Anti-CD38 antibodies and pharmaceutical compositions thereof for treatment of autoantibody-mediated autoimmune disease

Abstract

To provide an antibody or antibody fragment specific for CD38 for use in the treatment and / or prophylaxis of autoantibody-mediated autoimmune diseases and related conditions.SOLUTION: The present invention relates to the use of an antibody or antibody fragment specific for CD38 in the prophylaxis and / or treatment of autoantibody-mediated autoimmune diseases. According to the present invention, an anti-CD38 antibody is effective in the treatment of anti-PLA2R positive membranous glomerulonephropathy.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to antibodies or antibody fragments specific for CD38 that are useful in the treatment and / or prevention of autoantibody-mediated autoimmune diseases (AD). In particular, the present invention provides methods for reducing autoantibody titers by depleting antibody-secreting cells using anti-CD38 antibodies alone or in combination with one or more immunosuppressants. According to the present invention, anti-CD38 antibodies, alone or in combination, may be effective in the treatment and / or prevention of anti-PLA2R-positive membranous nephropathy (aMN). Anti-CD38 antibodies include, but are not limited to, MOR202. [Background technology]

[0002] Autoimmune diseases and autoantibodies Autoimmune diseases (AD) comprise over 70 different disorders affecting approximately 5% of the population in Western countries (Non-Patent Document 1). AD is a clinical condition caused by the activation of autoreactive T cells, autoreactive B cells, or both. Some ADs are characterized by the production of pathogenic autoantibodies. Autoantibodies are immunoglobulins that react with autoantigens. Such autoantigens may include proteins, nucleic acids, carbohydrates, lipids, or various combinations thereof, and may be present in all cells (e.g., DNA) or may be highly restricted to specific cell types in certain organs of the organism. In autoantibody-mediated humoral AD, autoantibodies usually occur at high titers in the serum of patients. For many ADs, a clear and distinct relationship between autoantibody formation, specificity, and pathogenesis has been demonstrated (Non-Patent Document 2). Pathogenic autoantibodies affect disease pathways in many ways, including accumulation 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 (Non-Patent Document 3).

[0003] Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE), for example, is a polygenic autoimmune disorder with a prevalence of approximately 50 cases per 100,000 people, affecting women more frequently than men. The central immune derangement in SLE patients is the inappropriate activation and proliferation of autoreactive memory B cells, leading to the proliferation of antibody-secreting cells and the production of various autoantibodies. The major autoantigens in SLE are nuclear components such as DNA or ribonucleoproteins (RNPs), and autoantibodies reactive to these antigens are high-affinity, somatically mutated, and of the IgG isotype. SLE patients exhibit high levels of serum antinuclear antibodies (ANA). Autoantibodies against cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cell antigens, endothelial cell antigens, nervous system antigens, plasma proteins, matrix proteins, and various antigens may also be present (Figure 12). In SLE, many of these autoantibodies lead to the formation of ICs, which appear to be directly pathogenic after accumulation in several tissues.

[0004] Treatment options for SLE include antimalarials, steroidal and nonsteroidal anti-inflammatory drugs, immunosuppressants (including cyclophosphamide (CTX), azathioprine (AZA), mycophenolate (MMF), and methotrexate (MTX)), and immune cell-targeted therapy (Non-Patent Document 4).

[0005] These immunosuppressive or cytotoxic drugs and anti-CD20-mediated B cell depletion can induce remission in SLE patients, but current treatment protocols often fail to prevent relapse (Non-Patent Document 5).

[0006] Graves' disease (Graves' disease) Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease affecting the thyroid gland. Graves' disease affects approximately 0.5% of men and 3% of women (Non-Patent Document 6). Hyperthyroidism often results from this disease and is the most common cause of hyperthyroidism in the United States (approximately 50-80% of cases). Symptoms of hyperthyroidism may include irritability, muscle weakness, sleep disturbances, rapid heart rate, decreased heat tolerance, diarrhea, unintentional weight loss, thickened skin over the tibia and bulging eyes known as pretibial myxedema, a condition caused by Graves' disease. The direct cause of Graves' disease is autoantibodies against the receptor for thyroid-stimulating hormone (thyroid-stimulating hormone receptor (TSHR)). Autoantibodies against thyroglobulin and the thyroid hormones T3 and T4 can also be produced. TSHR autoantibodies mimic TSH, causing uncontrolled TSHR activation and thereby hyperthyroidism. Treatment options for Graves' disease include antithyroid (thionamide) drugs, thyroid removal with radioactive iodine, and surgery (thyroidectomy). However, inhibiting the development or ongoing production of TSHR autoantibodies remains a challenge in treating Graves' disease.

[0007] Myasthenia gravis (MG) Myasthenia gravis (MG) affects 500–200 per million people. 30–30 per million new cases are diagnosed each year. MG is a long-term neuromuscular AD that leads to varying degrees of skeletal muscle weakness and abnormal fatigability. It is caused by the presence of an autoantibody reaction reactive with components of postsynaptic muscle endplates located at the neuromuscular junction (the junction between nerves and muscles). Specifically, these autoantibodies block or destroy nicotinic acetylcholine receptors, subsequently preventing nerve impulses from initiating muscle contraction. Other autoantibodies have been found against a related protein called MuSK, a muscle-specific kinase, and LRP4, as well as agrin and titin proteins. MG is generally treated with drugs known as acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine. Immunosuppressants such as prednisone or azathioprine are also often used. In certain cases, surgical removal of the thyroid gland can ameliorate the symptoms of the disease. Plasmapheresis and high-dose intravenous immunoglobulin (IVIG) may be used during acute flares of the condition to remove putative autoantibodies from the circulation or to dilute and bind circulating antibodies, respectively. Both of these treatments have relatively short-term benefits, generally measured in weeks, and are often associated with high costs. If respiratory muscles become significantly weaker, mechanical ventilation may be required.

[0008] Anti-PLA2R-positive membranous glomerulonephritis (aMN) 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 most common cause of nephrotic syndrome in adults (Non-Patent Document 7). Approximately 80% of membranous nephropathy cases are idiopathic, while 20% are associated with other diseases or exposures. The overall worldwide incidence is estimated at 1.2 / 100,000 people / year. Although the disease usually progresses slowly, approximately 30% to 40% of patients ultimately progress to end-stage kidney disease. Patients with MN who remain nephrotic are at increased risk for thromboembolic and cardiovascular events. However, although not all aspects of the pathogenesis of MN are understood, the disease can no longer be considered idiopathic. The M-type phospholipase A2 receptor (PLA2R), a transmembrane protein expressed on podocytes, has been defined as the major autoantigen in MN (Non-Patent Document 8). Autoantibodies binding to the PLA2R antigen are highly specific for primary MN. Recent studies have revealed that the presence of anti-PLA2R autoantibodies significantly correlates with disease activity in approximately 75% of IMN patients (Non-Patent Document 9). The fact that the disease-defining glomerular basement membrane alterations contain both PLA2R protein and antibody complex accumulation provides evidence that anti-PLA2R antibodies play a major causative role in MN. An additional 5% of patients who are negative for anti-PLA2R antibodies have antibodies against another podocyte antigen—thrombospondin type 1 domain-containing 7A (Non-Patent Document 10). In rare cases of neonatal MN, neutral endopeptidase (NEP), located on the podocyte foot process membrane, and the brush border of the renal tubule have been identified as relevant antigens (Non-Patent Document 11). In summary, 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 lower limbs and ankles, increased urinary protein, edema, hypoalbuminemia, and elevated serum lipids, especially high cholesterol. Therefore, autoimmune membranous nephropathy is an immune-mediated glomerular disease characterized by the presence of anti-PLA2R and / or anti-THSD7A autoantibodies. In neonatal autoimmune MN, autoantibodies against maternal NEP are present.

[0009] Currently, there is no approved standard treatment for myeloproliferative malignancies. Current treatment regimens primarily involve the off-label use of various non-immunosuppressive and immunosuppressive drugs. Patients diagnosed with myeloproliferative malignancies and with proteinuria >3.5 g / day initially receive supportive care with a combination of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs), statins, and diuretics, according to current clinical standards. If there is no response with a significant decrease in proteinuria within several months, escalation to immunosuppressive therapy (IST) is indicated. Immunosuppressive therapy includes corticosteroids alternating with alkylating agents (e.g., cyclophosphamide) and calcineurin inhibitors (CNIs, e.g., cyclosporin A, tacrolimus (FK506)), mycophenolate mofetil (MMF), or rituximab, although none of these drugs are approved for use in myeloproliferative malignancies. Adrenocorticotropic hormone (ACTH) is also used, although to a lesser extent. The therapeutic efficacy of these drug combinations appears to be similar: remission of proteinuria can be expected in approximately 50-60% of patients at 1 year and approximately 70-80% at 2-3 years, compared with a remission rate of approximately 30% (spontaneous remission) in controls treated with supportive care alone.

[0010] Of all patients with primary membranous nephropathy who do not receive IST, 30% to 40% progress to end-stage kidney disease within 10 years of disease onset. IST reduces the progression rate to less than 10%. Recurrence of proteinuria occurs in approximately 25% of patients previously treated with IST. These cases are usually re-treated with a different IST combination. The drawbacks of the above-mentioned ISTs are that they exhibit a significant degree of toxicity, associated with significant side effects, and a high recurrence rate. 25% of patients treated with cyclophosphamide experience adverse events, including infections, infertility, hematologic toxicity, and malignancies later in life. Disadvantages of CN include long-term nephrotoxicity, requiring close monitoring of drug levels and increased risk for hypertension and diabetes. The recurrence rate with calcineurin inhibitors appears to be higher than with cyclophosphamide (40% to 50% vs. 25%). Considerable evidence that anti-PLA2R antibodies correlate with disease activity is changing previously established treatment algorithms.

[0011] Recently introduced off-label therapy with the anti-CD20 therapeutic antibody rituximab allows for a more specific approach to IST by depleting the B cell population involved as precursors in the production of causative anti-PLA2R autoantibodies. Rituximab response rates appear to be comparable to those of alkylating agents and CNIs, while side effects appear to be fewer 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 primary source of endogenous immunoglobulins). There is only low resident CD20 expression on early plasmablasts compared with CD20 expression on mature B cells. This is a possible explanation for the suboptimal efficacy of rituximab therapy in patients with MN who have high anti-PLA2R antibody titers.

[0012] In this regard, direct targeting of plasmablasts as well as plasma cells should generally lead to a more pronounced reduction in immunoglobulins and therefore autoantibodies. A significant portion of anti-PLA2R antibodies in aMN may be produced by a long-lived plasma cell pool with a CD20-negative but CD38-positive immunophenotype, which is independent of the continuous replenishment of differentiating B cells. Therefore, direct plasma cell targeting strategies may have a more pronounced effect in suppressing pathogenic autoantibodies. This is particularly important for patients with an inadequate response to rituximab (anti-CD20) therapy, who maintain high levels of autoantibody titers despite B cell depletion.

[0013] pemphigus Pemphigus vulgaris is an autoimmune intraepidermal mucocutaneous disorder of the skin and mouth characterized by blistering. Lesions occur with a high incidence of 0.5–3.2 cases per 100,000 people per year. These lesions primarily occur between the ages of 40 and 60, with no gender predilection. Patients with pemphigus exhibit circulating autoantibodies against pemphigus antigens (desmoglein 3, desmoglein 1, desmocollins, and plakoglobin) on epidermal keratinocytes. Disruption of these antigens by antigen-autoantibody reactions has a profound effect on epidermal integrity, resulting in cell desquamation (acantholysis), suprabasilar clefting, and subsequent blister formation. Autoantibody binding to keratinocytes also results in the release of proteases and plasminogen activators (which convert plasminogen to plasmin) from the cells, further amplifying acantholysis. Treatment options for high-grade disease include systemic glucocorticoids and combinations of corticosteroids, immunosuppressants, pulse therapy, photophoresis, and plasmapheresis.

[0014] Sjögren's syndrome Sjögren's syndrome (SOS) is a systemic autoimmune disease characterized by focal infiltration of lymphocytes into exocrine and lacrimal glands, resulting in dry mouth (xerostomia) and dry eye (keratoconjunctivitis sicca), respectively. In Sjögren's syndrome, the presence of lesions is associated with chronic inflammatory infiltration accompanied by the release of 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 Golgin family, poly(ADP) ribose polymerase (PARP), and type 3 muscarinic receptor. Currently, no targeted treatment for Sjögren's syndrome is available, and current therapeutic approaches are limited to symptomatic treatment of dryness and fatigue symptoms with, for example, pilocarpine, bromhexine, and hydroxychloroquine, respectively.

[0015] anti-NMDA encephalitis The most common antibody-mediated acute autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NPL 12). Its incidence is estimated at 3-5 per 1,000,000 people per year. Anti-NMDA encephalitis represents a model disease for syndromes characterized by the detection of autoantibodies targeting synaptic structures. Anti-NMDAR antibodies are the most common, followed by antibodies against leucine-rich glioma inactivated-1 (LGI1). Contactin-associated protein-like 2 (Caspr2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA)-A and -B receptors, dipeptidyl-peptidase-like protein-6 (DPPX), and glycine receptor (GlyR) antibodies are other examples of neuronal cell surface antibodies. Anti-NMDAR encephalitis occurs primarily in young adults and children, primarily women (80%). Approximately 70% of patients develop prodromal symptoms (e.g., headache, fever, sudden changes in behavior, anxiety, hallucinations, and psychosis). Abnormal movements (e.g., orofacial dyskinesia, chorea, and stereotypic movements) and decreased consciousness, coma, and severe global autonomic dysregulation (often leading to hypoventilation and systolic asystole) result. Seizures and status epilepticus can occur at any stage of the disease. Approximately 50% of patients respond well to IVIG, steroids, or plasma exchange; the other 50% require rituximab alone or in combination with cyclophosphamide. However, in some patients, recovery is incomplete, requiring several years, and mortality from intensive care complications can be as high as 7%.

[0016] The presence of pathogenic autoantibodies in the autoantibody-mediated autoimmune diseases exemplified above is the result of failure or breakdown of central and / or peripheral B cell tolerance to the corresponding autoantigen.

[0017] Central and peripheral B-cell tolerance B cell development begins in the bone marrow, where somatic recombination of immunoglobulin heavy and light chain gene segments generates a nascent membrane-bound B cell receptor (BCR) repertoire. A downside to generating this enormous diversity in the initial BCR repertoire through random somatic V(D)J recombination is the concomitant generation of potentially pathogenic autoantibodies. At least three mechanisms exist to prevent the development of autoimmunity. First, autoreactive B cells are deleted by apoptosis. Second, autoreactive B cells reduce the autoreactive affinity of their BCRs through alteration of the VL domain by secondary Ig light chain recombination, a process called receptor editing. A third mechanism for suppressing autoreactive B cells is anergy, which renders such cells unresponsive to antigens. These central tolerance mechanisms occur in the bone marrow. Therefore, autoreactivity of the emerging antibody repertoire is prevented by the induction of apoptosis, receptor editing, and anergy in B cells expressing autoreactive antibodies (Non-Patent Document 13).

[0018] During B cell differentiation, transitional B cells emerge from the bone marrow and continue to mature in peripheral lymphoid organs (e.g., spleen, lymph nodes), where additional peripheral tolerance mechanisms occur. While the exact mechanisms of peripheral tolerance are still under investigation, ligand (antigen) recognition by the BCR is involved, as are central tolerance checkpoints in the bone marrow. These may also include regulating the migration and limiting the availability of BAFF, CD22, Siglec-G, miRNAs, and follicular regulatory T cells (Tregs).

[0019] The final product of B cell differentiation is an antibody-secreting plasma cell. Upon activation by antigen, mature naive B cells either progress directly to antibody-secreting cells (T cell-independent) or differentiate into sessile, non-dividing plasma cells or memory B cells during T cell-dependent immune responses in germinal centers via proliferation of pre-plasmablasts and plasmablasts. Both plasmablasts and plasma cells produce and secrete antibodies, thereby providing humoral immunity. When derived from autoreactive B cells, plasmablasts and plasma cells contribute to autoantibody production (Non-Patent Document 14).

[0020] Failure of one or more central and / or peripheral tolerance mechanisms leads to an increase in the number of circulating autoreactive B cells (i.e., autoantibody-expressing B cells) and autoreactive plasmablasts and plasma cells (i.e., autoantibody-expressing and -secreting cells), which favors the development of autoantibody-mediated AD. Once autoantibody production is initiated, their production levels are maintained either by the continuous activation of autoreactive B cells, which results in the continuous formation of short-lived plasma cells, or through the formation of long-lived plasma cells, or both (Non-Patent Document 15).

[0021] Because autoantibodies are often the underlying cause of autoimmune pathology, B cells, plasmablasts, and plasma cells are promising therapeutic targets in AD. Short-lived plasma cells respond to conventional immunosuppressants that directly inhibit proliferating plasmablasts and B cells. Non-proliferating short-lived plasma cells are no longer replenished and disappear within a few days of initiating these treatments. B cell-targeting treatments, such as anti-CD20 (rituximab) and anti-BAFF (belimumab) (see, e.g., Patent Documents 1 and 2), reduce B cell levels in patients in need of such reduction, thus attenuating the production of short-lived plasmablasts and plasma cells, but such treatments do not affect the long-lived memory plasma cell compartment. If autoantibody production is not affected by this therapeutic strategy, it should be considered that the autoantibodies are potentially secreted by long-lived memory plasma cells. Furthermore, it can be assumed 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.

[0022] In humans, a population of long-lived bone marrow-derived plasma cells is phenotypically defined as CD19-, CD38hi, and CD138+ (Non-Patent Document 16). CD20, a well-known general pan-B cell marker, is not normally expressed on human plasmablasts (Non-Patent Document 17) or long-lived human plasma cells (Non-Patent Document 16).

[0023] Potential mechanisms underlying the maintenance of long-term antibody responses can generally be divided into memory B cell-dependent and memory B cell-independent models. In a rhesus macaque animal model, after surgical removal of latent B cell reservoirs from solid tissues (e.g., spleen and lymph nodes) and depletion of all detectable tetanus-specific memory B cells from the circulation using an anti-CD20 antibody, tetanus-specific serum antibody titers continued to be maintained above a protective threshold for the lifespan of the immunized host, with decay rate kinetics indistinguishable from that of untreated controls (Non-Patent Document 18). Thus, antibody responses after tetanus vaccination are long-lived and provide lifelong protective immunity against the disease. Further analysis of tetanus-specific plasma cells revealed that 10 years after immunization, long-lived vaccine-induced plasma cells were preferentially identified in certain bone marrow compartments. Collectively, these studies provide a framework in which the maintenance of long-term serum antibody responses may be maintained by long-lived plasma cells, independently of memory B cells.

[0024] As noted above, current treatment options for AD include systemic immunosuppression (i.e., high-dose corticosteroids such as dexamethasone). The cytotoxic drug cyclophosphamide (Endoxan®) has been shown to suppress T-helper cell function and prolong B cell depletion due to a slower rate of B lymphocyte recovery from alkylating agents, thereby inhibiting B cell activation. Additional immunosuppressive drugs include, but are not limited to, azathioprine, mycophenolate, and methotrexate. Proteasome inhibitors, such as bortezomib, have been shown to deplete short- and long-lived plasma cells, and initial clinical trials using bortezomib for the treatment of SLE and thrombotic thrombocytopenic purpura are promising (NPL 19; NPL 20).

[0025] Patent Document 3 discloses anti-CD38 antibodies and claims their potential therapeutic use for numerous autoimmune diseases. Indeed, Patent Document 3 investigates anti-tetanus responses in a HuScid mouse model and presents experiments conducted using surrogate mouse anti-CD38 antibodies only in collagen-induced arthritis and SLE autoimmune mouse models. Patent Document 3 is silent regarding determining antibody titers in human samples after anti-CD38 treatment, and does not mention or present any data on anti-PLA2R-positive membranous nephropathy that is intended to be treated with anti-CD38 antibodies.

[0026] (Non-Patent Document 21) describes the use of the anti-CD38 antibody daratumumab for the treatment of autoimmune hemolytic anemia. (Non-Patent Document 22) evaluates the potential of daratumumab in the treatment of patients with RA and SLE.

[0027] (Non-Patent Document 23) discloses the use of the anti-CD20 antibody rituximab to deplete B cells in patients with idiopathic membranous nephropathy. This disclosure does not teach or suggest depletion of plasma cells with anti-CD38 antibodies in these patients.

[0028] Nevertheless, AD patients continue to experience high morbidity and rising mortality rates. Despite advances in the development of novel anti-autoimmune agents (such as bortezomib), many autoantibody-mediated AD cases, which almost certainly contain CD38-positive autoantibody-secreting cells, still have a poor prognosis. All of the above-mentioned treatment options have drawbacks, side effects, or limit their use to certain types of patient populations.

[0029] Thus, there is a high and unmet medical need for new and improved treatment methods for patients suffering from autoantibody-mediated AD.

[0030] The inventors have identified CD38 as a superior and effective antigen for directly targeting antibody-secreting cells, such as plasmablasts and plasma cells, in autoantibody-mediated autoimmune disorders (e.g., SLE, aMN). First, CD38 is highly expressed on plasmablasts and plasma cells (Figure 4). Second, CD38 expression is absent or significantly lower on other cell types compared to plasmablasts and plasma cells. Thus, the use of anti-CD38 antibodies may enable a sustainable therapeutic approach to target the source of pathogenic autoantibodies, potentially resulting in long-lasting effects due to the elimination of both short- and long-lived plasma cells. Essentially, this targeting approach can be generalized as follows: antibodies specific for the CD38 surface antigen on antibody-secreting cells are administered to patients. These anti-CD38 antibodies specifically bind to the CD38 antigen on both antibody-secreting cells that produce normal antibodies and pathogenic autoantibodies. Antibodies that bind to the CD38 surface antigen then lead to the destruction and depletion of these cells. Regardless of the approach, the primary goal is to reduce the cells that produce the autoantibodies.

[0031] Endogenous anti-tetanus antibody titers as a marker to assess the impact of MOR202 on plasma cell function Long-term studies in mice (NPL 24) and humans (NPL 25) highlight the advantage of inducing and maintaining effective serum concentrations of antibodies (antibody titers) that remain protective for the lifespan of the immune system. Protective humoral immunity is conferred by stable titers of specific antibodies, for example, produced by routine vaccination against measles, mumps, tetanus, diphtheria, or smallpox. Plasma cells and their immediate precursors are known to be the cellular basis of this humoral immunity, and serum specific antibody titers are useful markers of the humoral arm, so they can be used as indicators of the presence and / or activity of plasma cells that produce these antibodies. A mouse study using anti-CD20 treatment to deplete naive and memory B cells showed that B cell loss did not significantly affect the plasma cell pool, even after extended periods of time (NPL 26). Similarly, humans who underwent B cell-depleting therapy maintain serum antibody titers against common antigens for at least one year (NPL 27). These reports therefore demonstrate that (long-lived) plasma cells are an essential component of durable humoral memory in mice and humans. It is well documented that plasma cells can persist for long periods of time, even in the absence of input from recently activated naive or memory B cells. Here, we demonstrate for the first time that MOR202 administration leads to a reduction in endogenous anti-tetanus toxoid antibody titers in human subjects, and describe in the Examples how treatment of autoantibody-mediated membranous nephropathy, specifically anti-PLAR2-positive autoimmune MN, with MOR202 is achieved. [Prior art documents] [Patent documents]

[0032] [Patent Document 1] International Publication No. 2002002641 Brochure [Patent Document 2] International Publication No. 2009052293A1 Brochure [Patent Document 3] International Publication No. 2012092612 Brochure [Non-patent literature]

[0033] [Non-licensed document 1] Lleo et al.Autoimmunity Reviews 2010 Mar;9(5):A259-66 [Non-licensed document 2] Suurmond and Diamond,J Clin Invest.2015 Jun 1;125(6):2194-2202 [Non-licensed document 3] Ludwig et al.Front.Immunol.2017 May;8:603

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[0034] The present invention provides antibodies or antibody fragments specific for CD38 for use in the treatment and / or prevention of autoantibody-mediated autoimmune diseases and related conditions. In particular, the anti-CD38 antibodies or antibody fragments are for use in the treatment and / or prevention of idiopathic membranous glomerulonephritis. Preferably, the anti-CD38 antibodies or antibody fragments are for use in the treatment and / or prevention of anti-PLA2R-positive membranous glomerulonephritis. In some embodiments, the anti-CD38 antibodies or antibody fragments are for use in the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0035] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antibody fragment specific for CD38 for use in the treatment and / or prevention of autoantibody-mediated autoimmune diseases. In particular, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is for use in the treatment and / or prevention of idiopathic membranous glomerulonephritis. Preferably, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is for use in the treatment and / or prevention of anti-PLA2R-positive membranous glomerulonephritis. In some embodiments, the anti-CD38 antibody or antibody fragment of the pharmaceutical composition is for use in the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0036] MOR202, a monoclonal human anti-CD38 antibody, primarily targets antibody-secreting cells, such as plasmablasts and plasma cells, via antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Clinical trials with MOR202 demonstrated efficient killing of both neoplastic plasma cells (i.e., multiple myeloma cells) and benign plasma cells. In patients with multiple myeloma (MM), plasma cell depletion with MOR202 leads to a significant reduction in M-protein. M-protein, also known as M component, M spike, spike protein, paraprotein, or myeloma protein, is an immunoglobulin (antibody) or fragment thereof secreted by malignant, neoplastic plasma cell clones. Due to the abnormal monoclonal proliferation of malignant plasma cells in MM, M-protein is produced in significant excess, leading to numerous adverse effects in the body characteristic of MM (e.g., immune dysfunction, abnormally high blood viscosity, and kidney damage). MOR202 is effective in depleting plasma cells, the source of M-protein, resulting in a reduction in M-protein titers.

[0037] The effect of MOR202 on plasma cells was demonstrated by assessing serum anti-tetanus toxoid (anti-TT) antibody titers as a marker for specific plasma cell depletion. After MOR202 administration, serum anti-TT antibody levels were significantly reduced when compared to baseline levels before MOR202 administration.

[0038] Overall, the inventors demonstrate that MOR202 effectively reduces 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 spare low CD38-expressing cells (e.g., NK cells) and therefore provide an optimal safety profile.

[0039] This observed effect of MOR202 in reducing serum antibody titers is novel, and the prior art does not teach, suggest, or provide any rationale for using MOR202 for the treatment of autoantibody-mediated AD.

[0040] In a particular embodiment of the invention, the antibody or antibody fragment comprises an HCDR1 region of amino acid sequence SEQ ID NO:1, an HCDR2 region of amino acid sequence SEQ ID NO:2, an HCDR3 region of amino acid sequence SEQ ID NO:3, an LCDR1 region of amino acid sequence SEQ ID NO:4, an LCDR2 region of amino acid sequence SEQ ID NO:5 and an LCDR3 region of amino acid sequence SEQ ID NO:6 for use in the treatment and / or prevention of autoantibody-mediated autoimmune diseases, in particular for use in the treatment and / or prevention of systemic lupus erythematosus (SLE) or idiopathic membranous glomerulonephritis, preferably for use in the treatment and / or prevention of anti-PLA2R-positive membranous glomerulonephritis.

[0041] The present disclosure also provides pharmaceutical compositions comprising an antibody or antibody fragment specific for CD38 and a suitable pharmaceutical carrier, excipient, or diluent for use in the prevention and / or treatment of autoantibody-mediated autoimmune diseases.

[0042] In further particular embodiments, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the antibody or antibody fragment of the invention. In a more particular embodiment, the additional therapeutically active ingredient is an agent for the treatment of an autoantibody-mediated autoimmune disease.

[0043] In one aspect of the invention, the invention provides a method for the prevention and / or treatment of 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.

[0044] 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.

[0045] In particular, 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 administering to the subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0046] In one aspect, the present invention provides a method for the prevention and / or treatment of systemic lupus erythematosus (SLE) in a subject in need thereof, said method comprising administering to said subject an effective amount of a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment.

[0047] In one aspect, the present invention provides an antibody or antibody fragment specific for CD38 for use in the prevention and / or treatment of autoantibody-mediated AD in a mammal, particularly a human, affected by said autoimmune disease.

[0048] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0049] Furthermore, the antibodies or antibody fragments specific for CD38 useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable when prepared and used. [Brief explanation of the drawings]

[0050] [Figure 1]Figure 1 illustrates the major cell types of B cell differentiation and the levels of CD19, CD20, and CD38 expression. CD38 expression during B cell ontogeny is tightly regulated: CD38 is present on myeloid precursor B cells but is lost on mature B cells. On germinal center B cells, CD38 prevents apoptosis, but upon exit from the germinal center, memory B cells lack or express only low levels of antigen. On terminally differentiated, short-lived and long-lived plasma cells, which are antibody-secreting cells, CD38 is one of a few surface antigens that is highly expressed (Hamblin TJ, Blood 2003 102:1939-1940). [Figure 2] FIG. 2 illustrates the major B cell types targeted by anti-CD20 B cell-depleting antibody therapy (e.g., treatment with rituximab). [Figure 3] FIG. 3 illustrates the major antibody-secreting cell types targeted by anti-CD38 antibody therapy (e.g., treatment with MOR202). [Figure 4] FIG. 4 shows high CD38 expression on plasma cells of healthy individuals and multiple myeloma patients as determined by FACS. [Figure 5] FIG. 5 shows the percent change in anti-tetanus toxoid (anti-TT) antibody titers in subjects after administration of MOR202 on Day 15 of Cycle 1 (i.e., 2 weeks after initiation of MOR202 treatment) compared to baseline. [Figure 6] FIG. 6 shows the percent change in anti-tetanus toxoid (anti-TT) antibody titers in subjects after administration of MOR202 on Day 15 of Cycle 2 (i.e., 6 weeks after initiation of MOR202 treatment) compared to baseline. [Figure 7] FIG. 7 shows the change (%) in M-protein levels in a cohort of patients treated weekly with MOR202 in combination with dexamethasone compared to baseline (maximal response). [Figure 8] FIG. 8 shows the change (%) in M-protein levels in a cohort of patients treated weekly with MOR202 in combination with lenalidomide / dexamethasone compared to baseline (maximal response). [Figure 9]FIG. 9 shows the change (%) in M-protein levels in a cohort of patients treated weekly with MOR202 in combination with pomalidomide / dexamethasone compared to baseline (maximal response). [Figure 10] FIG. 10 shows the specific killing of CD38-high expressing multiple myeloma plasma cell lines by MOR202 while sparing CD38-low expressing NK cells compared to the anti-CD38 antibodies daratumumab (Dara) and isatuximab. [Figure 11] FIG. 11 shows the clinical trial schedule MOR202 being tested in aMN subjects. [Figure 12] FIG. 12 illustrates the various autoantibodies that can be detected in patients with systemic lupus erythematosus (SLE). DETAILED DESCRIPTION OF THE INVENTION

[0051] definition The following terms shall have the meanings given thereto below and are useful in understanding the description and intended scope of the present invention.

[0052] In 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, when present, have the following meanings unless otherwise indicated.

[0053] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or multiple analogs.

[0054] The term "CD38" refers to the protein known as CD38, which has the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1, T10.

[0055] Human CD38 (UniProt P28907) has the following amino acid sequence: MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI (SEQ ID NO: 9)

[0056] CD38 is an example of a type II transmembrane glycoprotein and an antigen 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 and (ecto)enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as a substrate for the formation of not only 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 second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 regulates extracellular NAD+ concentrations and thus cell survival by modulating NAD-induced cell death (NCID). In addition to Ca2+-mediated signaling, CD38 signaling occurs via crosstalk with antigen-receptor complexes or other types of receptor complexes, such as MHC molecules, on T and B cells, and is thus involved in several cellular responses, including the switching and secretion of IgG antibody secretion.

[0057] The term "anti-CD38 antibody," as used herein, includes anti-CD38 binding molecules in its broadest sense; it includes any molecule that specifically binds to CD38 or inhibits the activity or function of CD38, or exerts a therapeutic effect on CD38 in any way. It also includes any molecule that interferes with or inhibits CD38 functionality. 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, ankyrins, maxybodies / avimers, protein A-derived molecules, anticalins, affilins, protein epitope mimetics (PEMs), etc.), CD38-specific nucleic acids (including aptamers), or CD38-specific small organic molecules.

[0058] Antibodies specific for CD38 are disclosed, for example, in WO 199962526 (Mayo Foundation), which are incorporated by reference in their entireties; WO 200206347 (Crucell Holland); U.S. Patent Application Publication No. 2002164788 (Jonathan Ellis), which are incorporated by reference in their entireties; WO 2005103083 (MorphoSys AG), U.S. Patent Application No. 10 / 588,568, which are incorporated by reference in their entireties; WO 2006125640 (MorphoSys AG), U.S. Patent Application No. 11 / 920,830, and WO 2007042309 (MorphoSys AG), which are incorporated by reference in their entireties. AG), U.S. Patent Application No. 12 / 089,806, which is incorporated by reference in its entirety; WO 2006099875 (Genmab), U.S. Patent Application No. 11 / 886,932, which is incorporated by reference in its entirety; and WO 2008047242 (Sanofi-Aventis), U.S. Patent Application No. 12 / 441,466, which is incorporated by reference in its entirety.

[0059] 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 of which are incorporated by reference in their entirety.

[0060] 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, including murine, rat, chimeric, humanized, or human antibodies.

[0061] A "human antibody" or "human antibody fragment," as used herein, is an antibody or antibody fragment having variable regions in which the framework and CDR regions are derived from sequences of human origin. If the antibody contains a constant region, the constant region is also derived from such sequences. Human origin includes, but is not limited to, antibodies containing human germline sequences or mutated versions of human germline sequences, or consensus framework sequences derived from human framework sequence analysis, e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86. Human antibodies can be isolated, for example, from synthetic libraries or from transgenic mice (e.g., Xenomouse). An antibody or antibody fragment is human if its sequences are human, regardless of the species from which the antibody is physically derived, isolated, or produced.

[0062] The structure and location of immunoglobulin variable domains, e.g., CDRs, can be defined using well-known numbering schemes, such as the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (see, e.g., Sequences of Proteins of Immunological Interest, USDapartment of Health and Human Services (1991), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 USDapartment of Health and Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883; and Al-Lazikani et al. al., (1997) J. Mol. Biol. 273:927-948.

[0063] A "humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having constant and variable antibody regions, or portions thereof, derived from sequences of human origin, or in which only the CDRs are derived from another species. For example, a humanized antibody can be CDR-grafted, in which the CDRs of the variable domain are of non-human origin, while one or more frameworks of the variable domain are of human origin, and the constant domain (if any) is of human origin.

[0064] The term "chimeric antibody" or "chimeric antibody fragment" is defined herein as an antibody molecule having constant antibody regions derived from or corresponding to sequences found in one species and variable antibody regions derived from another species. Preferably, the constant antibody regions are derived from or correspond to sequences found in humans, and the variable antibody regions (e.g., VH, VL, CDR, or FR regions) are derived from sequences found in a non-human animal, such as a mouse, rat, rabbit, or hamster.

[0065] The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments having different antigen specificities. Furthermore, an isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemicals. Thus, in some embodiments, the antibody provided is an isolated antibody that is separated from antibodies of different specificities. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. However, an isolated antibody that specifically binds to an epitope, isoform, or target variant may have cross-reactivity to other related antigens, for example, from other species (e.g., species homologs).

[0066] The term "monoclonal antibody," as used herein, refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a unique binding site having a unique binding specificity and affinity for a particular epitope.

[0067] Furthermore, as used herein, an "immunoglobulin" (Ig) is defined herein as a protein belonging to the classes IgG, IgM, IgE, IgA, or IgD (or any subclass thereof) and includes all conventionally known antibodies and functional fragments thereof. The preferred class of immunoglobulin for use in the present invention is IgG.

[0068] 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, or stabilizing spatial distribution). Examples of binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; a F(ab)2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be linked by a synthetic linker, which allows them to be produced as a single protein chain using recombinant methods, in which the VL and VH regions pair to form a monovalent molecule (also known as a "single-chain fragment (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 encompassed within the term "antibody fragment." These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR, and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).Antibody fragments can be assembled into single-chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Pat. No. 5,641,870).

[0069] The present disclosure provides methods of treatment comprising administering a therapeutically effective amount of an anti-CD38 antibody as disclosed herein to a subject in need of such treatment. The terms "therapeutically effective amount" or "effective amount," as used herein, refer 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 symptoms associated with autoantibody-mediated autoimmune diseases and AD. The effective amount for a particular individual may vary depending on factors such as the condition being treated, the patient's overall health, the route and dose of administration, and the severity of side effects (Maynard, et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001) Good Laboratory and Good Clinical Practice, London, UK).

[0070] As used herein, "treat," "treating," and the like means to relieve, either temporarily or permanently, the symptoms, eliminate the cause of the symptoms, or prevent or delay the onset of symptoms of the specified disorder or condition.

[0071] "Preventing" or "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a subject who may be exposed to a disease-causing agent or who may be predisposed to the disease prior to disease onset). "Prevention" refers to a method aimed at preventing the onset of a disease or its symptoms or delaying the onset of a disease or its symptoms.

[0072] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure whose purpose is to prevent, rather than treat or cure, a disease. Non-limiting examples of prophylactic measures may include the administration of a vaccine; the administration of low molecular weight heparin to hospitalized patients who are at risk for thrombosis, for example, due to reduced mobility; and the administration of an antimalarial drug such as chloroquine before visiting a geographic area where malaria is endemic or where there is an increased risk of contracting malaria.

[0073] "Palliating" one or more symptoms of autoantibody-mediated AD means reducing the severity of one or more undesirable clinical symptoms in an individual or population of individuals with autoantibody-mediated AD.

[0074] "Administered" or "administration" includes, but is not limited to, delivery of a drug by an injectable form, such as intravenous, intramuscular, intradermal, or subcutaneous routes, or by a mucosal route, such as a nasal spray or aerosol for inhalation, or as an ingestible solution, capsule, or tablet. Preferably, administration is by an injectable form.

[0075] As used herein, the terms "subject," "subject in need thereof," and the like refer to a human or non-human animal that exhibits one or more symptoms or signs of an autoantibody-mediated autoimmune disease and / or has been diagnosed with an autoantibody-mediated autoimmune disease. Preferably, the subject is a primate, most preferably a human patient that has been diagnosed with an autoantibody-mediated autoimmune disease.

[0076] As used in this context, "subject" or "species" refers to any mammal, including rodents, such as mice or rats, and primates, such as cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), or humans (Homo sapiens). Preferably, the subject is a primate, most preferably a human.

[0077] As used herein, the term "autoantibody-mediated autoimmune disease," including "autoantibody-associated autoimmune disease," refers to a group of diseases characterized by the presence of autoantibodies (autoantibody positivity), where either (i) a causative correlation and direct contribution of the autoantibody to the pathogenesis of the disease and its associated symptoms has been given, or (ii) a causative correlation and direct contribution of the autoantibody to the pathogenesis of the disease and its associated symptoms may be given but is less clear. Autoantibody-mediated autoimmune diseases include, but are not limited to, representative diseases listed in Table 1.

[0078] [Table 1]

[0079] [Table 2]

[0080] [Table 3]

[0081] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0082] "Pharmacokinetics" or "PK," as used herein, describes how the body affects a particular drug after administration through mechanisms such as absorption and distribution, as well as metabolic changes in the drug within the body, and the effects and excretion routes of the drug's metabolites. The pharmacokinetic properties of a drug can be affected by the route of administration and the dose of the drug administered.

[0083] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the United States or a state government, or a corresponding agency in a country other than the United States, for use in animals, and more particularly in humans, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia.

[0084] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which an antibody or antibody fragment is administered.

[0085] Throughout this specification, unless the context requires otherwise, the words "comprise", "have" and "include" and individual variations thereof such as "comprises", "comprising", "has", "having", "includes" and "including" are understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0086] "MOR202" is an anti-CD38 antibody, also known as "MOR03087" or "MOR3087." The terms are used interchangeably in this disclosure. MOR202 has an IgG1 Fc region.

[0087] The amino acid sequence of MOR202 HCDR1 according to Kabat is: SYYMN (SEQ ID NO: 1).

[0088] The amino acid sequence of MOR202 HCDR2 according to Kabat is: GISGDPSNTYYADSVKG (SEQ ID NO: 2).

[0089] The amino acid sequence of MOR202 HCDR3 according to Kabat is: DLPLVYTGFAY (SEQ ID NO: 3).

[0090] The amino acid sequence of MOR202 LCDR1 according to Kabat is: SGDNLRHYYVY (SEQ ID NO: 4).

[0091] The amino acid sequence of MOR202 LCDR2 according to Kabat is: GDSKRPS (SEQ ID NO: 5).

[0092] The amino acid sequence of MOR202 LCDR3 is QTYTGGASL (SEQ ID NO: 6).

[0093] The amino acid sequence of the MOR202 variable heavy chain domain is QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 7) is.

[0094] The amino acid sequence of the MOR202 variable light chain domain is DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 8) is.

[0095] The DNA sequence encoding the MOR202 variable heavy chain domain is CAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACCTATTATGCGG ATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA (SEQ ID NO: 10) is.

[0096] The DNA sequence encoding the MOR202 variable light chain domain is GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGG CATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGCGGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 11) is.

[0097] The present invention The present invention relates to an antibody or antibody fragment specific for CD38, useful for preventing and / or treating autoantibody-mediated autoimmune diseases. In some embodiments, the antibody is MOR202, and the autoantibody-mediated AD is any selected from Table 1. In one embodiment, the antibody is MOR202, and the autoantibody-mediated AD is SLE. In a specific embodiment, the antibody is MOR202, and the autoantibody-mediated AD is idiopathic membranous glomerulonephritis, preferably anti-PLA2R-positive membranous glomerulonephritis.

[0098] The present invention also provides methods for preventing and / or treating autoantibody-mediated autoimmune diseases, comprising administering an antibody or antibody fragment specific to CD38 to a subject in need thereof. In some embodiments, the CD38-specific antibody or antibody fragment used in the methods is MOR202, and the autoantibody-mediated AD is any selected from Table 1. In one embodiment, the CD38-specific antibody or antibody fragment used in the methods is MOR202, and the autoantibody-mediated AD is SLE. In a specific embodiment, the CD38-specific antibody or antibody fragment used in the methods is MOR202, and the autoantibody-mediated AD is idiopathic membranous glomerulonephritis, preferably anti-PLA2R-positive membranous glomerulonephritis.

[0099] The present invention also provides pharmaceutical compositions comprising said antibody or antibody fragment specific to CD38, and methods for preventing and / or treating autoantibody-mediated autoimmune diseases by administering said antibody or antibody fragment specific to CD38.

[0100] Pharmaceutical Composition When used as a pharmaceutical, CD38-specific antibodies or antibody fragments are typically administered in pharmaceutical compositions. Such compositions can be prepared as is well known in the pharmaceutical arts and can include CD38-specific antibodies or antibody fragments. Generally, CD38-specific antibodies or antibody fragments are administered in effective amounts. The amount of CD38-specific antibodies or antibody fragments actually administered will generally be determined by a physician in light of the 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, and the like.

[0101] The compositions of the present disclosure are preferably pharmaceutical compositions comprising MOR202 and a pharmaceutically acceptable carrier, diluent or excipient for the treatment of autoantibody-mediated autoimmune diseases.

[0102] The pharmaceutically acceptable carrier should be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Pharmaceutically, the carrier enhances or stabilizes the composition or facilitates preparation of the composition. Pharmaceutically acceptable carriers include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0103] The composition should be sterile and fluid. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin.

[0104] The pharmaceutical compositions of the present disclosure can be administered by various routes known in the art. Selected administration routes for the antibodies or antibody fragments of the present disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral administration routes, such as by injection or infusion. Parenteral administration can refer to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intralesional, and intrasternal injection and infusion. Alternatively, compositions of the present disclosure can be administered via non-parenteral routes, such as topical, epidermal, cutaneous, or mucosal administration routes, e.g., intranasal, oral, vaginal, rectal, sublingual, transdermal, or topical. Additionally, the antibodies or antibody fragments of the present disclosure can be administered as sustained-release formulations, in which case less frequent administration is required. In addition, pulmonary administration can also be employed, eg, by use of an inhaler or nebulizer and formulation with an aerosolizing agent.

[0105] Antibodies or antibody fragments specific for CD38 are preferably formulated as injectable compositions. In a preferred embodiment, the anti-CD38 antibodies of the present disclosure are administered intravenously. In other embodiments, the anti-CD38 antibodies of the present disclosure are administered subcutaneously, intraarticularly, or intrathecally.

[0106] Depending on the route of administration, the active compounds, i.e., antibodies, antibody fragments, bispecific and multispecific molecules, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0107] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the CD38-specific antibody or antibody fragment in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier or the like. Optionally, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the injection site.

[0108] In one aspect, the present disclosure is directed to a composition comprising an anti-CD38 antibody for use in treating autoantibody-mediated AD, wherein the composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

[0109] An important aspect of the present disclosure is a pharmaceutical composition capable of mediating the killing of CD38-expressing, antibody-secreting cells (eg, plasmablasts, plasma cells) by ADCC and ADCP.

[0110] Treatment method 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 use in the prevention and / or treatment of an autoantibody-mediated autoimmune disease.

[0111] In one embodiment, 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 use in the prevention and / or treatment of systemic lupus erythematosus (SLE).

[0112] In another embodiment, 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 use in the prevention and / or treatment of idiopathic membranous nephropathy.

[0113] 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 use in the prevention and / or treatment of autoimmune membranous nephropathy.

[0114] In certain embodiments, 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 use in the prevention and / or treatment of anti-PLA2R-positive membranous nephropathy.

[0115] 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 use in the prevention and / or treatment of membranous nephropathy in patients with anti-PLA2R antibody titers.

[0116] In another embodiment, 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 use in the manufacture of a medicament for use in the prevention and / or treatment of an autoantibody-mediated autoimmune disease.

[0117] In one aspect, the disclosure provides use of an anti-CD38 antibody in the preparation of a medicament for the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0118] In another aspect, the disclosure provides the use of an anti-CD38 antibody in the preparation of a medicament for the treatment and / or prevention of idiopathic membranous nephropathy.

[0119] In another aspect, the disclosure provides the use of an anti-CD38 antibody in the preparation of a medicament for the treatment and / or prevention of autoantibody-mediated membranous nephropathy.

[0120] In a preferred aspect, the present disclosure provides the use of an anti-CD38 antibody in the preparation of a medicament for the treatment and / or prevention of anti-PLA2R-positive membranous nephropathy.

[0121] In another aspect, the disclosure provides for the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of an autoantibody-mediated autoimmune disease.

[0122] In another aspect, the disclosure provides the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0123] In another aspect, the disclosure provides the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of idiopathic membranous nephropathy.

[0124] In another aspect, the present disclosure provides the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of autoantibody-mediated membranous nephropathy.

[0125] In a preferred aspect, the present disclosure provides the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of anti-PLA2R-positive membranous nephropathy.

[0126] In one embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, or an antibody or antibody fragment specific for CD38 and another therapeutic agent, for use in the prevention and / or treatment of an autoantibody-mediated autoimmune disease, preferably autoantibody-mediated membranous nephropathy.

[0127] In another embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, or an antibody or antibody fragment specific for CD38 and another therapeutic agent, for use in the prevention and / or treatment of systemic lupus erythematosus (SLE).

[0128] In another embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, or an antibody or antibody fragment specific for CD38 and another therapeutic agent, for use in the prevention and / or treatment of idiopathic membranous nephropathy.

[0129] In a preferred embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, or an antibody or antibody fragment specific for CD38 and another therapeutic agent, for use in the prevention and / or treatment of anti-PLA2R-positive membranous nephropathy.

[0130] In one embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 and another therapeutic agent, or an antibody or antibody fragment specific for CD38 and another therapeutic agent, for use in the manufacture of a medicament for use in the prevention and / or treatment of an autoantibody-mediated autoimmune disease, preferably autoantibody-mediated membranous nephropathy.

[0131] In another aspect, the present disclosure provides use of a pharmaceutical composition comprising an anti-CD38 antibody and another therapeutic agent or an anti-CD38 antibody or antibody fragment in the preparation of a medicament for the treatment and / or prevention of an autoantibody-mediated autoimmune disease, preferably autoantibody-mediated membranous nephropathy.

[0132] In a preferred aspect, the present disclosure provides the use of a pharmaceutical composition comprising an anti-CD38 antibody and another therapeutic agent or an anti-CD38 antibody or antibody fragment in the preparation of a medicament for the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0133] In a preferred aspect, the present disclosure provides the use of a pharmaceutical composition comprising an anti-CD38 antibody and another therapeutic agent or an anti-CD38 antibody or antibody fragment in the preparation of a medicament for the treatment and / or prevention of idiopathic membranous nephropathy.

[0134] In another 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 the treatment and / or prevention of an autoantibody-mediated autoimmune disease, preferably autoantibody-mediated membranous nephropathy.

[0135] In one aspect, the disclosure provides the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0136] In certain aspects, the disclosure provides for the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for the treatment and / or prevention of idiopathic membranous nephropathy.

[0137] In certain aspects, the disclosure provides for the use of MOR202 and another therapeutic agent or a pharmaceutical composition comprising MOR202 in the preparation of a medicament for the treatment and / or prevention of anti-PLA2R-positive membranous nephropathy.

[0138] In certain embodiments, the additional therapeutic agent is an agent for treating an autoimmune disease. In certain embodiments, the agent is an immunosuppressant and is selected from the group including steroids (e.g., clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide, or dexamethasone), proteasome inhibitors (e.g., bortezomib), cytostatic agents (e.g., cyclophosphamide, azathioprine, methotrexate), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), and other immunosuppressants.

[0139] In a further method of treatment aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoantibody-mediated autoimmune disease, comprising the administration of an effective amount of one or more of the antibodies or antibody fragments specific for CD38 or pharmaceutical compositions herein described for the treatment and / or prevention of said condition.

[0140] In one aspect, the present invention provides a method for the treatment of autoantibody-mediated AD, preferably autoantibody-mediated membranous nephropathy, comprising administering to said subject an anti-CD38 antibody.

[0141] In one embodiment, the present disclosure provides a method for preventing and / or treating a mammal suffering from an autoantibody-mediated autoimmune disease, said method comprising administering an antibody or antibody fragment specific for CD38 and another therapeutic agent. In certain embodiments, said other therapeutic agent is an agent for treating an autoimmune disease. In certain embodiments, said agent is an immunosuppressant.

[0142] In the methods of treatment or use described herein, the autoimmune disease is in particular an autoantibody-mediated autoimmune disease (e.g., SLE, Graves' disease, myasthenia gravis, pemphigus vulgaris, autoimmune encephalitis, idiopathic membranous glomerulonephritis, anti-PLA2R-positive membranous glomerulonephritis).

[0143] In certain aspects, the present disclosure provides methods for the treatment and / or prevention of anti-PLA2R-positive membranous glomerulonephritis in a subject, the methods comprising administering to the subject an anti-CD38 antibody.

[0144] In one embodiment, the present disclosure provides a method for the prevention and / or treatment of a subject suffering from moderate to severe autoantibody-mediated AD, the method comprising the administration of an effective amount of one or more of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein for the treatment and / or prevention of said condition.

[0145] In some embodiments, the present disclosure provides methods for the prevention and / or treatment of a subject suffering from autoantibody-mediated AD, wherein the subject is refractory to corticosteroids or calcineurin inhibitors or other immunosuppressant treatments, including B-cell depletion therapy (e.g., with rituximab or any other anti-CD20 antibody or anti-BAFF antibody), the methods comprising the administration of an effective amount of one or more of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein for the treatment and / or prevention of the condition.

[0146] In one aspect, the invention provides methods of using anti-CD38 antibodies or antibody fragments to achieve a prophylactic or therapeutic effect in patients with autoantibody-mediated autoimmune diseases, preferably autoantibody-mediated membranous nephropathy.

[0147] Another embodiment provided herein is a method of using an anti-CD38 antibody to treat and / or prevent symptoms mediated by an autoantibody-mediated autoimmune disease.

[0148] In another aspect, provided herein is a method for reducing the incidence of, ameliorating, abrogating, or alleviating autoantibody-mediated disease symptoms, 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.

[0149] In a preferred embodiment, the present disclosure provides methods for treating patients exhibiting elevated levels of one or more autoantibody specificities associated with autoimmune disease.

[0150] In another aspect, the present disclosure provides methods for the treatment and / or prevention of SLE caused by the presence of anti-nuclear or anti-DNA autoantibodies or any other SLE autoantibody as listed in FIG.

[0151] In yet another aspect, the present invention provides methods for the treatment and / or prevention of SLE associated with the presence of anti-nuclear or anti-DNA autoantibodies or any other SLE autoantibody as listed in FIG.

[0152] In another aspect, the present disclosure provides methods for the treatment and / or prevention of diseases caused by the presence of anti-phospholipase A2 receptor (PLA2R) autoantibodies. In yet another aspect, the present invention provides methods for the treatment and / or prevention of diseases associated with the presence of anti-phospholipase A2 receptor (PLA2R) autoantibodies.

[0153] In another aspect, the present disclosure provides methods for the treatment and / or prevention of diseases caused by the presence of anti-thrombospondin type 1 domain-containing 7A autoantibodies. In yet another aspect, the present invention provides methods for the treatment and / or prevention of diseases associated with the presence of anti-thrombospondin type 1 domain-containing 7A autoantibodies.

[0154] In other embodiments, the present disclosure provides a method for reducing autoantibody titers in the serum of a subject suffering from an autoantibody-mediated autoimmune disease, the method comprising administering an effective amount of one or more of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein.

[0155] In a preferred embodiment, the present disclosure provides a method for reducing autoantibody titers in the serum of a subject suffering from idiopathic membranous glomerulonephritis, the method comprising administering an effective amount of one or more antibodies or antibody fragments specific for CD38 or pharmaceutical compositions described herein. For example, the methods provided herein comprise administering an anti-CD38 antibody to a patient with elevated levels of anti-PLA2R and / or anti-thrombospondin type 1 domain-containing 7A autoantibodies.

[0156] In one embodiment, the reduction (change) in autoantibody titers in the serum of a subject suffering from anti-PLA2R-positive membranous glomerulonephritis 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 after administration of an antibody or antibody fragment specific to CD38 or one or more of the pharmaceutical compositions described herein.

[0157] In another embodiment, the present disclosure provides a method for the treatment and / or prevention of proteinuria associated with anti-PLA2R-positive membranous glomerulonephritis in an individual, the method comprising administration of an effective amount of one or more antibodies or antibody fragments specific for CD38 or pharmaceutical compositions described herein.

[0158] In another aspect, the present disclosure provides a method for preventing decline in kidney function in an individual with anti-PLA2R-positive membranous nephropathy, the method comprising administering an effective amount of one or more antibodies or antibody fragments specific for CD38 or pharmaceutical compositions described herein.

[0159] In another aspect, the present disclosure provides a method for the treatment and / or prevention of hypercholesterolemia (high cholesterol) in an individual with membranous nephropathy, the method comprising the administration of an effective amount of one or more antibodies or antibody fragments specific for CD38 or pharmaceutical compositions described herein.

[0160] In one embodiment, the present disclosure refers to the use of an antibody or antibody fragment specific for CD38 for the treatment of an autoantibody-mediated autoimmune disease, wherein said antibody or antibody fragment binds to CD38-expressing plasma cells.

[0161] In a further embodiment, the present disclosure refers 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 CD38-expressing cells and leads to the depletion of such CD38-expressing cells.

[0162] In a preferred embodiment, the present disclosure refers to a method for the treatment of 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 CD38-expressing, antibody-secreting cells, leading to the depletion of such CD38-expressing, antibody-secreting cells, while sparing other (non-antibody-secreting) cells with low CD38 expression, such as NK cells.

[0163] In certain preferred embodiments, the present disclosure refers to a method for the treatment of 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 CD38-expressing, antibody-secreting cells and leads to the depletion of such CD38-expressing, antibody-secreting cells, while sparing NK cells, i.e., exhibits significantly higher specific cell killing of antibody-secreting cells than NK cells.

[0164] In one embodiment, the present disclosure refers to a method for the treatment of 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 CD38-expressing, antibody-secreting cells and leads to depletion of such CD38-expressing, antibody-secreting cells, while sparing other (non-antibody-secreting) cells of low CD38 expression, such as NK cells, with specific cell killing of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% of antibody-secreting plasma cells and specific cell killing of less than 30%, less than 25%, less than 20%, or less than 15% of non-antibody-secreting NK cells, as determined by a standard ADCC assay.

[0165] Antibodies or antibody fragments specific for CD38 can be administered as the sole active agent or in combination with other therapeutic agents. In certain embodiments, co-administration of two (or more) agents allows for the use of significantly lower doses of each, thereby resulting in reduced side effects.

[0166] In one embodiment, an antibody or antibody fragment specific for CD38 or a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 is administered as a medicament. In certain embodiments, the pharmaceutical composition further comprises an additional active ingredient.

[0167] Simultaneous administration, as will be apparent to those skilled in the art, includes any means of delivering two or more therapeutic agents to patients as part of the same treatment regimen.While two or more agents can be administered simultaneously in a single formulation, i.e., as a single pharmaceutical composition, this is not necessary.The agents can also be administered at different times in different formulations.

[0168] The therapies (eg, prophylactic or therapeutic agents) of the combination therapies of the disclosure can be administered simultaneously or sequentially to a subject.

[0169] The therapeutic agents (e.g., prophylactic or therapeutic agents) of the combination therapies disclosed herein can also be administered cyclically. Cycling therapy involves administering a first therapeutic agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administration of a second therapeutic agent (e.g., a second prophylactic or therapeutic agent) for a period of time, and repeating this sequential administration, i.e., cycling, to reduce the development of resistance to one of the therapeutic agents (e.g., drugs), to avoid or reduce side effects of one of the therapeutic agents (e.g., drugs), and / or to improve the efficacy of the therapeutic agents.

[0170] The therapeutic agents (e.g., prophylactic or therapeutic agents) of the combination therapies of the present disclosure can be administered to a subject simultaneously. The term "concurrently" is not limited to administration of the therapeutic agents (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather means that pharmaceutical compositions comprising an antibody or antibody fragment of the present disclosure are administered to a subject sequentially within a time interval such that the antibody of the present disclosure can act together with the other therapeutic agents to provide an improved benefit than if they were administered separately.

[0171] antibody In certain embodiments of the present disclosure, an 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 CDRs comprising any of the amino acid sequences of the CD38-specific antibodies as set forth in WO 2007 / 042309.

[0172] In one embodiment, the antibody or antibody fragment specific for CD38 comprises an HCDR1 region comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 region comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 region comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 region comprising the amino acid sequence of SEQ ID NO: 4, an LCDR2 region comprising the amino acid sequence of SEQ ID NO: 5, and an LCDR3 region comprising the amino acid sequence of SEQ ID NO: 6.

[0173] In one embodiment, the antibody or antibody fragment specific for CD38 comprises an HCDR1 region of SEQ ID NO: 1, an HCDR2 region of SEQ ID NO: 2, an HCDR3 region of SEQ ID NO: 3, an LCDR1 region of SEQ ID NO: 4, an LCDR2 region of SEQ ID NO: 5, and an LCDR3 region of SEQ ID NO: 6.

[0174] 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.

[0175] 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 to the variable light chain region of SEQ ID NO: 8.

[0176] A representative 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 known as MOR202.

[0177] In one embodiment, the present disclosure refers to a nucleic acid composition comprising a nucleic acid sequence or multiple nucleic acid sequences encoding an antibody or antibody fragment specific for CD38, wherein the antibody or antibody fragment comprises an HCDR1 region of SEQ ID NO: 1, an HCDR2 region of SEQ ID NO: 2, an HCDR3 region of SEQ ID NO: 3, an LCDR1 region of SEQ ID NO: 4, an LCDR2 region of SEQ ID NO: 5, and an LCDR3 region of SEQ ID NO: 6.

[0178] In another embodiment, the disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or fragment thereof, wherein the nucleic acid comprises a VH of SEQ ID NO:10 and a VL of SEQ ID NO:11.

[0179] In one embodiment, the disclosed antibody or antibody fragment specific for CD38 is a monoclonal antibody or antibody fragment.

[0180] In one embodiment, the disclosed antibodies or antibody fragments specific for CD38 are human, humanized, or chimeric antibodies.

[0181] In certain embodiments, the antibody or antibody fragment specific for CD38 is an isolated antibody or antibody fragment.

[0182] In another embodiment, the antibody or antibody fragment is a recombinant antibody or antibody fragment.

[0183] In a further embodiment, the antibody or antibody fragment is a recombinant human antibody or antibody fragment.

[0184] In a further embodiment, the recombinant human antibody or antibody fragment is an isolated recombinant human antibody or antibody fragment.

[0185] In a further embodiment, the recombinant human antibody or antibody fragment, or isolated recombinant human antibody or antibody fragment, is monoclonal.

[0186] In one embodiment, the disclosed antibody or antibody fragment is of the IgG isotype.

[0187] In another embodiment, the antibody is an IgG1.

[0188] In one embodiment, the antibody fragment is a bivalent antibody fragment.

[0189] In a particular embodiment of the invention, the anti-CD38 antibody is MOR202.

[0190] In one embodiment, the present disclosure refers to a pharmaceutical composition comprising MOR202 or a fragment thereof specific for CD38 and a pharmaceutically acceptable carrier or excipient.

[0191] In certain embodiments, the antibody or antibody fragment specific for CD38 is an antibody or antibody fragment that specifically binds to CD38.

[0192] In a specific embodiment, the CD38-specific antibody or antibody fragment is an antibody or antibody fragment that specifically binds to human CD38.

[0193] In a specific embodiment, the CD38-specific antibody or antibody fragment is an isolated monoclonal antibody or antibody fragment that specifically binds to human CD38.

[0194] In another embodiment, the present disclosure provides antibodies or antibody fragments specific for CD38, which deplete CD38-expressing, antibody-secreting cells.

[0195] In a preferred aspect, the present disclosure provides a prophylactic and / or therapeutic agent for reducing serum autoantibody levels in a subject with SLE, said agent comprising an anti-CD38 antibody as an active ingredient.

[0196] In a preferred aspect, the present disclosure provides a prophylactic and / or therapeutic agent for reducing serum autoantibody levels in a subject with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

[0197] In certain aspects, the present disclosure provides prophylactic and / or therapeutic agents for reducing serum anti-PLA2R autoantibody levels in a subject with aMN, said agents comprising an anti-CD38 antibody as an active ingredient.

[0198] In another aspect, the present disclosure provides a prophylactic and / or therapeutic agent for reducing anti-PLA2R autoantibody accumulation in the kidney of a subject with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

[0199] In a further aspect, the present disclosure provides a prophylactic and / or therapeutic agent for reducing proteinuria in a subject with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

[0200] In another aspect, the present disclosure provides a prophylactic and / or therapeutic agent for reducing hyperlipidemia (e.g., hypercholesterolemia, high cholesterol) in a subject with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

[0201] In another aspect, the present disclosure provides a prophylactic and / or therapeutic agent for restoring, ameliorating, or normalizing kidney function as indicated by glomerular filtration rate (eGFR) based on the CKD-epi equation in a subject with aMN, said agent comprising an anti-CD38 antibody as an active ingredient. [Example]

[0202] The representative antibody specific for CD38 used in the following examples is the human antibody MOR202.

[0203] Example 1: Efficacy of MOR202 on pre-existing antibody titers against tetanus toxoid as a vaccine antigen To assess the effect of MOR202 treatment on pre-existing antibody titers, we measured anti-tetanus toxoid titers in human serum collected from subjects at defined time points after MOR202 administration.

[0204] 1.1. Study Design The following bioanalytical evaluation was part of an open-label, multicenter, dose-escalation clinical trial 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 study was to quantitatively measure anti-tetanus toxoid (anti-TT) IgG antibody titers in human serum samples obtained during the study to demonstrate the effectiveness of the monoclonal anti-CD38 antibody (MOR03087 = MOR202) in reducing pre-existing antibody titers. Human serum samples were analyzed for anti-tetanus toxoid (anti-TT) IgG levels by ELISA (Table 4).

[0205] 1.2. Determination of anti-tetanus toxoid IgG by quantitative ELISA Serum samples were stored at -75 ± 15°C until analysis. A commercially available immunoassay kit (VaccZyme™ binding site, product code MK010) was used to measure anti-tetanus toxoid IgG in the samples. The assay was quality-checked at the bioanalytical testing site before sample analysis, and all measurements were performed according to the manufacturer's recommendations. Two quality control (QC) samples with batch-specific target values ​​and ranges were provided with the kit. 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), and 1.27 / 0.28 IU / mL (batch 5). During the qualification experiment, three additional concentration levels were evaluated according to the results of the qualification experiment: ULOQ (7 IU / mL), LLOQ (0.01 IU / mL), and HQC (2.8-3.5 IU / mL) (ULOQ: upper limit of quality assessment, LLOQ: lower limit of quality assessment, HQC: high quality control). Calibration standard samples were provided with the ready-to-use kit. One set of calibration standards consisted of 0.01, 0.03, 0.09, 0.26, 0.78, 2.33, and 7 IU / mL.

[0206] 1.2.1. Measurement performance Samples were analyzed in duplicate within an experiment (1 experiment = 1 96-well plate), along with one set of calibration standards and two sets of QC samples, as provided in the assay kit. No sample treatment was required for the performance of the anti-TT IgG ELISA. Samples were measured after dilution with sample diluent (minimum required dilution 1:101).

[0207] 1.2.2. Test Principles The VaccZyme™ Anti-Tetanus Toxoid IgG Enzyme Immunoassay Kit is a two-step enzyme-linked immunosorbent assay. Twelve wells, each cut into 8-well strips, are coated with tetanus toxoid from Clostridium tetani. Standards, controls, and diluted serum samples are added to the wells, and antibodies recognizing the tetanus toxoid antigen bind during the initial incubation. After washing the wells to remove all unbound protein, purified peroxidase-labeled rabbit anti-human IgG (gamma chain-specific) conjugate is added. The conjugate binds to the captured human antibody, and a further wash step removes excess unbound conjugate. Bound conjugates are visualized using 3,3',5,5'-tetramethylbenzidine (TMB) substrate, which yields a blue reaction product whose intensity is proportional to the antibody concentration in the sample. The reaction is stopped by adding phosphoric acid to each well, which produces a yellow endpoint color, which is read at 450 nm.

[0208] 1.2.3. Data Evaluation Data reduction of the output from the microplate reader was performed using Magellan™ software version 6.6 from TECAN Austria GmbH using a 4-parameter logistic regression. Optical densities of quality control and test samples were converted to concentrations (IU / mL) using a standard curve. Extrapolation was performed (extrapolation factor 1.1) to allow calculation of concentrations near the upper and lower limits of quantitation. All measured and calculated concentration data are reported to three significant digits.

[0209] 1.2.4.Results Human serum samples were analyzed in 22 assay runs. Inter-assay accuracy and precision data were assessed from calibration standard samples in 22 accepted assay runs. Accuracy (expressed as bias) and precision (expressed as coefficient of variation; CV) data are shown in Table 2.

[0210] [Table 4]

[0211] Inter-assay accuracy and precision data were evaluated from up to 22 sets of QC samples during 22 accepted assay runs. Accuracy (expressed as bias) and precision (expressed as coefficient of variation; CV) data are shown in Table 3.

[0212] [Table 5]

[0213] Anti-TT concentrations (IU / mL) in serum samples from 74 subjects for whom baseline and at least one of the "Cycle, Day 15" or "Cycle 2, Day 15" data points were available are shown in Table 4. Subjects who received concomitant medications during the clinical trial (such as IVIG administration or booster vaccination) were not included in the analysis because these concomitant medication factors would lead to biased results.

[0214] [Table 6]

[0215] [Table 7]

[0216] [Table 8]

[0217] [Table 9]

[0218] [Table 10]

[0219] [Table 11]

[0220] To determine the effect of MOR202 on anti-TT antibody titers, serum samples obtained on day 0 (before MOR202 treatment, designated "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, most subjects showed a significant decrease in anti-TT antibody titers compared to the baseline on day 0. The percent change in anti-TT concentrations in "baseline" samples obtained on day 0 compared to samples obtained on day 15 of cycle 1 (designated "Cycle 1, Day 15") is shown in Figure 5. The percent change in anti-TT concentrations in "baseline" samples obtained on day 0 compared to samples obtained on day 15 of cycle 2 (designated "Cycle 2, Day 15") is shown in Figure 6. In many of the MOR202-treated subjects, anti-TT antibody titers declined further (ie, a higher percentage change from Cycle 1, Day 15 to Cycle 2, Day 15), suggesting a long-term effect of MOR202 on antibody titers.

[0221] Taken together, these data demonstrate the efficacy of MOR202 in reducing serum antibody titers, and therefore, effective treatment and / or prevention of autoantibody-mediated AD with anti-CD38 antibodies (e.g., MOR202) is highly plausible.

[0222] Example 2: Determination of M-protein levels 2.1. Study Design M-protein levels were quantitatively determined in serum samples of multiple myeloma patients (enrolled in the study of Example 1) by capillary electrophoresis (CE) assays, specifically serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP).

[0223] 2.2. Capillary Electrophoresis - Test Principle Charged molecules are separated by their electrophoretic migration at a specific pH in an alkaline buffer. Separation occurs according to the electrolyte pH and electroosmotic flow. Each sample is diluted in a dilution buffer, and the capillary is filled with separation buffer; the sample is then injected by suction into the anodic end of the capillary. This is followed by high-pressure protein separation. This is followed by direct detection and quantification of the different protein fractions at specific wavelengths at the anodic end of the capillary.

[0224] Further assays for assessing M-protein levels include, but are not limited to, immunofixation electrophoresis (IFE), serum-free light chain (sFLC) assay, and total protein measurement (Keren DF and Schroeder L, Clin Chem Lab Med. 2016 Jun 1;54(6):947-61). Additionally, the IFE-based REFELX assay may be performed as described in WO 2017 / 149122.

[0225] 2.3 Results: FIG. 7 shows the changes given as percentage [%] in M-protein levels in multiple myeloma patients after MOR202 treatment.

[0226] The effect of MOR202 in reducing M-protein indirectly indicates the destruction and depletion of M-protein-producing malignant plasma cells. As shown in Figures 5 and 6, in addition to the results of Example 1, the reduction in M-protein after MOR202 administration (Figures 7-9) provides further evidence that MOR202 is effective in reducing antibody titers.

[0227] Example 3: Evaluation of natural killer (NK) cell-mediated ADCC 3.1 Experimental setup ADCC assays were performed to test the specific killing effects of MOR202, daratumumab, and isatuximab (SAR650984) on (i) a CD38-high multiple myeloma cell line (NCI-H929) and (ii) CD38-low human NK cells, mediated by natural killer cells. NK cells were purified from human blood by MACS (Miltenyi Biotec, Cat No. 130-092-657). NK cell purity was assessed by FACS using a CD3 / CD16+CD56 / CD45 Tritest™ (Becton Dickinson Cat No. 342411). NCI-H929 target cells were incubated with individual antibodies at defined concentrations and a 3:1 effector:target cell ratio for 2-4 hours at 37°C. For the NK cell:NK cell setup, target and effector cells were the same, so NK target cells were incubated with the respective antibodies alone for 2-4 hours at 37°C. To examine cytotoxicity, propidium iodide (PI) was added to the cell samples after incubation, and PI uptake into dead cells was immediately assessed by flow cytometry.

[0228] 3.2 Results The specific cell killing results [%] for MOR202, daratumumab and isatuximab in NCI-929 and NK cells are shown in FIG.

[0229] Example 4: Evaluation of the safety and efficacy of MOR202 in subjects with anti-PLA2R-positive membranous nephropathy (aMN) 4.1 Study design 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 evaluate the effect of MOR202 on serum anti-PLA2R antibody levels.

[0230] MOR202 dosing was based on the results of the clinical trial in multiple myeloma (MM) described in Example 1 and a PK / PD modeling approach. MOR202 was administered in a dose-escalation scheme of 0.1 to 16 mg / kg iv once weekly (QW) or every two weeks (Q2W), including a loading dose on Day 4 of Cycle 1. MOR202 was administered as a single agent (monotherapy) or in combination with dextromethorphan, porcine methylpropional / dextromethorphan, or lenalidomide / dextromethorphan. Overall treatment duration was based on clinical response with a maximum of 3 years of continuous treatment. Based on these results, a population-based PK / PD model was established, taking into account the different target expression rates between MM and aMN subjects. This model was used to mimic the drug exposure expected in this study (i.e., 16 mg / kg 4x QW, followed by 5x Q4W), and the results were compared with the data from the study described in Example 1, taking into account the same treatment duration. Six patients were dosed in the study of Example 1 at 16 mg / kg QW for at least 24 weeks, including a loading dose on day 4. This should result in a 2.4-fold excess in MOR202 exposure compared to the expected dose and dosing regimen in the current study at a similar maximum serum concentration. The objective of the 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 new to immunosuppressive therapy or who have failed to respond to immunosuppressive therapy (IST), including rituximab (anti-CD20) therapy.

[0231] Example 5: M-PLACE: A Phase Ib / IIa Multicenter, Open-Label Study for the Treatment of Two Cohorts of Patients with aMN with MOR202 (NCT04145440) A Phase Ib / IIa open-label, multicenter clinical trial to evaluate the safety and efficacy of the human anti-CD38 antibody MOR202 in anti-PLA2R antibody-positive membranous nephropathy (aMN) has been initiated with a projected enrollment of 30 participants and is recruiting at least 14 centers in the United States and six European locations. ClinicalTrials.gov identifier (NCT number): NCT04145440.

[0232] 5.1. Test Design 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 evaluate the effect of MOR202 on serum anti-PLA2R antibody levels.

[0233] The primary treatment rationale is the reduction of membranous nephropathy (MN) disease-specific anti-PLA2R antibodies through targeted depletion of autoantibody-producing plasma cells with the anti-CD38 antibody MOR202.

[0234] The patient population to be treated includes adult subjects with biopsy-proven MN positive for anti-PLA2R antibodies. Eligible ages for the study: 18-80 years (adults, elderly). All genders are eligible for the study.

[0235] Key inclusion criteria: Urinary protein / creatinine ratio ≥ 3.0 g / g (measured from a 24-hour urine collection) - Renal biopsy obtained within the last 6 months prior to the start of screening had an estimated glomerular filtration rate of ≥ 50 mL / min / 1.73 m 2 or >30 and <50 mL / min / 1.73 m 2 and interstitial fibrosis and tubular atrophy scores less than 25%. - Achieved a stable dose of supportive therapy with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker for at least 4 weeks prior to screening. Systolic BP≦150mmHg and diastolic BP≦100mmHg Vaccination against pneumococcus within the last 3 years prior to the date of signing of the informed consent (subjects may be vaccinated during screening to meet this criterion; the interval to the first dose of MOR202 must be at least 14 days). Cohort 1a (newly diagnosed patients): serum anti-PLA2R antibodies ≥ 150.0 response units (RU) / mL as measured by screening Euroimmun ELISA. Cohort 1b, relapse subjects: Must have achieved complete immunological and / or clinical remission as determined by the physician, and serum anti-PLA2R antibodies ≥ 50.0 RU / mL as measured by screening Euroimmun ELISA. Cohort 2: Prior treatment failure, i.e., subjects did not achieve complete immunological and / or clinical remission, per physician's judgment, during or after completion of a recognized IST containing cyclosporine A, tacrolimus, mycophenolate mofetil, ACTH, or alkylating agents (e.g., cyclophosphamide), or rituximab. Serum anti-PLA2R antibodies ≥ 20.0 RU / mL, as measured at screening by Euroimmun ELISA.

[0236] Key inclusion criteria: Hemoglobin < 90g / L · Thrombocytopenia: Platelets<100.0x10 9 / L ·Neutropenia: Neutrophils<1.5x10 9 / L ·Leukopenia: white blood cells <3.0x10 9 / L Hypogammaglobulinemia: Serum immunoglobulin ≦5.0g / L Secondary causes of MN (e.g., systemic lupus erythematosus, drug therapy, malignancy) Concomitant kidney disease other than MN (e.g., diabetic kidney disease, lupus nephritis, IgA nephropathy).

[0237] Cohort 1 includes approximately 20 aMN patients who are eligible for IST and have unfavorable prognostic features such as proteinuria (>5g / 24h) and high and stable serum titers of anti-PLA2R antibodies, and who are stable on supportive care treatment with an ACEI / ARB at screening (≥150.00 response units (RU) / mL, EuroImmun ELISA) or who are relapsing after a complete or partial proteinuric response including serum anti-PLA2R antibody titers <20 RU / mL for at least 6 months. Subjects can be newly diagnosed (Cohort 1a) or relapsing after proteinuria and a previous immune response to IST (Cohort 1b).

[0238] Cohort 2 includes approximately 10 aMN patients who did not respond immunologically to their last prior line of therapy and are therefore considered refractory, requiring second- or third-line IST. Prior therapy failure, i.e., subjects did not achieve a decrease in serum anti-PLA2R antibody titers to less than 20 RU / mL during or after completion of a recognized IST containing CSA, tacrolimus, MMF, ACTH, or an alkylating agent (e.g., cyclophosphamide), or rituximab, measured at least 6 months after initiation of therapy.

[0239] Exclusion criteria for both Cohort 1 and Cohort 2 were active infection, secondary causes of MN (e.g., SLE, medication, malignancy), type 1 or type 2 diabetes, pregnancy or lactation, and known or suspected hypersensitivity to the study drug and its excipients.

[0240] MOR202 monotherapy in the two cohorts will span a 24-week treatment phase followed by a 28-week observational follow-up phase (Figure 11).

[0241] 5.2.Administration of MOR202 (MOR03087) MOR202 is supplied as a lyophilized powder for reconstitution in a labeled glass vial. MOR202 should be stored at 2-8°C until use. For drug preparation, each vial should be reconstituted with 4.8 mL of water for injection (WFI). After reconstitution, each vial contains 325 mg of MOR202 (MOR03087) in a 5 mL extractable volume (65 mg / mL). For infusion, dilute in 250 mL of 0.9% sodium chloride solution.

[0242] All subjects are treated for 24 weeks, divided into six 28-day treatment cycles. A total of nine doses of MOR202 are administered on the following treatment days: Cycle 1, Days 1, 8, 15, and 22, and Cycles 2-6, Day 1 (Figure 11). During the first treatment cycle, MOR202 is administered at 16 mg / kg once weekly (i.e., four doses total for Cycle 1). During treatment cycles 2-6, MOR202 is administered at 16 mg / kg once every four weeks on the first day of each cycle (i.e., C2D1, C3D1, ...; five doses total for Cycles 2-6).

[0243] The initial MOR202 iv infusion is slow (approximately 90 minutes, approximately 3 mL / min). If no acute infusion reaction occurs, the infusion time may be shortened to 1 hour, or subsequent infusions may be shortened, but limited to the shortening steps outlined in Table 5. The infusion time should not be shorter than 30 minutes. Premedication of subjects with an antihistamine and antipyretic (e.g., paracetamol / acetaminophen) for prevention of infusion-related reactions (IRR) is recommended. As outlined in Table 5, for the first three applications, co-medication with iv dexamethasone (or an equivalent glucocorticoid administered iv) approximately 30 minutes before the start of the MOR202 infusion to prevent IRR is mandatory.

[0244] [Table 12]

[0245] 5.3. Safety, Immunogenicity, and Pharmacokinetic Evaluation Safety will be assessed through physical examination, vital signs, oxygen saturation, electrocardiogram, hematology and biochemistry tests, adverse events, and immunogenicity. Adverse events will be categorized according to the NCI CTCAE, version 4.03. To monitor immunogenicity and pharmacokinetics, the presence of anti-MOR202 antibodies (anti-drug antibodies) and serum concentrations of MOR202 will be assessed at selected time points during the study series.

[0246] 5.4.Efficacy Evaluation The primary efficacy assessments included: (i) serum anti-PLA2R antibody levels measured by ELISA before, during, and after MOR202 treatment to track the course of the immune response; (ii) proteinuria based on UPCR from 24-h urine / spot urine measured during and after MOR202 treatment; (iii) renal function measured before, during, and after MOR202 treatment by estimating glomerular filtration rate (eGFR) based on the CKD-epi equation; and (iv) urinary sodium excretion determined from 24-h urine.

[0247] Biomarkers The presence and titer of anti-PLA2R antibodies (i.e., kinetics of anti-PLA2R antibody titers) at selected time points are measured for all subjects during the study series. Optionally, additional autoantibody titers (e.g., anti-thrombospondin type 1 domain-containing 7A, anti-THSD7A), anti-tetanus toxoid, and / or anti-EBV antibodies at selected time points can be monitored. Serum concentrations of total IgG, IgA, and IgM can be assessed by ELISA. Quantitative NK cell, B cell, T cell (including regulatory T cells), plasmablast, and plasma cell counts can be determined at selected time points by peripheral blood flow cytometry or ELISPOT assay.

[0248] KDQOL-36 The Kidney Disease Quality of Life (KDQOL-36™) survey will be used to assess quality of life (QoL), defined as the change in score from baseline, in patients with autoimmune membranous nephropathy treated with MOR202.

[0249] Example 6: Determination of anti-PLA2R antibody levels Anti-phospholipase A2 receptor (PLA2R) antibody levels in human serum samples were quantitatively measured by monospecific ELISA (enzyme immunoassay with single antigen, Euroimmune, Order No. EA1254-G) according to the manufacturer's instructions. Briefly, polystyrene microplate strips coated with purified PLA2R antigen served as the solid phase. Serum dilutions of 1:101 were prepared and incubated on the antigen-bound microplate wells. If the sample was positive, the specific antibodies in the diluted serum sample bound to the PLA2R antigen coupled to the solid phase. Unbound antibodies were washed away, and in a further step, the bound anti-PLA2R-specific antibodies were detected with peroxidase-labeled anti-human IgG. Bound antibodies were visualized using a chromogen / substrate solution, which can promote a color reaction. The intensity of the color produced is proportional to the antibody concentration in the serum sample.

Claims

1. 1. A composition for use in treating an autoantibody-mediated autoimmune disease, the composition comprising an antibody or antibody fragment specific to CD38, the antibody comprising a heavy chain complementarity determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and a carrier, excipient, or diluent.

2. The composition of claim 1 , wherein the autoantibody-mediated autoimmune disease is membranous nephropathy.

3. 3. The composition of claim 1 or 2, wherein the antibody or antibody fragment depletes plasma cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cellular phagocytosis (ADCP).

4. The composition of any one of claims 1 to 3, wherein the antibody or antibody fragment exhibits significantly higher specific cell killing in plasma cells than in CD38 low expressing cells.

5. The composition according to claim 4 , wherein the CD38 low-expressing cells are natural killer (NK) cells.

6. The composition of any one of claims 1 to 5, wherein administration of the antibody or antibody fragment to a subject leads to a reduction in endogenous autoantibody titers in the subject.

7. The composition of claim 6, wherein the endogenous autoantibody titers comprise anti-PLA2R and / or anti-THSD7A autoantibodies.

8. The composition of claim 6, wherein the endogenous autoantibody titer comprises anti-PLA2R autoantibodies.

9. The composition of claim 6 , wherein the endogenous autoantibody titer comprises anti-THSD7A autoantibodies.

10. The composition of any one of claims 1 to 9, wherein the antibody or antibody fragment is a human antibody or antibody fragment.

11. The composition of any one of claims 1 to 10, wherein the antibody or antibody fragment is of the IgG1 isotype.

12. The composition of any one of claims 1 to 11, wherein the antibody or antibody fragment comprises 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.

13. The composition of claim 12, wherein the antibody is MOR202.

14. The composition of any one of claims 1 to 13, administered in combination with a further therapeutic agent.

15. The composition of claim 14 , wherein the additional therapeutic agent is an agent for the prevention and / or treatment of an autoantibody-mediated autoimmune disease.

16. The composition of claim 14 , wherein the additional therapeutic agent is an immunosuppressant or a proteasome inhibitor.

17. 17. The composition of claim 16, wherein the additional therapeutic agent is dexamethasone, azathioprine, mycophenolic acid, or methotrexate.

18. 17. The composition of claim 16, wherein the additional therapeutic agent is bortezomib.

19. The composition of any one of claims 1 to 18, wherein the antibody or antibody fragment is formulated for intravenous administration.

20. 20. The composition of any one of claims 1 to 19, wherein the antibody or antibody fragment is formulated for administration at 16 mg / kg once weekly in the first treatment cycle.

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