from high morbidity and increased mortality. Despite the progress made in the development of novel anti-autoimmune agents (such as bortezomib), the prognosis of many autoantibody-mediated AD, which is most likely to involve CD38-positive autoantibody-secreting cells, remains poor. All of the above-mentioned treatment options have disadvantages, side effects, or their use is limited to certain types of patient groups.

[0037] Therefore, there remains a high and unmet medical need for new and improved treatments for patients suffering from autoantibody-mediated AD.

[0038] The present inventors have identified that CD38 represents an excellent and effective antigen for directly targeting antibody secreting cells such as plasmablasts and plasma cells in autoantibody-mediated autoimmune diseases (e.g., SLE, aMN). First, CD38 shows very high expression on plasmablasts and plasma cells ( Figure 4 ), and secondly, CD38 is not expressed on other cell types, or is expressed at a significantly lower level, compared to plasmablasts and plasma cells. Therefore, the use of anti-CD38 antibodies can be used as a sustainable treatment method to target the source of pathogenic autoantibodies with a potential long-lasting effect due to the elimination of short-lived and long-lived plasma cells. In essence, this targeting effect can be summarized as follows: antibodies specific for the CD38 surface antigen of antibody-secreting cells are administered to the patient. These anti-CD38 antibodies specifically bind to the CD38 antigen of both antibody-secreting cells that produce normal antibodies and pathogenic autoantibodies. Then, the antibodies bound to the CD38 surface antigen lead to the destruction and consumption of these cells. Regardless of the approach used, the main goal is to reduce the cells that produce autoantibodies.

[0039] Endogenous anti-tetanus antibody titer as a marker to evaluate the effect of MOR202 on plasma cell function

[0040] Longitudinal studies in mice (Manz RA et al., Nature. 1997; 388: 133-134) and humans (Hammarlund E et al., Nat Med. 2003 Sep; 9 (9): 1131-7) have highlighted the advantages of inducing and maintaining effective serum antibody concentrations (antibody titers) that persist and are protective for a long time, up to the life of the immune system. Stable titers of specific antibodies, such as those produced by conventional vaccinations against, for example, measles, mumps, tetanus, diphtheria or smallpox, can confer protective humoral immunity. Plasma cells and their immediate precursor cells are known as the cellular basis of this humoral immunity, and since serum specific antibody titers are valuable markers of the humoral arm, they can be used as indicators of the presence and / or activity of plasma cells that produce these antibodies. Mouse studies using anti-CD20 treatment to deplete naive and memory B cells showed that even over long periods of time, loss of B cells did not significantly affect the plasma cell pool (Ahuja A et al., Proc Natl Acad Sci USA. 2008 Mar 25; 105(12): 4802-7). Similarly, humans undergoing B cell ablation therapy maintain serum antibody titers against common antigens for at least one year (Cambridge G et al., Arthritis Rheum. 2006 Mar; 54(3): 723-32). Therefore, these reports indicate that (long-lived) plasma cells are an important component of persistent humoral memory in mice and humans. It is recognized that plasma cells can persist for a long time even without the infusion of newly activated naive or memory B cells. Here, the inventors show for the first time that the administration of MOR202 leads to a reduction in endogenous anti-tetanus toxoid antibody titers in human subjects, and describe in the examples how to put the treatment of autoantibody-mediated membranous nephropathy, particularly anti-PLAR2-positive autoimmune MN, with MOR202 into practice. Summary of the invention

[0041] The present invention provides antibodies or antibody fragments specific for CD38 for treating and / or preventing autoimmune diseases and related conditions mediated by autoantibodies. In particular, anti-CD38 antibodies or antibody fragments are used to treat and / or prevent idiopathic membranous glomerulonephritis. Preferably, anti-CD38 antibodies or antibody fragments are used to treat and / or prevent anti-PLA2R positive membranous glomerulonephritis. In some aspects, anti-CD38 antibodies or antibody fragments are used to treat and / or prevent systemic lupus erythematosus (SLE).

[0042] In addition, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antibody fragment specific to CD38 for treating and / or preventing autoimmune diseases mediated by autoantibodies. Specifically, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is used to treat and / or prevent idiopathic membranous glomerulonephritis. Preferably, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is used to treat and / or prevent anti-PLA2R positive membranous glomerulonephritis. In some aspects, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is used to treat and / or prevent systemic lupus erythematosus (SLE).

[0043] The monoclonal human anti-CD38 antibody MOR202 targets antibody secreting cells such as plasmablasts and plasma cells primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). During clinical trials of MOR202, efficient killing of tumor plasma cells (i.e., multiple myeloma cells) and benign plasma cells has been demonstrated. In patients with multiple myeloma (MM), the consumption of plasma cells by MOR202 can lead to a significant reduction in M-protein. M-protein, also referred to as M component, M spike, spike protein, paraprotein or myeloma protein, is an immunoglobulin (antibody) or fragment thereof secreted by a malignant tumor plasma cell clone. Due to the abnormal monoclonal proliferation of malignant plasma cells in MM, M-protein is produced in large quantities in excess, resulting in a variety of deleterious effects on MM signs (e.g., impaired immune function, abnormally high blood viscosity and kidney damage). MOR202 can effectively eliminate plasma cells as a source of M-protein, thereby resulting in a reduction in M-protein titer.

[0044] The effect of MOR202 on plasma cells was demonstrated by assessing anti-tetanus toxoid (anti-TT) antibody titers in serum as a marker of specific plasma cell depletion. Following administration of MOR202, serum anti-TT antibody levels were significantly reduced compared to the baseline prior to administration of MOR202.

[0045] Overall, the inventors demonstrated that MOR202 is highly effective in reducing malignant (M-protein) and / or protective antibody (anti-TT) levels in human serum, indicating long-term depletion of plasmablasts and plasma cells. In contrast to other anti-CD38 antibodies, MOR202 is expected to retain cells with low CD38 expression (e.g., NK cells), thus providing an optimal safety profile.

[0046] This observed effect of MOR202 on reducing serum antibody titers is novel, and the prior art does not teach, suggest or provide any rationale for using MOR202 to treat autoantibody-mediated AD.

[0047] In a specific aspect of the present invention, the antibody or antibody fragment comprises a HCDR1 region of an amino acid sequence of SEQ ID NO: 1, a HCDR2 region of an amino acid sequence of SEQ ID NO: 2, a HCDR3 region of an amino acid sequence of SEQ ID NO: 3, a LCDR1 region of an amino acid sequence of SEQ ID NO: 4, a LCDR2 region of an amino acid sequence of SEQ ID NO: 5, and a LCDR3 region of an amino acid sequence of SEQ ID NO: 6, and is used to treat and / or prevent autoimmune diseases mediated by autoantibodies, specifically for treating and / or preventing systemic lupus erythematosus (SLE) or idiopathic membranous glomerulonephritis, preferably for treating and / or preventing anti-PLA2R-positive membranous glomerulonephritis.

[0048] The present disclosure also provides a pharmaceutical composition comprising an antibody or antibody fragment specific to CD38 and a suitable pharmaceutical carrier, excipient or diluent for preventing and / or treating autoimmune diseases mediated by autoantibodies.

[0049] In another specific aspect, the pharmaceutical composition may further comprise other therapeutically active ingredients suitable for use in combination with the antibody or antibody fragment of the present invention. In a more specific aspect, the other therapeutically active ingredient is an agent for treating autoimmune diseases mediated by autoantibodies.

[0050] In one aspect of the present invention, the present invention provides a method for preventing and / or treating autoantibody-mediated AD in a subject, particularly a human, in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0051] The present invention also provides a method for preventing and / or treating idiopathic membranous glomerulonephritis (IMN) in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0052] Specifically, the present invention provides a method for preventing and / or treating anti-PLA2R-positive membranous glomerulonephritis (aMN) in a subject in need thereof, the method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0053] In one aspect, the present invention provides a method for preventing and / or treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0054] In one aspect, the present invention provides antibodies or antibody fragments specific for CD38 for use in preventing and / or treating autoantibody-mediated AD in mammals, particularly humans, suffering from such autoimmune diseases.

[0055] Other objects and advantages will become apparent to those skilled in the art in view of the ensuing detailed description.

[0056] Furthermore, antibodies or antibody fragments specific for CD38 useful in the pharmaceutical compositions and treatment methods disclosed herein are pharmaceutically acceptable for preparation and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 Schematic diagram of the major cell types of B cell differentiation and the levels of CD19, CD20 and CD38 expression. The expression of CD38 is strictly regulated during B cell ontogeny: CD38 is present on bone marrow precursor B cells, but is lost on mature B cells. On germinal center B cells, CD38 can prevent apoptosis, but after leaving the germinal center, memory B cells lack or have only reduced antigen levels. On terminally differentiated short-lived and long-lived plasma cells that are antibody secreting cells, CD38 is one of the few surface antigens present and is highly expressed (Hamblin TJ, Blood 2003 102: 1939-1940).

[0058] Figure 2 The major B cell types targeted by anti-CD20 B cell depleting antibody therapy (eg, treatment with rituximab) are schematically shown.

[0059] Figure 3 The major antibody-secreting cell types targeted by anti-CD38 antibody therapy (eg, treatment with MOR202) are schematically shown.

[0060] Figure 4 High CD38 expression on plasma cells of healthy individuals and patients with multiple myeloma as determined by FACS is shown.

[0061] Figure 5 Shown are the changes (%) in anti-tetanus toxoid (anti-TT) antibody titers in subjects after administration of MOR202 on Day 15 of Cycle 1 (ie, 2 weeks after the start of MOR202 treatment) compared to baseline.

[0062] Figure 6 Shown are the changes (%) in anti-tetanus toxoid (anti-TT) antibody titers in subjects after administration of MOR202 at Day 15 of Cycle 2 (ie, 6 weeks after initiation of MOR202 treatment) compared to baseline.

[0063] Figure 7 Shown are the changes (%) in M-protein levels in the group of patients treated with MOR202 plus dexamethasone once weekly compared to baseline (best response).

[0064] Figure 8 Shown are the changes (%) in M-protein levels in the group of patients treated weekly with MOR202 in combination with lenalidomide / dexamethasone compared to baseline (best response).

[0065] Fig. 9 Shown are the changes (%) in M-protein levels in the group of patients treated weekly with MOR202 in combination with pomalidomide / dexamethasone compared to baseline (best response).

[0066] Fig.10 Compared with the anti-CD38 antibodies daratumumab (Dara) and isatuximab, MOR202 showed specific killing of multiple myeloma plasma cell lines that highly expressed CD38, while sparing NK cells that lowly expressed CD38.

[0067] Fig.11 A timeline of clinical trials of MOR202 being tested in subjects with aMN is shown.

[0068] Fig.12 Various autoantibodies that may be detected in patients with systemic lupus erythematosus (SLE) are exemplified. DETAILED DESCRIPTION

[0069] definition

[0070] The following terms are intended to have the meanings presented below, and can be used to understand the description and intended scope of the present invention.

[0071] When describing the present invention, which may include antibodies, antibody fragments, pharmaceutical compositions comprising such antibodies or antibody fragments, and methods of using such antibodies, antibody fragments and compositions, the following terms, if present, have the following meanings, unless otherwise indicated.

[0072] The articles "a" and "an" may be used herein to refer to one or more than one (ie, at least one) of the grammatical objects of the article. For example, "an analogue" refers to one or more than one analogue.

[0073] The term "CD38" refers to the protein known as CD38, with the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1, T10.

[0074] Human CD38 (UniProt P28907) has the following amino acid sequence:

[0075] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGY LADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI(SEQ ID NO:9).

[0076] CD38 is a type II transmembrane glycoprotein and is an example of an antigen that is highly expressed on antibody-secreting cells, including autoantibody-secreting plasmablasts and plasma cells. Functions attributed to CD38 include both receptor-mediated adhesion and signaling events, as well as (extracellular) enzymatic activities. As an extracellular enzyme, CD38 uses NAD+ as a substrate to form cyclic ADP-ribose (cADPR) and ADPR, but also nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to act as Ca 2+ By converting NAD+ to cADPR, CD38 regulates extracellular NAD+ concentration and thus regulates cell survival by modulating NAD-induced cell death (NCID). 2+ In addition to signaling of IgG, CD38 signaling also occurs through interaction with antigen receptor complexes on T cells and B cells or other types of receptor complexes such as MHC molecules, in this way participating in several cellular responses and also participating in the conversion and secretion of IgG antibodies.

[0077] As used herein, the term "anti-CD38 antibody" includes anti-CD38 binding molecules in the broadest sense; including any molecule that specifically binds to CD38 or inhibits the activity or function of CD38, or exhibits a therapeutic effect on CD38 in any other way. Including any molecule that interferes with or inhibits the function of CD38. The term "anti-CD38 antibody" includes, but is not limited to, antibodies that specifically bind to CD38, alternative protein scaffolds that bind to CD38 (e.g., fibronectin scaffolds, anchor proteins, large antibodies / affinity polymers (maxybodies / avimers), protein A-derived molecules, anticalins, affilins, protein epitope mimetics (PEM), etc.), nucleic acids specific for CD38 (including aptamers) or small organic molecules specific for CD38.

[0078] Antibodies specific for CD38 are described, for example, in WO199962526 (Mayo Foundation); WO200206347 (Crucell Holland); US2002164788 (Jonathan Ellis), which are incorporated by reference in their entirety; WO2005103083 (MorphoSys AG), U.S. Ser. No. 10 / 588,568, which is incorporated by reference in its entirety; WO2006125640 (MorphoSys AG), U.S. Ser. No. 11 / 920,830, which is incorporated by reference in its entirety; and WO2007042309 (MorphoSys AG). AG), U.S. Ser. No. 12 / 089,806, which is incorporated by reference in its entirety; WO2006099875 (Genmab), U.S. Ser. No. 11 / 886,932, which is incorporated by reference in its entirety; and WO2008047242 (Sanofi-Aventis), U.S. Ser. No. 12 / 441,466, which is incorporated by reference in its entirety.

[0079] Combinations of antibodies specific for CD38 and other agents are described, for example, in WO200040265 (Research Development Foundation); WO2006099875 and WO2008037257 (Genmab); and WO2010061360, WO2010061359, WO2010061358 and WO2010061357 (Sanofi Aventis), all incorporated by reference in their entirety.

[0080] Preferably, the anti-CD38 antibody for use as described herein is an antibody specific for CD38. More preferably, the anti-CD38 antibody is an antibody or antibody fragment, such as a monoclonal antibody, that specifically binds to CD38 and depletes antibody-secreting cells. Such antibodies can be of any type, such as mouse antibodies, rat antibodies, chimeric antibodies, humanized antibodies or human antibodies.

[0081] As used herein, "human antibodies" or "human antibody fragments" are antibodies and antibody fragments having variable regions in which both the framework region and the CDR region are derived from sequences of human origin. If the antibody comprises a constant region, the constant region is also derived from these sequences. Human origin includes, but is not limited to, antibodies of human germline sequences or mutant forms of human germline sequences or comprising a consensus framework sequence derived from human framework sequence analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296:57-86. Human antibodies can also be isolated from synthetic libraries or from transgenic mice (e.g., XenoMouse). If the sequence of an antibody or antibody fragment is human, then the antibody or antibody fragment is human, regardless of which species the antibody is physically derived, isolated or manufactured from.

[0082] The structure and position of immunoglobulin variable domains, such as 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, for example, see Sequences of Proteins of Immunological Interest, US Department of Health and Human Services (1991), Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948; Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication No. 91-3242 U.S. Department 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., (1997) J. Mol. Biol. 273:927-948.

[0083] "Humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having constant antibody regions and variable antibody regions or portions thereof derived from human sequences, or only CDRs derived from another species. For example, a humanized antibody can be CDR-grafted, wherein the CDRs of the variable domains are from non-human sources, while one or more frameworks of the variable domains are human, and the constant domains (if any) are human.

[0084] The term "chimeric antibody" or "chimeric antibody fragment" is defined herein as an antibody molecule having a constant antibody region derived from or corresponding to a sequence found in one species and a variable antibody region derived from another species. Preferably, the constant antibody region is derived from or corresponds to a sequence found in humans, while the variable antibody region (e.g., VH, VL, CDR or FR region) is derived from a sequence found in a non-human animal such as a mouse, rat, rabbit or hamster.

[0085] 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. In addition, the isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemical substances. Therefore, in some aspects, the antibody provided is an isolated antibody that has been separated from antibodies having different specificities. The isolated antibody may be a monoclonal antibody. The isolated antibody may be a recombinant monoclonal antibody. However, the isolated antibody that specifically binds to the epitope, isotype or variant of the target may cross-react with other related antigens, for example from other species (e.g., species homologs).

[0086] As used herein, the term "monoclonal antibody" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody consists of a unique binding site displaying a unique binding specificity and affinity for a particular epitope.

[0087] In addition, "immunoglobulin" (Ig) as used herein is defined as a protein belonging to the IgG, IgM, IgE, IgA or IgD class (or any subclass thereof), and includes all conventionally known antibodies and functional fragments thereof. A preferred class of immunoglobulins for use in the present invention is IgG.

[0088] The phrase "antibody fragment" as used herein refers to one or more portions of an antibody that retain the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, stabilizing spatial distribution). Examples of binding fragments include, but are not limited to, a monovalent fragment Fab fragment consisting of VL, VH, CL, and CH1 domains; a bivalent fragment F(ab)2 fragment comprising two Fab fragments connected by a disulfide bridge in the hinge region; a Fd fragment consisting of VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment consisting of a VH domain (Ward et al., (1989) Nature 341: 544-546); and isolated complementary determining regions (CDRs). In addition, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by synthetic linkers that enable them to be made into a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (referred to as "single-chain fragment Fv (scFv)"; see, e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be included within the term "antibody fragment". These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as used for intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23: 1126-1136). Antibody fragments can be grafted into a backbone based on a polypeptide such as type III fibronectin (Fn3) (see U.S. Pat. No. 6,703,199 describing a fibronectin polypeptide monoclonal antibody). Antibody fragments can be incorporated into a single chain molecule comprising a pair of tandem Fv fragments (VH-CH1-VH-CH1) that form a pair of antigen binding sites together with complementary light chain polypeptides (Zapata et al., (1995) Protein Eng. 8: 1057-1062; and U.S. Pat. No. 5,641,870).

[0089] The present disclosure provides a method of treatment comprising administering a therapeutically effective amount of an anti-CD38 antibody as disclosed to a subject in need of such treatment. As used herein, a "therapeutically effective amount" or "effective amount" refers to the amount of an antibody specific for CD38 required to elicit 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 autoimmune diseases and symptoms associated with the AD. The effective amount for a specific individual may vary, depending on a variety of factors, such as the condition being treated, the patient's overall health, the method, route and dosage 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).

[0090] As used herein, the terms "treat," "treat," "treatment," and the like refer to alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, or preventing or slowing the onset of symptoms of the disease or disorder.

[0091] "Preventing" or "prevention" refers to reducing the risk of acquiring or developing a disease or condition (i.e., causing at least one clinical symptom of the disease not to occur in a subject who may be exposed to a pathogenic agent or who is susceptible to the disease prior to the onset of the disease). "Prevention" also refers to methods intended to prevent the onset of a disease or its symptoms or to delay the onset of a disease or its symptoms.

[0092] The term "prophylaxis" is related to "prevention" and refers to measures or procedures aimed at preventing rather than treating or curing a disease. Non-limiting examples of prophylaxis may include the administration of vaccines; administration of low molecular weight heparin to hospitalized patients at risk of thrombosis due to reasons such as immobilization; pre-administration of antimalarial agents such as chloroquine before visiting geographic areas where malaria is prevalent or where the risk of contracting malaria is high.

[0093] "Alleviating" one or more symptoms of autoantibody-mediated AD refers to reducing the extent of one or more undesirable clinical manifestations in an individual or population of individuals having autoantibody-mediated AD.

[0094] "Administering" or "dosing" includes, but is not limited to, drug delivery by an injectable form such as intravenous, intramuscular, intradermal or subcutaneous routes or mucosal routes, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet. Preferably, administration is by an injectable form.

[0095] As used herein, the terms "subject", "subject in need thereof", etc. refer to a human or non-human animal that exhibits one or more symptoms or signs of an autoantibody-mediated autoimmune disease and / or is diagnosed with an autoantibody-mediated autoimmune disease. Preferably, the subject is a primate, most preferably a human patient diagnosed with an autoantibody-mediated autoimmune disease.

[0096] 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, most preferably a human.

[0097] As used herein, the term "autoantibody-mediated autoimmune disease" includes "autoantibody-associated autoimmune disease" and refers to a group of diseases characterized by the presence of autoantibodies (autoantibody positive), wherein (i) the causal relevance and direct contribution of the autoantibodies to the disease and its associated symptoms are given, or (ii) the causal relevance and direct contribution of the autoantibodies to the disease and its associated symptoms are less clear, but can be given. Autoantibody-mediated autoimmune diseases include, but are not limited to, the diseases exemplarily listed in Table 1.

[0098] Table 1. Examples of autoantibody-mediated autoimmune diseases

[0099]

[0100]

[0101]

[0102]

[0103] As used herein, the term "about" when used with reference to a specific recited value means that the value may differ 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 ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0104] As used herein, "pharmacokinetics" or "PK" describes how the body affects a drug after administration through mechanisms such as absorption and distribution, as well as the effects and pathways of metabolic changes in a particular drug and the excretion of the drug's metabolites. The pharmacokinetic properties of a drug may be affected by the route of administration and the dose administered.

[0105] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency or equivalent of a Federal or state government in countries outside the United States or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0106] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which the antibody or antibody fragment is administered.

[0107] Throughout the specification, unless the context requires otherwise, the words "comprises", "having" and "comprising" and their respective variations will be understood to imply the inclusion of stated elements or integers or groups of elements or integers but not the exclusion of any other elements or integers or groups of elements or integers.

[0108] "MOR202" is an anti-CD38 antibody also referred to as "MOR03087" or "MOR3087." These terms are used interchangeably in this disclosure. MOR202 has an IgG1 Fc region.

[0109] The amino acid sequence of MOR202 HCDR1 according to Kabat is:

[0110] SYYMN (SEQ ID NO: 1).

[0111] The amino acid sequence of MOR202 HCDR2 according to Kabat is:

[0112] GISGDPSNTYYADSVKG (SEQ ID NO:2).

[0113] The amino acid sequence of MOR202 HCDR3 according to Kabat is:

[0114] DLPLVYTGFAY (SEQ ID NO: 3).

[0115] The amino acid sequence of MOR202 LCDR1 according to Kabat is:

[0116] SGDNLRHYYVY (SEQ ID NO: 4).

[0117] The amino acid sequence of MOR202 LCDR2 according to Kabat is:

[0118] GDSKRPS (SEQ ID NO: 5).

[0119] The amino acid sequence of MOR202 LCDR3 is: QTYTGGASL (SEQ ID NO: 6).

[0120] The amino acid sequence of the variable heavy domain of MOR202 is:

[0121] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPG KGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7).

[0122] The amino acid sequence of the MOR202 variable light domain is:

[0123] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYQQKPGQAP VLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYT GGASLVFGGGTKLTVLGQ (SEQ ID NO: 8).

[0124] The DNA sequence encoding the variable heavy domain of MOR202 is:

[0125] CAGGTGCAATTGGTGGAAAGCGGCGCGGCCTGGTGCAACCGGGCGGCAGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGCCAAGCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACCTATTATGC GGATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA(SEQ ID NO:10).

[0126] The DNA sequence encoding the variable light domain of MOR202 is:

[0127] GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCA GGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGGATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGCGGCGGCACGAAGTTAACCGTTCTTGGCCAG(SEQ ID NO:11).

[0128] The present invention

[0129] The present invention relates to antibodies or antibody fragments specific for CD38, which can be used to prevent and / or treat autoimmune diseases mediated by autoantibodies. In some aspects, the antibody is MOR202, and the autoantibody-mediated AD is any one selected from Table 1. In one aspect, the antibody is MOR202, and the autoantibody-mediated AD is SLE. In a specific aspect, the antibody is MOR202, and the autoantibody-mediated AD is idiopathic membranous glomerulonephritis, preferably anti-PLA2R positive membranous glomerulonephritis.

[0130] The present invention also provides a method for preventing and / or treating an autoimmune disease mediated by an autoantibody, the method comprising administering an antibody or antibody fragment specific to CD38 to a subject in need thereof. In some aspects, the antibody or antibody fragment specific to CD38 used in the method is MOR202, and the autoantibody-mediated AD is selected from Table 1. In one aspect, the antibody or antibody fragment specific to CD38 used in the method is MOR202, and the autoantibody-mediated AD is SLE. In a specific aspect, the antibody or antibody fragment specific to CD38 used in the method is MOR202, and the autoantibody-mediated AD is idiopathic membranous glomerulonephritis, preferably anti-PLA2R positive membranous glomerulonephritis.

[0131] The present invention also provides a pharmaceutical composition comprising the antibody or antibody fragment specific to CD38, and a method for preventing and / or treating autoimmune diseases mediated by autoantibodies by administering the antibody or antibody fragment specific to CD38.

[0132] Pharmaceutical composition

[0133] When used as a medicament, the antibody or antibody fragment specific for CD38 is generally administered in a pharmaceutical composition. Such a composition can be prepared in a manner well known in the pharmaceutical art and comprises an antibody or antibody fragment specific for CD38. Generally, the antibody or antibody fragment specific for CD38 is administered in an effective amount. The actual amount of the antibody or antibody fragment specific for CD38 is generally determined by the physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual antibody or antibody fragment administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0134] The composition of the present disclosure is preferably a pharmaceutical composition comprising MOR202 and a pharmaceutically acceptable carrier, diluent or excipient for use in treating autoimmune diseases mediated by autoantibodies.

[0135] Pharmaceutically acceptable carriers should be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Pharmaceutical carriers enhance or stabilize the composition, or facilitate the preparation of the composition. Pharmaceutically acceptable carriers include physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc.

[0136] The composition should be sterile and fluid. Can for example be by using a coating such as lecithin, by keeping the required particle size in the case of a dispersant and by using a surfactant to keep suitable fluidity. In many cases, it is preferred to include an isotonic agent in the composition, such as sugar, polyols such as mannitol or sorbitol and sodium chloride. The long-term absorption of the injectable composition can be achieved by including an agent such as aluminum monostearate or gelatin that delays absorption in the composition.

[0137] Pharmaceutical compositions of the present disclosure can be applied by multiple approaches known in the art. The route of administration selected by the antibody or antibody fragment of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion. Parenteral administration can represent the mode of administration except enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intralesional and intrasternal injection and infusion. Alternatively, compositions of the present disclosure can be applied by non-parenteral routes, such as local, epidermal, skin or mucosal routes of administration, such as intranasal, oral, vaginal, rectal, sublingual, transdermal or topical administration. In addition, the antibody or antibody fragment can be applied as a sustained release formulation, in which case less frequency of application is required. Additionally, pulmonary administration may be employed, for example, by use of an inhaler or nebulizer and formulation with an aerosolizing agent.

[0138] Antibodies or antibody fragments specific for CD38 are preferably formulated as injectable compositions. In preferred aspects, the anti-CD38 antibodies of the present disclosure are administered intravenously. In other aspects, the anti-CD38 antibodies of the present disclosure are administered subcutaneously, intraarticularly, or intraspinally.

[0139] Depending on the route of administration, the active compound, ie, antibody, antibody fragment, bispecific and multispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0140] Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the antibody or antibody fragment specific for CD38 in such a composition is usually a minor component, usually about 0.05-10% by weight, and the rest is an injectable carrier, etc. If necessary, the composition may also contain a solubilizer and a local anesthetic, such as lidocaine, to relieve pain at the injection site.

[0141] In one aspect, the present disclosure relates to a composition comprising an anti-CD38 antibody for use in treating autoantibody-mediated AD, the composition further comprising one or more pharmaceutically acceptable carriers and / or diluents.

[0142] An important aspect of the present disclosure is a pharmaceutical composition capable of mediating killing of antibody-secreting cells (eg, plasmablasts, plasma cells) expressing CD38 via ADCC and ADCP.

[0143] Treatment

[0144] In one embodiment, the present invention provides an antibody or antibody fragment specific for CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38, for preventing and / or treating autoimmune diseases mediated by autoantibodies.

[0145] In one embodiment, the present disclosure provides an antibody or antibody fragment specific to CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific to CD38, for preventing and / or treating systemic lupus erythematosus (SLE).

[0146] In another embodiment, the present disclosure provides an antibody or antibody fragment specific to CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific to CD38, for preventing and / or treating idiopathic membranous nephropathy.

[0147] In one embodiment, the present invention provides an antibody or antibody fragment specific for CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38, for preventing and / or treating autoimmune membranous nephropathy.

[0148] In a specific embodiment, the present disclosure provides an antibody or antibody fragment specific to CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific to CD38, for preventing and / or treating anti-PLA2R-positive membranous nephropathy.

[0149] In another aspect, the present disclosure provides an antibody or antibody fragment specific for CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38, for preventing and / or treating membranous nephropathy in a patient with an anti-PLA2R antibody titer.

[0150] In another embodiment, the present disclosure provides an antibody or antibody fragment specific to CD38, or a pharmaceutical composition comprising an antibody or antibody fragment specific to CD38, for preparing a medicament for preventing and / or treating autoimmune diseases mediated by autoantibodies.

[0151] In one aspect, the present disclosure provides use of an anti-CD38 antibody in the preparation of a medicament for treating and / or preventing systemic lupus erythematosus (SLE).

[0152] In another aspect, the present disclosure provides use of an anti-CD38 antibody in the preparation of a medicament for treating and / or preventing idiopathic membranous nephropathy.

[0153] In another aspect, the present disclosure provides use of an anti-CD38 antibody in the preparation of a medicament for treating and / or preventing autoantibody-mediated membranous nephropathy.

[0154] In a preferred aspect, the present disclosure provides use of an anti-CD38 antibody in the preparation of a medicament for treating and / or preventing anti-PLA2R-positive membranous nephropathy.

[0155] In other aspects, the present disclosure provides the use of MOR202 in the preparation of a medicament for treating and / or preventing autoimmune diseases mediated by autoantibodies.

[0156] In other aspects, the present disclosure provides use of MOR202 in the preparation of a medicament for treating and / or preventing systemic lupus erythematosus (SLE).

[0157] In other aspects, the present disclosure provides use of MOR202 in the preparation of a medicament for treating and / or preventing idiopathic membranous nephropathy.

[0158] In other aspects, the present disclosure provides use of MOR202 in the preparation of a medicament for treating and / or preventing autoantibody-mediated membranous nephropathy.

[0159] In a preferred aspect, the present disclosure provides use of MOR202 in the preparation of a medicament for treating and / or preventing anti-PLA2R-positive membranous nephropathy.

[0160] In one embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38 and another therapeutic agent, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, for preventing and / or treating autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0161] In another embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38 and another therapeutic agent, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, for preventing and / or treating systemic lupus erythematosus (SLE).

[0162] In another embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38 and another therapeutic agent, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, for preventing and / or treating idiopathic membranous nephropathy.

[0163] In a preferred embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38 and another therapeutic agent, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, for preventing and / or treating anti-PLA2R-positive membranous nephropathy.

[0164] In one embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38 and another therapeutic agent, or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, for the preparation of a medicament for preventing and / or treating autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0165] In other aspects, the present disclosure provides the use of an anti-CD38 antibody and another therapeutic agent or a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment in the preparation of a medicament for treating and / or preventing autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0166] In a preferred aspect, the present disclosure provides use of an anti-CD38 antibody and another therapeutic agent or a pharmaceutical composition comprising the anti-CD38 antibody or antibody fragment in the preparation of a medicament for treating and / or preventing systemic lupus erythematosus (SLE).

[0167] In a preferred aspect, the present disclosure provides the use of an anti-CD38 antibody and another therapeutic agent or a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment in the preparation of a medicament for treating and / or preventing idiopathic membranous nephropathy.

[0168] In other aspects, the present disclosure provides the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for treating and / or preventing autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0169] In one aspect, the present disclosure provides the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for treating and / or preventing systemic lupus erythematosus (SLE).

[0170] In a specific aspect, the present disclosure provides the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for treating and / or preventing idiopathic membranous nephropathy.

[0171] In a specific aspect, the present invention provides the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for treating and / or preventing anti-PLA2R positive membranous nephropathy.

[0172] In a specific embodiment, the another therapeutic agent is an autoimmune disease therapeutic agent. In a specific embodiment, the agent is an immunosuppressant and is selected from steroids (e.g., clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide or dexamethasone), proteasome inhibitors (e.g., bortezomib), cytostatics (e.g., cyclophosphamide, azathioprine, methotrexate), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus) and other immunosuppressants.

[0173] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from an autoantibody-mediated autoimmune disease, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein for treating and / or preventing the condition.

[0174] In one aspect, the present invention provides a method for treating autoantibody-mediated AD, preferably autoantibody-mediated membranous nephropathy, comprising administering an anti-CD38 antibody to the subject.

[0175] In one embodiment, the present disclosure provides a method for preventing and / or treating a mammal suffering from an autoantibody-mediated autoimmune disease, wherein the method comprises administering an additional therapeutic agent together with an antibody or antibody fragment specific for CD38. In a specific embodiment, the additional therapeutic agent is an autoimmune disease therapeutic agent. In a specific embodiment, the agent is an immunosuppressant.

[0176] In the methods of treatment or use described herein, the autoimmune disease is specifically an autoimmune disease mediated by autoantibodies (eg, SLE, Graves' disease, myasthenia gravis, pemphigus vulgaris, autoimmune encephalitis, idiopathic membranous glomerulonephritis, anti-PLA2R positive membranous glomerulonephritis).

[0177] In a specific aspect, the present disclosure provides a method for treating and / or preventing anti-PLA2R-positive membranous glomerulonephritis in a subject, the method comprising administering an anti-CD38 antibody to the subject.

[0178] In one embodiment, the present disclosure provides a method for preventing and / or treating a subject with moderate to severe autoantibody-mediated AD, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein for treating and / or preventing the condition.

[0179] In some embodiments, the present disclosure provides a method for preventing and / or treating a subject with autoantibody-mediated AD, wherein the subject is resistant to treatment with other immunosuppressant therapies including corticosteroids or calcineurin inhibitors or B cell depletion therapies (e.g., using rituximab or any other anti-CD20 antibody or anti-BAFF antibody), the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein for treating and / or preventing the condition.

[0180] In one aspect, the invention provides methods of using anti-CD38 antibodies or antibody fragments to achieve prophylactic or therapeutic benefit in patients suffering from autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0181] Another aspect provided herein is a method of using an anti-CD38 antibody to treat and / or prevent symptoms mediated by an autoimmune disease mediated by an autoantibody.

[0182] Another aspect provided herein is a method for reducing the incidence, ameliorating the symptoms of an autoantibody-mediated disease, inhibiting the symptoms of an autoantibody-mediated disease, alleviating the symptoms of an autoantibody-mediated disease, and / or delaying the onset, development, or progression of an autoantibody-mediated disease in a subject, the method comprising administering to the subject an effective amount of an anti-CD38 antibody.

[0183] In a preferred embodiment, the present disclosure provides methods for treating a patient who exhibits elevated levels of one or more autoantibodies specifically associated with an autoimmune disease.

[0184] In other aspects, the present disclosure provides methods for treating and / or preventing autoimmune diseases caused by anti-nuclear or anti-DNA autoantibodies or Fig.12 The presence of any of the other SLE autoantibodies listed in the method for causing SLE.

[0185] In other aspects, the present invention provides methods for treating and / or preventing autoantibodies to anti-nuclear or anti-DNA antibodies or Fig.12 The presence of any other SLE autoantibodies listed in the SLE related methods.

[0186] In other aspects, the present disclosure provides methods for treating and / or preventing diseases caused by the presence of anti-phospholipase A2 receptor (PLA2R) autoantibodies. In other aspects, the present disclosure provides methods for treating and / or preventing diseases associated with the presence of anti-phospholipase A2 receptor (PLA2R) autoantibodies.

[0187] In other aspects, the present disclosure provides methods for treating and / or preventing diseases caused by the presence of anti-thrombospondin type 1 7A domain autoantibodies. In other aspects, the present disclosure provides methods for treating and / or preventing diseases associated with anti-thrombospondin type 1 7A domain autoantibodies.

[0188] In other embodiments, the disclosure provides a method of reducing the titer of autoantibodies in the serum of a subject suffering from an autoantibody-mediated autoimmune disease, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein.

[0189] In a preferred embodiment, the present disclosure provides a method for reducing the titer of autoantibodies in the serum of a subject with idiopathic membranous glomerulonephritis, the method comprising administering an effective amount of an antibody or antibody fragment or one or more pharmaceutical compositions specific to CD38 as described herein. For example, the method provided herein comprises administering an anti-CD38 antibody to a patient with elevated levels of anti-PLA2R and / or anti-type 1 thrombospondin 7A domain autoantibodies.

[0190] In one embodiment, the reduction (change) in autoantibody titer in the serum of a subject with anti-PLA2R-positive membranous glomerulonephritis after administration of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to baseline.

[0191] In another embodiment, the disclosure provides a method for treating and / or preventing proteinuria associated with anti-PLA2R-positive membranous glomerulonephritis in an individual, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein.

[0192] In another aspect, the present disclosure provides a method for preventing decreased renal function in an individual with anti-PLA2R-positive membranous nephropathy, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein.

[0193] In another aspect, the disclosure provides a method for treating and / or preventing hypercholesterolemia (high cholesterol) in an individual with membranous nephropathy, the method comprising administering an effective amount of an antibody or antibody fragment specific for CD38 or one or more pharmaceutical compositions described herein.

[0194] In one embodiment, the disclosure relates to the use of an antibody or antibody fragment specific for CD38 in treating an autoantibody-mediated autoimmune disease, wherein the antibody or antibody fragment binds to plasma cells expressing CD38.

[0195] In other embodiments, the disclosure relates to methods of treating an autoantibody-mediated autoimmune disease in a subject, comprising administering to the subject a pharmaceutical composition comprising an antibody or antibody fragment that binds to cells expressing CD38 and causes depletion of such cells expressing CD38.

[0196] In a preferred embodiment, the present disclosure relates to a method for treating an autoantibody-mediated autoimmune disease in a subject, comprising administering to the subject a pharmaceutical composition comprising an antibody or antibody fragment that binds to and causes depletion of antibody-secreting cells expressing CD38 while retaining other low CD38-expressing (non-antibody-secreting) cells such as NK cells.

[0197] In a specific preferred embodiment, the present disclosure relates to a method for treating an autoantibody-mediated autoimmune disease in a subject, comprising administering to the subject a pharmaceutical composition comprising an antibody or antibody fragment that binds to antibody-secreting cells expressing CD38 and causes the consumption of such antibody-secreting cells expressing CD38 while retaining NK cells, i.e., wherein the antibody has significantly higher specific cell killing of antibody-secreting cells than NK cells.

[0198] In one embodiment, the present disclosure relates to a method for treating an autoantibody-mediated autoimmune disease in a subject, comprising administering to the subject a pharmaceutical composition comprising an antibody or antibody fragment that binds to and causes depletion of antibody-secreting cells expressing CD38, while sparing other low CD38-expressing (non-antibody-secreting) cells, such as NK cells, wherein the specific cell killing of antibody-secreting plasma cells is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% as determined in a standard ADCC assay, and wherein the specific cell killing of non-antibody-secreting NK cells is less than 30%, less than 25%, less than 20%, or less than 15%.

[0199] Antibodies or antibody fragments specific for CD38 can be administered as the sole active agent, or can be administered in combination with other therapeutic agents. In a specific embodiment, co-administration of two (or more) drugs allows the dosage of each drug to be significantly reduced, thereby reducing the side effects seen.

[0200] In one embodiment, the antibody or antibody fragment specific for CD38 or the pharmaceutical composition comprising the antibody or antibody fragment specific for CD38 is administered as a medicament. In a specific embodiment, the pharmaceutical composition further comprises other active ingredients.

[0201] It will be apparent to those skilled in the art that co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. While the two or more agents may be administered simultaneously in a single formulation, i.e., as a single pharmaceutical composition, this is not required. The agents may be administered at different times in different formulations.

[0202] The therapies (eg, prophylactic or therapeutic agents) of the combination therapies of the present disclosure can be administered to a subject concomitantly or sequentially.

[0203] Therapies (e.g., prophylactic or therapeutic agents) of the combination therapy of the present disclosure can also be administered in cycles. Cycling therapy involves administering a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administering a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, and repeating the sequential administration, i.e., the cycle, to reduce the development of resistance to one of the therapies (e.g., agents), avoid or reduce the side effects of one of the therapies (e.g., agents), and / or improve the efficacy of the therapy.

[0204] The therapies (e.g., prophylactic or therapeutic agents) of the combination therapy of the present disclosure can be administered to the subject simultaneously. The term "simultaneously" is not limited to administering the therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but means that the pharmaceutical composition comprising the antibody or antibody fragment of the present disclosure is administered to the subject in an order and time interval such that the antibody of the present disclosure can act together with the other therapies to provide an increased benefit compared to administering them in other ways.

[0205] Antibody

[0206] In certain embodiments of the present disclosure, the antibody or antibody fragment specific for CD38 according to the present disclosure comprises a variable heavy chain variable region, a variable light chain region, a heavy chain, a light chain and / or a CDR comprising any amino acid sequence of a CD38-specific antibody as described in WO2007 / 042309.

[0207] In one embodiment, the antibody or antibody fragment specific for CD38 comprises: a HCDR1 region comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 region comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 region comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 region comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 region comprising the amino acid sequence of SEQ ID NO: 6.

[0208] In one embodiment, the antibody or antibody fragment specific for CD38 comprises the HCDR1 region of SEQ ID NO: 1, the HCDR2 region of SEQ ID NO: 2, the HCDR3 region of SEQ ID NO: 3, the LCDR1 region of SEQ ID NO: 4, the LCDR2 region of SEQ ID NO: 5, and the LCDR3 region of SEQ ID NO: 6.

[0209] In one embodiment, the antibody or antibody fragment specific for CD38 comprises the variable heavy chain region of SEQ ID NO:7 and the variable light chain region of SEQ ID NO:8.

[0210] In another embodiment, the antibody or antibody fragment comprises a variable heavy chain region of SEQ ID NO:7 and a variable light chain region of SEQ ID NO:8 or a variable heavy chain region and a variable light chain region that are at least 60%, at least 70%, at least 80%, at least 90% or at least 95% identical to the variable heavy chain region of SEQ ID NO:7 and the variable light chain region of SEQ ID NO:8.

[0211] An exemplary antibody or antibody fragment comprising a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 7 and a variable light chain region comprising the amino acid sequence of SEQ ID NO: 8 is the human anti-CD38 antibody designated MOR202.

[0212] In one embodiment, the present disclosure relates to a nucleic acid composition comprising one or more nucleic acid sequences encoding the antibody or antibody fragment specific for CD38, wherein the antibody or antibody fragment comprises the HCDR1 region of SEQ ID NO: 1, the HCDR2 region of SEQ ID NO: 2, the HCDR3 region of SEQ ID NO: 3, the LCDR1 region of SEQ ID NO: 4, the LCDR2 region of SEQ ID NO: 5, and the LCDR3 region of SEQ ID NO: 6.

[0213] In another embodiment, the disclosure relates to a nucleic acid encoding an isolated monoclonal antibody or fragment thereof, wherein the nucleic acid comprises the VH of SEQ ID NO:10 and the VL of SEQ ID NO:11.

[0214] In one embodiment, the disclosed antibodies or antibody fragments specific for CD38 are monoclonal antibodies or antibody fragments.

[0215] In one embodiment, the disclosed antibodies or antibody fragments specific for CD38 are human antibodies, humanized antibodies, or chimeric antibodies.

[0216] In certain embodiments, the antibody or antibody fragment specific for CD38 is an isolated antibody or antibody fragment.

[0217] In another embodiment, the antibody or antibody fragment is a recombinant antibody or antibody fragment.

[0218] In another embodiment, the antibody or antibody fragment is a recombinant human antibody or antibody fragment.

[0219] In another embodiment, the recombinant human antibody or antibody fragment is an isolated recombinant human antibody or antibody fragment.

[0220] In another embodiment, the recombinant human antibody or antibody fragment or isolated recombinant human antibody or antibody fragment is monoclonal.

[0221] In one embodiment, the disclosed antibodies or antibody fragments are of the IgG isotype.

[0222] In another embodiment, the antibody is IgG1.

[0223] In one embodiment, the antibody fragment is a bivalent antibody fragment.

[0224] In a specific aspect of the invention, the anti-CD38 antibody is MOR202.

[0225] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising MOR202 or a fragment thereof having specificity for CD38 and a pharmaceutically acceptable carrier or excipient.

[0226] In certain embodiments, the antibody or antibody fragment specific for CD38 is an antibody or antibody fragment that specifically binds CD38.

[0227] In certain embodiments, the antibody or antibody fragment specific for CD38 is an antibody or antibody fragment that specifically binds to human CD38.

[0228] In certain embodiments, the antibody or antibody fragment specific for CD38 is an isolated monoclonal antibody or antibody fragment that specifically binds to human CD38.

[0229] In another embodiment, the present disclosure provides antibodies or antibody fragments specific for CD38 that deplete antibody-secreting cells expressing CD38.

[0230] In a preferred aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing serum autoantibody levels in a subject with SLE, the agent comprising an anti-CD38 antibody as an active ingredient.

[0231] In a preferred aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing serum autoantibody levels in a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0232] In a specific aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing serum anti-PLA2R autoantibody levels in a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0233] In another aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing anti-PLA2R autoantibodies deposited in the kidney of a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0234] In another aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing proteinuria in a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0235] In another aspect, the present disclosure provides a preventive and / or therapeutic agent for reducing hyperlipidemia (eg, hypercholesterolemia, high cholesterol) in a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0236] In another aspect, the present disclosure provides a preventive and / or therapeutic agent for restoring, improving or normalizing renal function indicated by glomerular filtration rate (eGFR) based on the CKD-epi equation in a subject with aMN, the agent comprising an anti-CD38 antibody as an active ingredient.

[0237] Working Example

[0238] An exemplary antibody specific for CD38 used in the following examples is the human antibody MOR202.

[0239] Example 1: Efficacy of MOR202 on pre-existing antibody titers to tetanus toxoid as vaccine antigen.

[0240] To assess the effect of MOR202 treatment on pre-existing antibody titers, the inventors determined anti-tetanus toxoid titers in human sera collected from subjects at defined time points after MOR202 administration.

[0241] Study design

[0242] The following bioanalytical evaluation is part of an open-label, multicenter, dose-escalation clinical study to characterize the safety and preliminary efficacy of the human anti-CD38 antibody MOR03087 in adult subjects with relapsed / refractory multiple myeloma. The purpose of this experiment is to quantitatively determine the anti-tetanus toxoid (anti-TT) IgG antibody titers in human serum samples obtained during the study to confirm that the monoclonal anti-CD38 antibody (MOR03087 = MOR202) can effectively reduce pre-existing antibody titers. The anti-tetanus toxoid (anti-TT) IgG levels of human serum samples were analyzed by ELISA (Table 4).

[0243] 1.2. Determination of anti-tetanus toxoid IgG by quantitative ELISA

[0244] Serum samples were stored at -75 ± 15 °C until analysis. To determine anti-tetanus toxoid IgG in samples, a commercially available immunoassay kit (VaccZyme TM , Binding Site, Product Code MK010). Prior to sample analysis, the assay was qualified at the bioanalytical testing site, and all measurements were performed in accordance with the manufacturer's recommendations. The kit provides two quality control (QC) samples with batch-specific target values ​​and ranges. QC target values ​​(high QC / low QC): 1.31 / 0.22 IU / mL (Batch 1), 1.32 / 0.23 IU / mL (Batch 2), 1.39 / 0.25 IU / mL (Batch 3), 1.3 / 0.25 IU / mL (Batch 4), 1.27 / 0.28 IU / mL (Batch 5). In the qualified run, three additional concentration levels were evaluated based on the results of the qualified run: ULOQ (7 IU / mL), LLOQ (0.01 IU / mL), HQC (2.8–3.5 IU / mL) (ULOQ: upper limit of quantification, LLOQ: lower limit of quantification, HQC: high quality control). Calibration standard samples are provided with the kit and are ready for immediate use. One set of calibration standards consists of: 0.01, 0.03, 0.09, 0.26, 0.78, 2.33, 7 IU / mL.

[0245] Measuring performance

[0246] The samples were analyzed in duplicate in a run (one run = one 96-well plate) together with one set of calibration standards and two sets of QC samples provided in the assay kit. No sample work up was required for the anti-TT IgG ELISA. The samples were measured after dilution with sample diluent (minimum required dilution 1:101).

[0247] 1.2.2. Test principle

[0248] VaccZyme TM The Anti-Tetanus Toxoid IgG Enzyme Immunoassay Kit is a two-step ELISA assay. The wells of 12 split 8-well strips are coated with Tetanus Toxoid from Clostridium tetani. Calibrators, controls and diluted serum samples are added to the wells, and antibodies recognizing the Tetanus Toxoid antigen bind during the first incubation. After washing the wells to remove all unbound protein, a purified peroxidase-labeled rabbit anti-human IgG (γ chain specific) conjugate is added. The conjugate binds to the captured human antibody and excess unbound conjugate is removed by further washing steps. The bound conjugate is visualized with 3,3',5,5'tetramethylbenzidine (TMB) substrate, which produces a blue reaction product whose intensity is proportional to the concentration of the antibody in the sample. Phosphoric acid is added to each well to stop the reaction. This produces a yellow endpoint color that is read at 450nm.

[0249] Data evaluation

[0250] Using 4-parameter logic, using Magellan from TECAN Austria GmbH TM Software version 6.6 performed data simplification on the microplate reader readings. The optical density of the quality control and research samples was converted to concentration (IU / mL) using a standard curve. Extrapolation (extrapolation factor 1.1) was performed so that concentrations close to the upper and lower limits of quantification could be calculated. All measured and calculated concentration data were reported with 3 significant figures.

[0251] 1.2.4. Results

[0252] Human serum samples were analyzed in 22 assay runs. Inter-assay accuracy and precision data were evaluated from calibration standard samples in 22 accepted runs. Accuracy (expressed as bias) and precision (expressed as coefficient of variation; CV) data are shown in Table 2.

[0253] Table 2. Accuracy and precision of calibration standards

[0254]

[0255] Inter-assay accuracy and precision data were evaluated from up to 22 sets of QC samples in 22 accepted runs. Accuracy (expressed as bias) and precision (expressed as coefficient of variation; CV) data are shown in Table 3.

[0256] Table 3. Accuracy and precision of quality control samples

[0257]

[0258] Table 4 shows the anti-TT concentrations (IU / mL) of serum samples from 74 subjects for whom at least one of the baseline and "Cycle 1, Day 15" or "Cycle 2, Day 15" data points were available. Subjects who received concomitant medications (e.g., IVIG administration or booster vaccinations) during the clinical study were not included in the analysis because these concomitant medication factors biased the results.

[0259] Table 4. Anti-TT antibody concentrations in human serum samples after administration of MOR202

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] To determine the effect of MOR202 on anti-TT antibody titers, serum samples obtained on day 0 (before MOR202 treatment, indicated as "baseline" in Table 4), day 15 (cycle 1), and day 43 (= cycle 2, day 15) after MOR202 administration were analyzed. On day 15 of cycle 1 after MOR202 treatment, the anti-TT antibody titers of most subjects showed a significant decrease compared to the baseline on day 0. Figure 5 The % change in anti-TT concentration of the "baseline" sample obtained on Day 0 compared to the anti-TT concentration of the sample obtained on Day 15 of Cycle 1 (labeled "Cycle 1, Day 15") is shown in FIG. Figure 6The % change in anti-TT concentration of the "baseline" sample obtained on Day 0 compared to the anti-TT concentration of the sample obtained on Day 15 of Cycle 2 (labeled "Cycle 2, Day 15") is shown in . In the majority of MOR202-treated subjects, anti-TT antibody titers decreased further (i.e., a higher percentage change from Cycle 1, Day 15 to Cycle 2, Day 15), indicating a long-term effect of MOR202 on antibody titers.

[0267] Taken together, these data demonstrate that MOR202 is effective in reducing serum antibody titers. Therefore, it is highly plausible that anti-CD38 antibodies (eg, MOR202) may be used for the effective treatment and / or prevention of autoantibody-mediated AD.

[0268] Example 2: Determination of M-protein levels

[0269] Study design

[0270] The M-protein levels in serum samples of multiple myeloma patients (participating in the experiment of Example 1) were quantitatively determined by capillary electrophoresis (CE) assays, specifically serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP).

[0271] 2.2. Capillary electrophoresis - test principle

[0272] Charged molecules are separated by their electrophoretic mobility at a specific pH in an alkaline buffer. Separation occurs according to the electrolyte pH and electroosmotic flow. Each sample is diluted in dilution buffer and the capillary is filled with separation buffer; the sample is then injected into the anodic end of the capillary by aspiration. High voltage protein separation is then performed. Subsequently, direct detection and quantification of the different protein fractions is performed at a specific wavelength at the cathodic end of the capillary.

[0273] Other assays for assessing M-protein levels include, but are not limited to, immunofixation electrophoresis (IFE), serum-free light chain (sFLC) assays, and total protein determination (Keren DF and Schroeder L, Clin Chem Lab Med. 2016 Jun 1; 54(6): 947-61). In addition, an IFE-based REFELX assay as described in WO / 2017 / 149122 may be performed.

[0274] 2.3 Results:

[0275] Figure 7 Shown are changes given in percentage [%] in M-protein levels in multiple myeloma patients after MOR202 treatment.

[0276] The effect of MOR202 in reducing M-protein indirectly suggests the destruction and depletion of malignant plasma cells that produce M-protein. Figure 5 and Figure 6 In addition to the results of Example 1 shown above, the reduction of M-protein after MOR202 administration ( Figures 7 to 9 ) also provided further evidence that MOR202 can effectively reduce antibody titers.

[0277] Example 3: Evaluation of Natural Killer (NK) Cell-Mediated ADCC

[0278] 3.1 Experimental Setup

[0279] ADCC assays were performed to test the natural killer cell-mediated specific killing effects of MOR202, daratumumab, and isatuximab (SAR650984) on (i) multiple myeloma cell lines (NCI-H929) that highly express CD38 and (ii) human NK cells that lowly express CD38. NK cells were purified from human blood by MACS (Miltenyi Biotec, Cat. No. 130-092-657). The purity of NK cells was assessed by FACS using CD3 / CD16+CD56 / CD45 TritestTM (Becton Dickinson, Cat. No. 342411). NCI-H929 target cells were incubated with each antibody at a defined concentration at a ratio of 3:1 effector cells to target cells at 37°C for 2-4h. NK target cells were incubated with each antibody only for 2-4 h at 37°C, since for the NK cell:NK cell setup, target and effector cells were identical. To determine cytotoxicity, propidium iodide (PI) was added to the cell samples after incubation, and PI uptake in dead cells was immediately assessed by flow cytometry.

[0280] 3.2 Results

[0281] Fig.10 The results of specific killing [%] of NCI-929 and NK cells by MOR202, daratumumab, and isatuximab are shown.

[0282] Example 4: Evaluation of the safety of MOR202 in subjects with anti-PLA2R-positive membranous nephropathy (aMN) and efficacy

[0283] 4.1 Study design

[0284] The objectives of this 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 MOR202 on serum anti-PLA2R antibody levels.

[0285] The MOR202 dose is based on the clinical study results and PK / PD modeling methods in multiple myeloma (MM) in Example 1. In Example 1, MOR202 was administered intravenously at 0.1-16 mg / kg in a dose escalation regimen, once a week (QW) or once every two weeks (Q2W), including a loading dose on the 4th day of cycle 1. MOR202 is used as a single agent (monotherapy) or in combination with DEX, POM / DEX or LEN / DEX. The overall duration of treatment is based on clinical response, and the longest continuous treatment can be up to 3 years. According to the results, a population-based PK / PD model was established, taking into account the different target expression rates between MM and aMN subjects. As expected in this study, the model was used to simulate drug exposure (ie, at a dose of 16 mg / kg: 4×QW, then 5×Q4W), and the results were compared with the research data of Example 1 considering the same treatment time. In the study of Example 1, 6 patients were administered 16 mg / kg QW for at least 24 weeks, including a loading dose on the 4th day. This would result in a 2.4-fold excess exposure to MOR202 compared to the expected dose and dosing schedule in the current study with similar maximum serum concentrations. The purpose of this trial is to evaluate the safety and efficacy of the human anti-CD38 antibody MOR202 in patients with anti-PLA2R-positive membranous nephropathy (aMN) who are either first eligible for immunosuppressive therapy or unresponsive to immunosuppressive therapy (IST) including rituximab (anti-CD20) therapy.

[0286] Example 5: M-PLACE: a phase Ib / IIa multicenter open-label study using MOR202 to treat two groups of aMN patients (NCT04145440)

[0287] A Phase Ib / IIa open-label multicenter clinical trial has been initiated to evaluate the safety and efficacy of the human anti-CD38 antibody MOR202 in anti-PLA2R antibody-positive membranous nephropathy (aMN) with an estimated enrollment of 30 participants and is currently recruiting at least 14 centers at 6 sites in the United States and Europe. ClinicalTrials.gov identifier (NCT number): NCT04145440.

[0288] Study design

[0289] The objectives of this 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 MOR202 on serum anti-PLA2R antibody levels.

[0290] The main therapeutic principle is to reduce membranous nephropathy (MN) disease-specific anti-PLA2R antibodies by targeted depletion of autoantibody-producing plasma cells through the anti-CD38 antibody MOR202.

[0291] The patient population to be treated includes adult subjects with biopsy-proven anti-PLA2R antibody-positive MN. Ages eligible for the study: 18 to 80 years (adults, elderly). All genders are eligible for the study.

[0292] Key inclusion criteria:

[0293] Urine protein to creatinine ratio ≥ 3.0 g / g (measured from a 24-hour urine collection)

[0294] Estimated glomerular filtration rate ≥50 mL / min / 1.73 m on renal biopsy obtained within the last six months before initiation of screening 2 or >30 and <50 mL / min / 1.73 m 2 , and interstitial fibrosis and tubular atrophy scores were less than 25%.

[0295] Supportive treatment with an ACE inhibitor or angiotensin II receptor blocker for at least 4 weeks at a stable dose prior to screening.

[0296] Systolic blood pressure ≤ 150 mmHg, diastolic blood pressure ≤ 100 mmHg

[0297] · Pneumococcal vaccination within the last three years prior to the date of signing the informed consent form (subjects may be vaccinated during the screening process to meet this criterion; the interval from the first dose of MOR202 must be at least 14 days).

[0298] • Group 1a (newly diagnosed patients): serum anti-PLA2R antibodies ≥ 150.0 reactive units (RU) / mL as determined by Euroimmun ELISA screening.

[0299] Group 1b, relapsed subjects: must have complete immune and / or clinical remission according to the investigator's judgment and serum anti-PLA2R antibodies ≥ 50.0 RU / mL as determined by Euroimmun ELISA screening.

[0300] Group 2: Failure of previous therapy, i.e., subjects who have never achieved complete immune and / or clinical remission during or after completing a recognized IST containing cyclosporine A, tacrolimus, mycophenolate mofetil, ACTH or alkylating agents (e.g., cyclophosphamide) or rituximab, according to the investigator's judgment. Serum anti-PLA2R antibodies ≥ 20.0 RU / mL as determined by Euroimmun ELISA screening.

[0301] Key exclusion criteria:

[0302] Hemoglobin <90 g / L.

[0303] Thrombocytopenia: Platelets <100.0×10 9 / L.

[0304] Neutropenia: neutrophils <1.5×10 9 / L.

[0305] Leukopenia: WBC <3.0×10 9 / L.

[0306] Hypogammaglobulinemia: serum immunoglobulin ≤5.0 g / L.

[0307] Secondary causes of MN (eg, systemic lupus erythematosus, drug therapy, malignancy)

[0308] Concomitant renal diseases other than MN (e.g., diabetic kidney disease, lupus nephritis, IgA nephropathy).

[0309] Group 1 includes approximately 20 patients with aMN who were stable on supportive care with ACEI / ARB at screening and who have unfavorable prognostic features that qualify them for IST, such as proteinuria (>5 g / 24 h) and high and stable serum titers of anti-PLA2R antibodies (≥150.00 reaction units (RU) / mL, EuroImmun ELISA), or who have relapsed after at least 6 months of complete or partial proteinuria response (including serum anti-PLA2R antibody titers less than 20 RU / mL). Subjects may be newly diagnosed (Group 1a) or relapsed after previous proteinuria and immune response to IST (Group 1b).

[0310] Group 2 includes approximately 10 patients with aMN who require 2nd or 3rd line IST and who have no immune response to the previous line of therapy and are therefore considered refractory. Failure of previous therapy, i.e., subjects who have never had a decrease in serum anti-PLA2R antibody titer below 20 RU / mL during or after completion of a recognized IST containing CSA, tacrolimus, MMF, ACTH, or alkylating agents (e.g., cyclophosphamide) or rituximab, measured at least 6 months after the start of therapy.

[0311] Exclusion criteria for both groups 1 and 2 were active infection, secondary causes of MN (e.g., SLE, drug therapy, malignancy), type 1 or type 2 diabetes, pregnancy or breastfeeding, and known or suspected hypersensitivity to the study drug and its excipients.

[0312] Both groups had a 24-week treatment phase with MOR202 monotherapy, followed by a 28-week observational follow-up phase ( Fig.11 ).

[0313] 5.2. Administration of MOR202 (MOR03087)

[0314] MOR202 is provided as a lyophilized powder for reconstitution in labeled glass vials. MOR202 must be stored at 2-8°C until use. For drug preparation, each vial must be reconstituted with 4.8 mL of water for injection (WFI). After reconstitution, each vial contains 325 mg of MOR202 (MOR03087) in 5 mL of extractable volume (65 mg / mL). For infusion, it is diluted in 250 mL of 0.9% sodium chloride solution.

[0315] All subjects will be treated for 24 weeks, allocated to six 28-day treatment cycles. A total of 9 doses of MOR202 will be administered on the following treatment days: Days 1, 8, 15, and 22 of Cycle 1, and Day 1 of Cycles 2-6 ( Fig.11 ). In the first treatment cycle, MOR202 was administered at 16 mg / kg once a week (i.e., 4 doses in total in cycle 1). In treatment cycles 2-6, MOR202 was administered at 16 mg / kg once every 4 weeks on the first day of each cycle (i.e., C2D1, C3D1...; 5 doses in total in cycles 2-6).

[0316] The first intravenous infusion of MOR202 should be slow (approximately 90 minutes at approximately 3 mL / min). If no infusion reactions occur, the infusion time may be shortened to 1 hour or less for subsequent infusions, subject to the shortening steps listed in Table 5. The infusion time should not be shorter than 30 minutes. It is recommended that subjects be premedicated with antihistamines and antipyretics (e.g., acetaminophen / paracetamol) to prevent infusion-related reactions (IRRs). As shown in Table 5, for the first 3 applications, co-medication with intravenous dexamethasone (or an equivalent amount of glucocorticoid administered intravenously) is mandatory approximately 30 minutes before starting the MOR202 infusion to prevent IRRs.

[0317] Table 5: MOR202 Infusion Guidelines

[0318] MOR202 infusion number 1 2 3 4th and later Minimum infusion time 90min 60min 30min 30min Maximum infusion rate 3mL / min 4.5mL / min 9mL / min 9mL / min Dexamethasone intravenous dosage 16mg 16mg 8mg Not mandatory

[0319] 5.3. Safety, Immunogenicity and Pharmacokinetics Evaluation

[0320] Safety will be assessed based on physical examination, vital signs, oxygen saturation, electrocardiogram, blood and biochemical tests, adverse reactions, and immunogenicity. Adverse reactions will be rated according to NCI CTCAE version 4.03. To monitor immunogenicity and pharmacokinetics, the presence of anti-MOR202 antibodies (anti-drug antibodies) and serum concentrations of MOR202 at selected time points during the study will be assessed, respectively.

[0321] 5.4. Efficacy evaluation

[0322] The main efficacy assessments included: (i) serum anti-PLA2R antibody levels measured by ELISA to track the course of the immune response before, during and after MOR202 treatment. (ii) proteinuria measured by UPCR based on 24-hour urine / spot urine during and after MOR202 treatment. (iii) renal function determined by estimating glomerular filtration rate (eGFR) based on the CKD-epi equation before, during and after MOR202 treatment. (iv) urinary sodium excretion measured from 24-hour urine.

[0323] 5.5. Biomarkers

[0324] The presence and titer of anti-PLA2R antibodies (i.e., the kinetics of anti-PLA2R antibody titer) at selected time points will be determined for all subjects during the study. Optionally, other autoantibody titers (e.g., anti-1 type thrombospondin 7A domains, anti-THSD7A), anti-tetanus toxoid and / or anti-EBV antibodies at selected time points can be monitored. The serum concentrations of total IgG, IgA and IgM can be assessed by ELISA. Quantitative NK cells, B cells, T cells (including regulatory T cells), plasmablasts, plasma cell numbers at selected time points can be determined by peripheral blood flow cytometry or ELISPOT assays.

[0325] 5.6.KDQOL-36

[0326] Kidney Disease Quality of Life (KDQOL-36 TM ) survey was used to assess quality of life (QoL), defined as the change in score from baseline, in patients with autoimmune MN treated with MOR202.

[0327] Example 6: Determination of anti-PLA2R antibody levels

[0328] Anti-phospholipase A2 receptor (PLA2R) antibody levels in human serum samples will be quantitatively determined by monospecific ELISA (enzyme immunoassay with a single antigen, Euroimmune, order number EA1254-G) according to the manufacturer's instructions. Briefly, polystyrene microwell strips coated with purified PLA2R antigen are used as the solid phase. A serum dilution of 1:101 is prepared and incubated on the antigen bound to the wells of the microplate. If the sample is positive, the specific antibodies in the diluted serum sample will attach to the PLA2R antigen bound to the solid phase. Unbound antibodies are washed away, and in the next step, the attached anti-PLA2R specific antibodies are detected with peroxidase-labeled anti-human IgG. The bound antibodies are visualized using a chromogen / substrate solution that promotes a color development reaction. The intensity of the color produced is proportional to the concentration of the antibodies in the serum sample. Sequence Listing <110> Mofoss <120> Anti-CD38 antibodies and pharmaceutical compositions thereof for treating autoimmune diseases mediated by autoantibodies <130> MS289PCT <140> <141> <160> 11 <170> PatentIn Version 3.5 <210> 1 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 1 Ser Tyr Tyr Met Asn 1 5 <210> 2 <211> 17 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 2 Gly Ile Ser Gly Asp Pro Ser Asn Thr Tyr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 3 <211> 11 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 3 Asp Leu Pro Leu Val Tyr Thr Gly Phe Ala Tyr 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 4 Ser Gly Asp Asn Leu Arg His Tyr Tyr Val Tyr 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 5 Gly Asp Ser Lys Arg Pro Ser 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 6 Gln Thr Tyr Thr Gly Gly Ala Ser Leu 1 5 <210> 7 <211> 120 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 7 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Asp Pro Ser Asn Thr Tyr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Pro Leu Val Tyr Thr Gly Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 8 <211> 109 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 8 Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Leu Arg His Tyr Tyr Val 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr Thr Gly Gly Ala Ser Leu 85 90 95 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 <210> 9 <211> 300 <212> PRT <213> Homo sapiens <400> 9 Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys 1 5 10 15 Arg Leu Ser Arg Arg Ala Gln Leu Cys Leu Gly Val Ser Ile Leu Val 20 25 30 Leu Ile Leu Val Val Val Leu Ala Val Val Val Pro Arg Trp Arg Gln 35 40 45 Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg Phe Pro Glu Thr Val Leu 50 55 60 Ala Arg Cys Val Lys Tyr Thr Glu Ile His Pro Glu Met Arg His Val 65 70 75 80 Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys 85 90 95 His Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu 100 105 110 Gly Thr Gln Thr Val Pro Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile 115 120 125 Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe Thr 130 135 140 Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys 145 150 155 160 Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp 165 170 175 Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val 180 185 190 Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu 195 200 205 Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser 210 215 220 Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala 225 230 235 240 Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp 245 250 255 Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln 260 265 270 Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val 275 280 285 Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser Glu Ile 290 295 300 <210> 10 <211> 360 <212> DNA <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 10 caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60 agctgcgcgg cctccggatt taccttttct tcttattata tgaattgggt gcgccaagcc 120 cctgggaagg gtctcgagtg ggtgagcggt atctctggtg atcctagcaa tacctattat 180 gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240 ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtgatctt 300 cctcttgttt atactggttt tgcttattgg ggccaaggca ccctggtgac ggttagctca 360 <210> 11 <211> 327 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: Synthetic polynucleotide" <400> 11 gatatcgaac tgacccagcc gccttcagtg agcgttgcac caggtcagac cgcgcgtatc 60 tcgtgtagcg gcgataatct tcgtcattat tatgtttatt ggtaccagca gaaacccggg 120 caggcgccag ttcttgtgat ttatggtgat tctaagcgtc cctcaggcat cccggaacgc 180 tttagcggat ccaacagcgg caacaccgcg accctgacca ttagcggcac tcaggcggaa 240 gacgaagcgg attattattg ccagacttat actggtggtg cttctcttgt gtttggcggc 300 ggcacgaagt taaccgttct tggccag 327

Claims

1. Use of an antibody or antibody fragment specific for CD38 in the preparation of a medicament for treating autoantibody-mediated membranous nephropathy, wherein the antibody or antibody fragment specific for CD38 comprises a HCDR1 region of an amino acid sequence of SEQ ID NO: 1, a HCDR2 region of an amino acid sequence of SEQ ID NO: 2, a HCDR3 region of an amino acid sequence of SEQ ID NO: 3, a LCDR1 region of an amino acid sequence of SEQ ID NO: 4, a LCDR2 region of an amino acid sequence of SEQ ID NO: 5, and a LCDR3 region of an amino acid sequence of SEQ ID NO: 6, wherein the antibody or antibody fragment specific for CD38 depletes plasma cells by ADCC and / or ADCP, administration of the antibody or antibody fragment specific for CD38 results in a reduction in endogenous autoantibody titer, the endogenous autoantibody titer comprises an anti-PLA2R autoantibody titer, and wherein the autoantibody-mediated membranous nephropathy is anti-PLA2R-positive membranous nephropathy.

2. The use according to claim 1, wherein the autoantibody-mediated membranous nephropathy is anti-THSD7A-positive membranous nephropathy.

3. The use according to claim 1, wherein the antibody or antibody fragment specific for CD38 shows significantly higher specific cell killing against plasma cells than against cells that lowly express CD38. The use according to claim 3 , wherein the cells with low CD38 expression are NK cells.

5. The use according to claim 1, wherein the endogenous autoantibody titer comprises an anti-THSD7A autoantibody titer.

6. The use according to claim 1, wherein the antibody or antibody fragment specific for CD38 is a human antibody.

7. The use according to claim 1, wherein the antibody or antibody fragment specific for CD38 is IgG1.

8. The use according to claim 1, wherein the antibody or antibody fragment specific for CD38 comprises a variable heavy chain region of SEQ ID NO: 7 and a variable light chain region of SEQ ID NO:

8.

9. The use according to any one of claims 1 to 8, wherein the medicament is used in combination with another therapeutic agent to treat autoantibody-mediated membranous nephropathy.

10. The use according to claim 9, wherein the additional therapeutic agent is an agent for preventing and / or treating autoimmune diseases mediated by autoantibodies.

11. The use according to claim 10, wherein the additional therapeutic agent is an immunosuppressive drug.

12. The use according to claim 11, wherein the immunosuppressive drug is dexamethasone, azathioprine, mycophenolic acid, methotrexate, or a proteasome inhibitor.

13. The use according to claim 12, wherein the proteasome inhibitor is bortezomib.

14. The use according to any one of claims 1 to 8, wherein the antibody or antibody fragment specific for CD38 is administered intravenously.

15. The use according to any one of claims 1 to 8, wherein the antibody or antibody fragment specific for CD38 is administered once a week at 16 mg / kg in the first treatment cycle.

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