Anti-CD38 antibodies and pharmaceutical compositions thereof for the treatment of antibody-mediated autoimmune diseases

Abstract

The present invention relates to the use of an antibody or antibody fragment specific for CD38 in the prevention 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.

Description

Technical Field

[0001] The present invention relates to an antibody or antibody fragment specific for CD38 that is useful in the treatment and / or prevention of autoimmune diseases (AD) mediated by autoantibodies. In particular, the present invention provides a method for reducing autoantibody titers due to depletion of antibody-secreting cells using an anti-CD38 antibody alone or in combination with one or more immunosuppressive drugs. According to the present invention, the anti-CD38 antibody may be effective alone or in combination in the treatment and / or prevention of anti-PLA2R positive membranous nephropathy (aMN). Examples of anti-CD38 antibodies include, but are not limited to, MOR202.

Background Art

[0002] Autoimmune Diseases and Autoantibodies Autoimmune diseases (AD) include more than 70 various disorders that affect 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 or autoreactive B cells or both. Certain types of AD are characterized by the production of pathogenic autoantibodies. Autoantibodies are immunoglobulins that react with autoantigens. Such autoantigens can include proteins, nucleic acids, carbohydrates, lipids, or various combinations thereof, and can be present in all cells (e.g., DNA) or highly restricted to specific cell types in certain organs of an organism. In autoantibody-mediated humoral AD, autoantibodies usually occur at high titers in the patient's serum. For many ADs, a clear and obvious association between autoantibody formation, specificity, and pathogenesis has been demonstrated (Non-Patent Document 2). Pathogenic autoantibodies affect disease pathways in many ways, including the accumulation of immune complexes (IC) 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) is a polygenic autoimmune disorder with a prevalence of approximately 50 cases per 100,000 people, and a higher incidence in women than in men. The central immunological derangement in SLE patients is the inappropriate activation and proliferation of autoreactive memory B cells, which leads 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 ribonucleoprotein (RNP), and the autoantibodies reactive to these antigens are of high affinity, somatically mutated, and of the IgG isotype. SLE patients show high levels of serum antinuclear antibodies (ANA). Autoantibodies against cytoplasmic antigens, cell membrane antigens, phospholipid-related antigens, blood cells, endothelial cells, 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 immune complexes (ICs) that are thought to become directly pathogenic after accumulation in several tissues.

[0004] Treatment options for SLE include antimalarials, steroids and non-steroidal anti-inflammatory drugs, immunosuppressive drugs (including cyclophosphamide (CTX), azathioprine (AZA), mycophenolic acid (MMF), and methotrexate (MTX)), and immunocyte-targeted therapies (Non-Patent Document 4).

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

[0006] Graves' disease Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid gland. Graves' disease occurs in approximately 0.5% of men and 3% of women (Non-Patent Document 6). As a result of this disease, hyperthyroidism often occurs, and it is the most common cause of hyperthyroidism in the United States (about 50 - 80% of the causes). The symptoms of hyperthyroidism can include irritability, muscle weakness, sleep disturbances, rapid heartbeat, reduced tolerance to heat, diarrhea, unintentional weight loss, thickening of the skin on the shins known as pretibial myxedema, and bulging of the eyes, a condition caused by Graves' ophthalmopathy. The direct cause of Graves' disease is autoantibodies against the receptor for thyroid-stimulating hormone (thyroid-stimulating hormone receptor (TSHR)). Autoantibodies against thyroglobulin and against thyroid hormones T3 and T4 can also be produced. TSHR autoantibodies mimic TSH and activate TSHR uncontrollably, thereby causing hyperthyroidism. Treatment options for Graves' disease include antithyroid (thionamide) drugs, thyroid ablation with radioactive iodine, and surgery (thyroidectomy). However, inhibiting the generation or ongoing production of TSHR autoantibodies remains a challenge in treating Graves' disease.

[0007] Myasthenia gravis (MG) Myasthenia gravis (MG) affects 50 - 200 per million people. Every year, 3 - 30 per million people are newly diagnosed. MG is a chronic neuromuscular AD that leads to varying degrees of skeletal muscle weakness and abnormal fatigue, and is caused by the presence of an autoimmune reaction reactive to components of the postsynaptic muscle endplate located at the neuromuscular junction (the junction between nerve and muscle). In particular, these autoantibodies block or destroy nicotinic acetylcholine receptors, subsequently preventing nerve impulses from triggering muscle contraction. Other autoantibodies have been discovered against a related protein called MuSK, muscle - specific kinase and LRP4, agrin, and titin protein. Generally, MG is 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 can improve the symptoms of the disease. Plasmapheresis and high - dose intravenous immunoglobulin (IVIG) can be used during acute relapses of the condition to remove putative autoantibodies from the circulation or to dilute and bind circulating antibodies, respectively. Both of these treatments are beneficial for a relatively short period, generally evaluated on a weekly basis and often associated with high costs. If the respiratory muscles become significantly weak, a ventilator may be required.

[0008] Anti - PLA2R - positive membranous glomerulonephritis (aMN) Historically, anti-PLA2R-autoantibody-mediated membranous nephropathy (aMN), which is often called 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 nephropathies are idiopathic, while 20% are associated with other diseases or exposures. The overall worldwide incidence is estimated to be 1.2 / 100,000 people / year. Although this disease usually progresses slowly, approximately 30% - 40% of patients will ultimately progress to end-stage kidney disease. MN patients who remain nephrotic have an increased risk of thromboembolic and cardiovascular events. However, although not all aspects of MN pathogenesis are understood, this 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 that bind to the PLA2R antigen are highly specific for primary MN. Recent studies have revealed that the presence of anti-PLA2R autoantibodies correlates quite well with disease activity in approximately 75% of IMN patients (Non-Patent Document 9). The fact that the glomerular basement membrane changes that define the disease contain both PLA2R protein and antibody complexes provides evidence that anti-PLA2R antibodies act as a major cause 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 neonatal MN cases, neutral endopeptidase (NEP) located on the podocyte foot process membrane and the brush border of renal tubules have been identified as relevant antigens (Non-Patent Document 11). In summary, approximately 80% of IMN patients have antibodies against specific and identifiable podocyte antigens. Symptoms of membranous nephropathy include, but are not limited to, swelling of the lower extremities and ankles, increased urinary protein, edema, hypoalbuminemia, elevated serum lipids, especially hypercholesterolemia. Therefore, autoimmune membranous nephropathy is an immune-mediated glomerular disease characterized by the presence of anti-PLA2R autoantibodies and / or anti-THSD7A autoantibodies. In neonatal autoimmune MN, there are autoantibodies against NEP transferred from the mother.

[0009] Currently, there is no approved standard treatment for MN. The most recent treatment regimens mainly involve off-label use of various non-immunosuppressive and immunosuppressive drugs. Patients diagnosed with MN and having proteinuria > 3.5 g / day initially receive supportive therapy with a combination of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), a statin, and a diuretic according to the most recent clinical standards. If there is no response with a significant reduction in proteinuria within several months, escalation to immunosuppressive therapy (IST) is indicated. Although none of these drugs are approved for use in MN, immunosuppressive therapy includes corticosteroids in alternation with alkylating agents (e.g., cyclophosphamide) and calcineurin inhibitors (CNIs, e.g., cyclosporine A, tacrolimus (FK506)), mycophenolate-mofetil (MMF), or rituximab. Although relatively few in number, adrenocorticotropic hormone (ACTH) has been used. The therapeutic effects of these drug combinations appear to be similar: remission of proteinuria can be expected in about 50 - 60% of patients at 1 year and about 70 - 80% at 2 - 3 years, compared with a remission rate of about 30% (spontaneous remission) in controls treated with supportive therapy alone.

[0010] Among all patients with primary membranous nephropathy who have not received IST, 30% - 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 is seen in approximately 25% of patients previously treated with IST. These cases are usually retreated with different combinations of IST. The drawbacks of the above-mentioned ISTs are that they exhibit a considerable degree of toxicity, are accompanied by significant side effects, and have a high recurrence rate. 25% of patients treated with cyclophosphamide exhibit adverse events, which include subsequent infections in life, infertility, blood toxicity, and malignancies. The drawbacks of CN include long-term nephrotoxicity, and it is necessary to carefully monitor drug levels and the increased risks for hypertension and diabetes. The recurrence rate with calcineurin inhibitors is thought to be higher than when using cyclophosphamide (40 - 50% vs 25%). Considerable evidence indicating that anti-PLA2R antibodies correlate with disease activity has led to a change in the previously established treatment algorithm.

[0011] The recently introduced off-label therapy with the anti-CD20 therapeutic antibody rituximab enables a more specific IST approach by depleting the B cell population that is involved as a precursor in the production of the causative anti-PLA2R autoantibodies. The rituximab response rate is thought to be comparable to that of alkylating agents and CNI, while the side effects are thought to be fewer than in the case of other drugs used in IST. However, CD20, the target of rituximab, is not present on mature long-lived antibody-secreting plasma cells (the major source of endogenous immunoglobulins). On early plasmablasts, there is only a small number of constitutive CD20 expressions compared to CD20 expression on mature B cells. This is a possible explanation for the suboptimal efficacy of rituximab therapy in MN patients with high anti-PLA2R antibody titers.

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

[0013] Pemphigus Pemphigus vulgaris is an autoimmune epidermolysis bullosa of the skin and mouth where blistering occurs. The lesions occur at a high incidence of 0.5 - 3.2 cases per 100,000 people per year. These lesions mainly occur in people aged 40 - 60 years, with no gender bias. Pemphigus patients show circulating autoantibodies against pemphigus antigens (desmoglein 3, desmoglein 1, desmocollin, plakoglobin) on epithelial keratinocytes. The breakdown of these antigens due to the antigen-autoantibody reaction has a significant impact on the integrity of the epidermis, resulting in cell detachment (acantholysis), suprabasilar clefting, and subsequently, blistering. As a result of the binding of autoantibodies to keratinocytes, the release of proteases and plasminogen activators (which convert plasminogen to plasmin) from cells also occurs, further amplifying acantholysis. Treatment options for advanced lesions include systemic glucocorticoids, and combinations of corticosteroids, immunosuppressants, pulse therapy, photopheresis, and plasmapheresis.

[0014] Sjögren's syndrome Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltrates in the exocrine and lacrimal glands, resulting in dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca), respectively. In Sjögren's syndrome, the presence of lesions is associated with chronic inflammatory infiltrates 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 the muscarinic type 3 receptor. Currently, there is no targeted therapy available for Sjögren's syndrome, and current treatment approaches are only symptomatic, for example, treating dryness and fatigue symptoms with 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 (Non-Patent Document 12). Its incidence is estimated to be 3 - 5 per 1,000,000 population and year. Anti-NMDA encephalitis corresponds to a model disease for a syndrome 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). Antibodies against 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) are other examples of neuronal cell surface antibodies. Anti-NMDAR encephalitis mainly occurs in young adults and children, mainly in females (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 stereotypies) and decreased consciousness, lethargy, and severe overall autonomic dysregulation (often leading to hypoventilation and hypotension) result. Seizures and status epilepticus can occur at all stages of the disease. Approximately 50% of patients respond well to IVIG, steroids, or plasma exchange, and the other 50% require rituximab alone or in combination with cyclophosphamide. However, in some patients, recovery is incomplete and takes several years, and the mortality rate due to intensive care complications can be as high as 7%.

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

[0017] Central and peripheral B cell tolerance B cell development begins in the bone marrow. There, a diverse repertoire of naive membrane-bound B cell receptors (BCRs) is generated by somatic recombination of immunoglobulin heavy and light chain gene segments. A negative aspect of generating this vast diversity in the initial BCR repertoire by random somatic V(D)J recombination is the concomitant generation of autoantibodies that may be pathogenic. There are at least three mechanisms that 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 a change in the VL domain by secondary Ig light chain recombination, a process called receptor editing. A third mechanism for suppressing autoreactive B cells is anergy, by which such cells become non-responsive to antigen. These central tolerance mechanisms occur in the bone marrow. Thus, the autoreactivity of the emerging antibody repertoire is prevented by induction of apoptosis, receptor editing, and anergy in B cells that express autoreactive antibodies (Non-Patent Document 13).

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

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

[0020] One or more failures of central and / or peripheral tolerance mechanisms lead to an increase in many circulating autoreactive B cells (i.e., autoantibody-expressing B cells) and autoreactive plasmablasts and plasma cells (i.e., autoantibody-expressing and secreting cells) that are favorable for the development of autoimmune-mediated AD. Once autoantibody production is initiated, their production levels are maintained either by continuous activation of autoreactive B cells that result 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] Since autoantibodies are often a fundamental cause of autoimmune pathologies, B cells, plasmablasts, and plasma cells are promising therapeutic targets in AD. Short-lived plasma cells respond to conventional immunosuppressive drugs that directly inhibit proliferating plasmablasts and B cells. Since non-proliferating short-lived plasma cells are no longer replenished, they disappear within a few days of the start of these treatments. Treatments targeting B cells, such as anti-CD20 (rituximab) and anti-BAFF (belimumab) (see, for example, (Patent Document 1), (Patent Document 2)), reduce B cell levels in patients who require such reduction and thus attenuate the production of short-lived plasmablasts and plasma cells, but such treatments do not affect the long-lived memory plasma cell compartment. It should be considered that autoantibodies may potentially be secreted by long-lived memory plasma cells if autoantibody production is not affected by this treatment strategy. Furthermore, it can be assumed that blocking factors or cells that stimulate autoreactive B cells by targeting, for example, type I interferon (IFN), TH cells, or regulatory T (Treg) cells prevents the generation of short-lived plasmablasts and plasma cells but does not prevent plasma cell memory.

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

[0023] The 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 the rhesus monkey animal model, after surgically removing potential B cell reservoirs from solid tissues (such as the spleen and lymph nodes) and depleting all detectable tetanus-specific memory B cells from the circulation using anti-CD20 antibodies, the tetanus-specific serum antibody titers were shown to continue to be maintained above the protective threshold for the lifespan of the immunized host, and the decay rate kinetics were indistinguishable from those of untreated subjects (Non-Patent Document 18). Therefore, the antibody response after tetanus vaccination is long-lived and provides lifelong protective immunity against this disease. Further analysis of tetanus-specific plasma cells revealed that long-lived vaccine-induced plasma cells were preferentially identified in certain bone marrow compartments 10 years after immunization. Collectively, these studies provide a framework in which the maintenance of long-term serum antibody responses appears to be maintained by long-lived plasma cells independently of memory B cells.

[0024] As described above, current treatment options for AD include systemic immunosuppression (i.e., with corticosteroids such as high-dose dexamethasone). The cytotoxic drug cyclophosphamide (Endoxan®) suppresses T-helper cell function and causes a prolonged decrease in B cells due to the slower recovery rate of B lymphocytes from alkylating agents, thereby showing that cyclophosphamide suppresses B cell activation. Additional immunosuppressive drugs include, but are not limited to, azathioprine, mycophenolic acid, and methotrexate. Proteasome inhibitors, such as bortezomib, have been shown to deplete short-lived and long-lived plasma cells, and the first clinical trials using bortezomib for the treatment of SLE and thrombotic thrombocytopenic purpura are promising (Non-Patent Document 19; Non-Patent Document 20).

[0025] (Patent Document 3) discloses anti-CD38 antibodies and claims their possible therapeutic uses for a very large number of autoimmune diseases. In fact, (Patent Document 3) investigated the anti-tetanus response in a HuScid mouse model and presented experiments conducted using alternative mouse anti-CD38 antibodies only in collagen-induced arthritis and SLE autoimmune mouse models. (Patent Document 3) is silent regarding the determination of antibody titers in human samples after anti-CD38 treatment, makes no mention of, and shows no data regarding, anti-PLA2R-positive membranous nephropathy 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 for depleting 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, the prevalence of AD patients remains high and the mortality rate is increasing. Despite progress in the development of new anti-autoimmune agents (such as bortezomib), many autoimmune-mediated ADs that almost certainly include CD38-positive autoantibody-secreting cells still have a poor prognosis. All of the treatment options mentioned above have drawbacks, side effects, or their use is limited to certain types of patient groups.

[0029] Therefore, there is a high and still unaddressed medical need for new and improved treatment methods for patients suffering from autoimmune-mediated AD.

[0030] The inventors have confirmed that CD38 is an excellent 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 shows very high expression on plasmablasts and plasma cells (Figure 4), and second, compared to plasmablasts and plasma cells, CD38 expression is absent or significantly lower in other cell types. Thus, by using anti-CD38 antibodies, it becomes possible to target the source of pathogenic autoantibodies as a sustainable therapeutic approach, and the effect may persist for a long time due to the elimination of short-lived and long-lived plasma cells. Essentially, such targeting can be generalized as follows: antibodies specific for the CD38 surface antigen of antibody-secreting cells are administered to the patient. These anti-CD38 antibodies specifically bind to the CD38 antigen of both antibody-secreting cells that produce normal antibodies and pathogenic autoantibodies. Next, the antibodies that bind to the CD38 surface antigen result in the destruction and depletion of these cells. Regardless of the approach, the main goal is to reduce the cells that produce autoantibodies.

[0031] Endogenous anti-tetanus antibody titer as a marker to evaluate the effect of MOR202 on plasma cell function Long-term tests in mice (Non-Patent Document 24) and humans (Non-Patent Document 25) highlight the advantage of inducing and maintaining an effective serum concentration (antibody titer) of antibodies that remain defensive over the lifespan of the immune system. Defensive humoral immunity is conferred, for example, by the stable titers of specific antibodies produced by routine vaccination against, for example, measles, mumps, tetanus, diphtheria or smallpox. Plasma cells and their immediate precursors are known as the cellular basis of this humoral immunity, and since serum-specific antibody titers are useful markers of the humoral arm, they can be used as indicators of the presence and / or activity of plasma cells that produce these antibodies. Mouse studies using anti-CD20 treatment to deplete naive and memory B cells have shown that loss of B cells did not significantly affect the plasma cell pool even after a long time (Non-Patent Document 26). Similarly, humans receiving B cell depletion therapy maintain serum antibody titers against common antigens for at least one year (Non-Patent Document 27). Thus, these reports indicate that (long-lived) plasma cells are an essential component of persistent humoral memory in mice and humans. It is well supported that plasma cells can persist over a long period without input from recently activated naive or memory B cells. Here, the inventors first show that administration of MOR202 leads to a decrease in endogenous anti-tetanus toxoid antibody titers in human subjects, and describe in the examples how treatment of autoimmune membranous nephropathy mediated by autoantibodies with MOR202, particularly anti-PLAR2-positive autoimmune MN, is achieved.

Prior Art Documents

Patent Documents

[0032]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0033] [Non-Patent Document 1] Lleo et al., Autoimmunity Reviews 2010 Mar; 9(5): A259-66 [Non-Patent Document 2] Suurmond and Diamond, J Clin Invest. 2015 Jun 1; 125(6): 2194-2202 [Non-Patent Document 3] Ludwig et al., Front. Immunol. 2017 May; 8: 603 [Non-Patent Document 4] Yildirim-Toruner C, Allergy Clin Immunol. 2011 Feb; 127(2): 303-12 [Non-Patent Document 5] Stichweh, D., Curr. Opin. Rheumatol. 2004 16: 577-587.5 [Non-Patent Document 6] Burch HB, Cooper DS, 2015, JAMA 314(23): 2544-54 [Non-Patent Document 7] Ronco P, Debiec H, Lancet. 2015 May 16; 385(9981): 1983-92 [Non-Patent Document 8] Beck LH Jr et al., N Engl J Med. 2009 Jul 2; 361(1): 11-21 [Non-Patent Document 9] Bomback AS, Clin J Am Soc Nephrol. 2018 May 7; 13(5): 784-786 [Non-Patent Document 10] Tomas NM et al., N Engl J Med 2014; 371: 2277-2287 [Non-Patent Document 11] Ronco P et al., J Am Soc Nephrol. (2005) 16: 1205-13 [Non-Patent Document 12] Granerod J et al. Lancet Infect Dis 2010, 10:835-44

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Non-Patent Document 19

Non-Patent Document 20

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Non-Patent Document 24

[0034] The present invention provides an antibody or antibody fragment specific for CD38 for use in the treatment and / or prevention of autoimmune diseases and related conditions mediated by autoantibodies. In particular, the anti - CD38 antibody or antibody fragment is for use in the treatment and / or prevention of idiopathic membranous glomerulonephritis. Preferably, the anti - CD38 antibody or antibody fragment 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 is 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 autoimmune diseases mediated by autoantibodies. In particular, the anti - CD38 antibody or antibody fragment of the present 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 present 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 present pharmaceutical composition is for use in the treatment and / or prevention of systemic lupus erythematosus (SLE).

[0036] MOR202, a monoclonal human anti-CD38 antibody, targets antibody-secreting cells such as plasmablasts and plasma cells mainly through antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). During clinical trials with MOR202, efficient killing of neoplastic plasma cells (i.e., multiple myeloma cells) as well as benign plasma cells was demonstrated. In patients suffering from multiple myeloma (MM), plasma cell depletion by MOR202 leads to a marked decrease in M-protein. M-protein, also known as the M-component, M-spike, spike protein, paraprotein or myeloma protein, is an immunoglobulin (antibody) or a 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 extremely in excess, which leads to a number of harmful effects in the body characteristic of MM (e.g., immunodeficiency, abnormally high blood viscosity and kidney damage). MOR202 is effective in the depletion of plasma cells, the source of M-protein, and consequently leads to a decrease in M-protein titer.

[0037] The effect of MOR202 on plasma cells is demonstrated by the evaluation of the serum anti-tetanus toxoid (anti-TT) antibody titer as a marker for specific plasma cell depletion. After administration of MOR202, the serum anti-TT antibody level decreased significantly compared to the baseline before MOR202 administration.

[0038] Overall, the inventors have shown that MOR202 effectively reduces the levels of malignant (M-protein) and / or protective antibodies (anti-TT) 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 thus result in an optimal safety profile.

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

[0040] In certain embodiments of the present invention, the antibody or antibody fragment is for use in the treatment and / or prevention of autoantibody-mediated autoimmune diseases, particularly 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, and comprises the HCDR1 region of amino acid sequence SEQ ID NO: 1, the HCDR2 region of amino acid sequence SEQ ID NO: 2, the HCDR3 region of amino acid sequence SEQ ID NO: 3, the LCDR1 region of amino acid sequence SEQ ID NO: 4, the LCDR2 region of amino acid sequence SEQ ID NO: 5, and the LCDR3 region of amino acid sequence SEQ ID NO: 6.

[0041] The present disclosure also provides a pharmaceutical composition 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 a further particular embodiment, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the antibody or antibody fragment of the present invention. In a more particular embodiment, the additional therapeutically active ingredient is an agent for the treatment of autoantibody-mediated autoimmune diseases.

[0043] In one aspect of the present invention, the present invention provides a method for the prevention and / or treatment of autoantibody-mediated AD in a subject in need thereof, particularly in a human, 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, said method comprising administering to said 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, said method comprising administering to said 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 preventing and / or treating 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 preventing and / or treating autoantibody-mediated AD in a mammal, particularly a human, suffering from said autoimmune disease.

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

[0049] Furthermore, the antibody or antibody fragment specific for CD38 useful in the pharmaceutical compositions and treatment methods disclosed herein is pharmaceutically acceptable when prepared and used. BRIEF DESCRIPTION OF THE DRAWINGS

[0050]

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Mode for Carrying Out the Invention

[0051] Definitions The following terms are to have the meanings given with them below and are useful for understanding the description and intended scope of the present invention.

[0052] When describing the present invention, which may include antibodies, antibody fragments, pharmaceutical compositions containing such antibodies or antibody fragments, and methods of using such antibodies, antibody fragments, and compositions, the following terms, where present and unless otherwise indicated, shall have the following meanings.

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

[0054] The term "CD38" refers to a protein known as CD38 with 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)enzyme activity. As an ectoenzyme, CD38 uses NAD+ as a substrate not only for the formation of cyclic ADP-ribose (cADPR) and ADPR, but also for the formation of nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to act as second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 regulates extracellular NAD+ concentration and thus cell survival by modulating NAD-induced cell death (NCID). In addition to Ca2+-mediated signaling, CD38 signaling occurs via cross-talk with antigen-receptor complexes or other types of receptor complexes, such as MHC molecules, on T and B cells, and thus participates in several cellular responses and also in the switching and secretion of IgG antibodies.

[0057] As used herein, the term "anti-CD38 antibody" includes anti-CD38 binding molecules in its broadest sense; any molecule that specifically binds to CD38 or inhibits the activity or function of CD38, or exerts a therapeutic effect on CD38 in some way is included. Any molecule that interferes with or inhibits CD38 functionality is included. 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, ankyrin, maxybodies / abimers, protein A-derived molecules, anticalins, affilins, protein epitope mimics (PEM), etc.), nucleic acids specific for CD38 (including aptamers), or small organic molecules specific for CD38.

[0058] Antibodies specific for CD38 are described, for example, in WO 99 / 62526 (Mayo Foundation), which is incorporated herein by reference in its entirety; WO 02 / 06347 (Crucell Holland); US 2002 / 164788 (Jonathan Ellis), which is incorporated herein by reference in its entirety; WO 05 / 103083 (MorphoSys AG), US patent application Ser. No. 10 / 588,568, which is incorporated herein by reference in its entirety, WO 06 / 125640 (MorphoSys AG), US patent application Ser. No. 11 / 920,830, which is incorporated herein by reference in its entirety, and WO 07 / 042309 (MorphoSys AG), US patent application Ser. No. 12 / 089,806, which is incorporated herein by reference in its entirety; WO 06 / 099875 (Genmab), US patent application Ser. No. 11 / 886,932, which is incorporated herein by reference in its entirety; and WO 08 / 047242 (Sanofi-Aventis), US patent application Ser. No. 12 / 441,466, which is incorporated herein by reference in its entirety.

[0059] Combinations of antibodies specific for CD38 and other agents are described, for example, in WO 00 / 40265 pamphlet (Research Development Foundation), which is incorporated by reference in its entirety; WO 06 / 099875 pamphlet and WO 08 / 037257 pamphlet (Genmab); and WO 10 / 061360 pamphlet, WO 10 / 061359 pamphlet, WO 10 / 061358 pamphlet and WO 10 / 061357 pamphlet (Sanofi Aventis).

[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, such as mouse, rat, chimeric, humanized or human antibodies.

[0061] "Human antibody" or "human antibody fragment", as used herein, is an antibody or antibody fragment having a variable region 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. Examples of human origin include, but are not limited to, antibodies containing human germline sequences or mutant versions of human germline sequences or consensus framework sequences derived from human framework sequence analysis 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 sequence is human, regardless of the species from which the antibody is physically derived, isolated or manufactured.

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

[0063] A "humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having a constant antibody region and a variable antibody region or a portion thereof derived from sequences of human origin, or only the CDRs are from another species. For example, a humanized antibody can be CDR-grafted, where 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 a constant antibody region derived from or corresponding to a sequence found in one species and a variable antibody region from another species. Preferably, the constant antibody region is derived from or corresponds to a sequence found in humans, and the variable antibody region (e.g., VH, VL, CDR, or FR region) is derived from a sequence found in a non-human animal, such as a mouse, rat, rabbit, or hamster.

[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. Additionally, an isolated antibody or antibody fragment may not substantially contain other cellular materials and / or chemical substances. Thus, in some embodiments, the provided antibody is an isolated antibody that has been separated from antibodies of different specificities. An isolated antibody can be a monoclonal antibody. An isolated antibody can be a recombinant monoclonal antibody. However, an isolated antibody that specifically binds to an epitope, isoform, or target variant may have cross-reactivity, for example, with other related antigens from other species (e.g., species homologs).

[0066] As used herein, the term "monoclonal antibody" refers to the preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition presents a unique binding site having binding specificity and affinity specific to a particular epitope.

[0067] Furthermore, as used herein, "immunoglobulin" (Ig) according to this specification is defined as a protein belonging to class 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] As used herein, the phrase "antibody fragment" refers to one or more portions of an antibody that retain the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, stabilizing spatial distribution). Examples of binding fragments include: a monovalent fragment consisting of Fab fragment, VL, VH, CL, and CH1 domains; a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region, i.e., F(ab)2 fragment; an Fd fragment consisting of VH and CH1 domains; an Fv fragment consisting of VL and VH domains of a single arm of an antibody; a dAb fragment consisting of a VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs), without limitation. Further, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be linked by a synthetic linker using recombinant methods that enable them to be made as a single protein chain, where the VL and VH regions pair to form a monovalent molecule (also known as "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 can be obtained using conventional techniques known to those skilled in the art, and these 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). Based on polypeptides such as type III fibronectin (Fn3), antibody fragments can be grafted onto a scaffold (see U.S. Patent No. 6,703,199, which describes fibronectin polypeptide monobodies).Antibody fragments can be incorporated into single-chain molecules that include pairs of tandem Fv segments (VH-CH1-VH-CH1) that together with complementary light chain polypeptides form pairs of antigen-binding sites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Patent No. 5,641,870).

[0069] The present disclosure provides a method of treatment comprising administering a therapeutically effective amount of an anti-CD38 antibody as disclosed herein to a subject in need of such treatment. "Therapeutically effective amount" or "effective amount" as used herein refers to the amount of an antibody specific for CD38 necessary to induce a desired biological response. According to the present disclosure, a therapeutically effective amount is the amount of an antibody specific for CD38 necessary to treat and / or prevent an autoimmune disease mediated by autoantibodies and the symptoms associated with said AD. The effective amount for a particular individual can vary depending on factors such as the condition being treated, the overall health of the patient, the route and dosage of administration, and the severity of side effects (Maynard, et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001) Good Laboratory and Good Clinical Practice, London, UK).

[0070] As used herein, "treat", "treating", etc. mean, either temporarily or permanently, alleviating symptoms, eliminating the cause of symptoms, or preventing or delaying the appearance of symptoms of a designated disorder or condition.

[0071] "Preventing" or "prevention" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., at least one of the clinical symptoms of the disease does not develop in a subject who may be exposed to a disease-causing agent or is prone to developing the disease before the onset of the disease). "Prevention" refers to a method that aims to prevent the onset of a disease or its symptoms or delay the onset of a disease or its symptoms.

[0072] The term "prophylaxis" is related to "prevention" and refers to means or procedures that are aimed at preventing rather than treating or curing a disease. Non-limiting examples of prophylactic means may include administration of a vaccine; administration of low molecular weight heparin to inpatients at risk of thrombosis, for example for movement restriction; administration of an antimalarial agent such as chloroquine prior to visiting a geographical area where malaria is endemic or where there is a high risk of contracting malaria.

[0073] "Palliating" one or more symptoms of autoantibody-mediated AD means reducing the degree 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 in an injectable form, such as by intravenous, intramuscular, intradermal or subcutaneous routes, or by mucosal routes, such as nasal spray or inhalation aerosol, or as an ingestible solution, capsule or tablet. Preferably, administration is by an injectable form.

[0075] As used herein, terms such as "subject", "subject in need thereof" mean 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 diagnosed with an autoantibody-mediated autoimmune disease.

[0076] As used in this context, the term "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" includes "autoantibody-related autoimmune disease" and refers to a group of diseases characterized by the presence of autoantibodies (autoantibody positive), where (i) a causal correlation and direct contribution of the autoantibodies to the pathogenesis of the disease and its associated symptoms are provided, or (ii) a causal correlation and direct contribution of the autoantibodies to the pathogenesis of the disease and its associated symptoms are not very clear but may be provided. Representative diseases listed in Table 1 are included as autoantibody-mediated autoimmune diseases, but are not limited thereto.

[0078] [Table 1]

[0079] [Table 2]

[0080] [Table 3]

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

[0082] "Pharmacokinetics" or "PK," as used herein, describes how the body affects a specific drug after administration through mechanisms such as absorption and distribution and metabolic changes of the drug in the body, and the effects and excretion pathways 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 Government or a state government, or corresponding agency of a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.

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

[0085] Throughout this specification, unless the context requires otherwise, the words "comprise," "have," and "include" and their individual variations such as "comprises," "comprising," "has," "having," "includes," and "including" are to be construed as indicating the presence of the 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 and is also known as 「MOR03087」 or 「MOR3087」. This term is 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 as follows.

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

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

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

[0098] The present invention also provides a method for the prevention and / or treatment of self-antibody-mediated autoimmune diseases, which comprises administering an antibody or antibody fragment specific for CD38 to a subject in need of prevention and / or treatment of self-antibody-mediated autoimmune diseases. In some embodiments, the antibody or antibody fragment specific for CD38 used in the method is MOR202 and the self-antibody-mediated AD is any one selected from Table 1. In one embodiment, the antibody or antibody fragment specific for CD38 used in the method is MOR202 and the self-antibody-mediated AD is SLE. In certain embodiments, the antibody or antibody fragment specific for CD38 used in the method is MOR202 and the self-antibody-mediated AD is idiopathic membranous glomerulonephritis, preferably anti-PLA2R-positive membranous glomerulonephritis.

[0099] The present invention also provides a pharmaceutical composition comprising the antibody or antibody fragment specific for CD38, and a method for the prevention and / or treatment of an autoantibody-mediated autoimmune disease by administering the antibody or antibody fragment specific for CD38.

[0100] Pharmaceutical composition When used as a medicament, an antibody or antibody fragment specific for CD38 is generally administered in a pharmaceutical composition. Such compositions can be prepared as is well known in the art of pharmacy and can contain an antibody or antibody fragment specific for CD38. Generally, an antibody or antibody fragment specific for CD38 is administered in an effective amount. The amount of the antibody or antibody fragment specific for CD38 actually administered is generally determined by a physician in light of relevant circumstances including the condition to be treated, the selected route of administration, the actual antibody or antibody fragment being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

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

[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 the 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. For example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants, appropriate fluidity can be maintained. In many cases, it is preferable to include in the composition an isotonic agent, such as sugar, a polyalcohol, such as mannitol or sorbitol, etc., and sodium chloride. The long-term absorption of an injectable composition can be brought about by including in the composition a substance 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. The selected routes of administration for the antibodies or antibody fragments of the present disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intraspinal or other parenteral routes of administration, such as by injection or infusion. Parenteral administration can generally denote an administration form other than enteral and topical administration by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, intrathecal, intraspinal, epidural, intracerebral, intralesional and intrasternal injection and infusion. Alternatively, the compositions of the present disclosure can be administered via local, epidermal, dermal or mucosal routes of administration, such as non-parenteral routes such as intranasal, oral, vaginal, rectal, sublingual, transdermal or topical. Further, the antibody or antibody fragment can be administered as a sustained release formulation, in which case less frequent administration is required. Further, pulmonary administration can also be used, for example, by the use of an inhaler or nebulizer and formulation with an aerosolizing agent.

[0105] An antibody or antibody fragment specific for CD38 is preferably formulated as an injectable composition. In a preferred embodiment, the anti-CD38 antibody of the present disclosure is administered intravenously. In other embodiments, the anti-CD38 antibody of the present disclosure is administered subcutaneously, intraarticularly or intraspinally.

[0106] Depending on the route of administration, the active compounds, namely antibodies, antibody fragments, bispecific and multispecific molecules, can be coated in substances that protect the compound from acids and other natural state actions that can inactivate the compound.

[0107] Injectable compositions generally are based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As before, antibodies or antibody fragments specific for CD38 in such compositions generally are minor components, being about 0.05 to 10% by weight, with the remainder often being an injectable carrier or the like. Optionally, the composition may also contain solubilizing agents and local anesthetics such as lidocaine to relieve 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 the treatment of autoantibody-mediated AD, said composition further comprising one or more pharmaceutically acceptable carriers and / or diluents.

[0109] An important aspect of the present disclosure is a pharmaceutical composition that can mediate the killing of CD38-expressing antibody-secreting cells (e.g., plasmablasts, plasma cells) by ADCC and ADCP.

[0110] Treatment Methods In one embodiment, the present invention provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 or an antibody or antibody fragment specific for CD38 for use in the prevention and / or treatment of autoantibody-mediated autoimmune diseases.

[0111] In one embodiment, the present disclosure provides a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 or 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 a pharmaceutical composition comprising an antibody or antibody fragment specific for CD38 or 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 present disclosure provides the 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 present 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 present 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 other aspects, the present 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 other aspects, the present disclosure provides for the use of MOR202 in the preparation of a medicament for the treatment and / or prevention of systemic lupus erythematosus (SLE).

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

[0124] In other aspects, the present disclosure provides for 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 for 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 the prevention and / or treatment of an autoantibody-mediated autoimmune disease, preferably an autoantibody-mediated membranous nephropathy.

[0131] In another 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 an autoantibody-mediated autoimmune disease, preferably an 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 a pharmaceutical composition comprising MOR202 and another therapeutic agent or MOR202 in the preparation of a medicament for the treatment and / or prevention of an autoantibody-mediated autoimmune disease, preferably an autoantibody-mediated membranous nephropathy.

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

[0136] In certain embodiments, the present 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 embodiments, the present 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 another therapeutic agent is a therapeutic agent for autoimmune diseases. In certain embodiments, the medicament is an immunosuppressant and is selected from the group consisting of steroids (such as clobetasol propionate, desoximetasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, budesonide or dexamethasone), proteasome inhibitors (such as bortezomib), cell division arrest agents (such as cyclophosphamide, azathioprine, methotrexate), drugs acting on immunophilins (such as cyclosporine, tacrolimus, sirolimus) and other immunosuppressants.

[0139] In a further method of treatment regime, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoantibody-mediated autoimmune disease, the method comprising administering one or more effective amounts of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition 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 an autoantibody-mediated AD, preferably autoantibody-mediated membranous nephropathy, comprising administering an anti-CD38 antibody to the subject.

[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 another therapeutic agent is an autoimmune disease therapeutic agent. In certain embodiments, said agent is an immunosuppressive agent.

[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 a method for treating and / or preventing anti-PLA2R positive membranous glomerulonephritis in a subject, said method comprising administering an anti-CD38 antibody to said subject.

[0144] In one embodiment, the present disclosure provides a method for preventing and / or treating a subject suffering from moderate to severe autoantibody-mediated AD, said method comprising administering one or more effective amounts 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 a method for preventing and / or treating a subject suffering from autoantibody-mediated AD, wherein said subject is resistant to other immunosuppressive drug treatments including corticosteroids or calcineurin inhibitors or B cell depletion therapy (e.g., by rituximab or any other anti-CD20 antibody or anti-BAFF antibody), said method comprising administering one or more effective amounts of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein for the treatment and / or prevention of said condition.

[0146] In one aspect, the present invention provides a method of using an anti-CD38 antibody or antibody fragment to achieve a prophylactic or therapeutic effect in a subject with an autoantibody-mediated autoimmune disease, preferably an autoantibody-mediated membranous nephropathy.

[0147] Another aspect 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, remitting, suppressing, alleviating autoantibody-mediated disease symptoms, and / or delaying the onset, occurrence, 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 a method for treating a patient exhibiting an elevated level of one or more autoantibody specificities associated with an autoimmune disease.

[0150] In other aspects, the present disclosure provides methods for the treatment and / or prevention of SLE caused by the presence of antinuclear or anti-DNA autoantibodies or any other SLE autoantibodies such as those listed in FIG. 12.

[0151] In still other aspects, the present invention provides methods for the treatment and / or prevention of SLE associated with the presence of antinuclear or anti-DNA autoantibodies or any other SLE autoantibodies such as those listed in FIG. 12.

[0152] In other aspects, 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 still other aspects, 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 other aspects, the present disclosure provides methods for treating and / or preventing diseases caused by the presence of anti-thrombospondin type 1 domain-containing 7A autoantibodies. In yet other aspects, the present invention provides methods for treating and / or preventing 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 the autoantibody titer in the serum of a subject suffering from an antibody-mediated autoimmune disease, the method comprising administering one or more effective amounts 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 the autoantibody titer in the serum of a subject suffering from idiopathic membranous glomerulonephritis, the method comprising administering one or more effective amounts of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein. For example, the methods provided herein include 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 the autoantibody titer 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 administering one or more of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein.

[0157] In another embodiment, the present disclosure provides a method for treating and / or preventing proteinuria associated with anti-PLA2R positive membranous glomerulonephritis in an individual, the method comprising administering one or more effective amounts of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition described herein.

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

[0159] In another aspect, the present disclosure provides a method for treating and / or preventing hypercholesterolemia (hypercholesterol) in an individual with membranous nephropathy, the method comprising administering one or more effective amounts of an antibody or antibody fragment specific for CD38 or a pharmaceutical composition 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 the 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 induces depletion of such CD38-expressing cells.

[0162] In a preferred 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 antibody-secreting cells and induces depletion of such CD38-expressing antibody-secreting cells while sparing other (antibody non-secreting) cells with low CD38 expression such as NK cells.

[0163] In a particular preferred 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 antibody-secreting cells and induces depletion of such CD38-expressing antibody-secreting cells, i.e., exhibits significantly higher specific cell killing in antibody-secreting cells than in NK cells, while sparing NK cells.

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

[0165] The antibody or antibody fragment 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 reducing side effects.

[0166] In certain embodiments, 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] Co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen, as will be apparent to those skilled in the art. While two or more agents can be co-administered in a single formulation, i.e., as a single pharmaceutical composition, this is not essential. The agents can be administered at different times in different formulations.

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

[0169] The therapeutic agents (e.g., prophylactic or therapeutic agents) of the combination therapy of the present disclosure can also be administered periodically. Cyclic therapy includes administration of a first therapeutic agent (e.g., a first prophylactic or therapeutic agent) over a period of time, followed by administration of a second therapeutic agent (e.g., a second prophylactic or therapeutic agent) over a period of time and repetition of this sequential administration, i.e., a cycle, to reduce the development of resistance to one of the therapeutic agents (e.g., drugs), to avoid or reduce one side effect 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 therapy of the present disclosure can be administered to a subject simultaneously. The term "simultaneously" is not limited to administration of the therapeutic agents (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather means that a pharmaceutical composition comprising an antibody or antibody fragment of the present disclosure is administered to the subject sequentially within a time interval such that the antibody of the present disclosure can act together with other therapeutic agents to improve the benefit as compared to when they are administered separately.

[0171] antibody In certain embodiments of the present disclosure, the antibody or antibody fragment specific for CD38 according to the present disclosure comprises a variable heavy chain variable region, a variable light chain region, a heavy chain, a light chain, and / or a CDR comprising any of the amino acid sequences of CD38-specific antibodies as shown in WO 2007 / 042309 pamphlet.

[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 the HCDR1 region of SEQ ID NO: 1, the HCDR2 region of SEQ ID NO: 2, the HCDR3 region of SEQ ID NO: 3, the LCDR1 region of SEQ ID NO: 4, the LCDR2 region of SEQ ID NO: 5, and the LCDR3 region of SEQ ID NO: 6.

[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 the variable heavy chain region of SEQ ID NO: 7 and the variable light chain region of SEQ ID NO: 8, or a variable heavy chain region and a variable light chain region having at least 60%, at least 70%, at least 80%, at least 90% or at least 95% identity 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 the variable heavy chain region containing the amino acid sequence of SEQ ID NO: 7 and the variable light chain region containing 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 a plurality of nucleic acid sequences encoding the antibody or antibody fragment specific for CD38, wherein the antibody or antibody fragment comprises the HCDR1 region of SEQ ID NO: 1, the HCDR2 region of SEQ ID NO: 2, the HCDR3 region of SEQ ID NO: 3, the LCDR1 region of SEQ ID NO: 4, the LCDR2 region of SEQ ID NO: 5, and the LCDR3 region of SEQ ID NO: 6.

[0178] In another embodiment, the present disclosure refers to a nucleic acid encoding an isolated monoclonal antibody or a fragment thereof, wherein the nucleic acid comprises VH of SEQ ID NO: 10 and 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 antibody or antibody fragment specific for CD38 is a human, humanized or chimeric antibody.

[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 IgG1.

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

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

[0190] In one embodiment, the present disclosure refers to a pharmaceutical composition comprising MOR202 or fragments 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 certain embodiments, the antibody or antibody fragment specific for CD38 is an antibody or antibody fragment that specifically binds to human CD38.

[0193] In certain embodiments, the antibody or antibody fragment specific for CD38 is an isolated monoclonal antibody or antibody fragment that specifically binds to human CD38.

[0194] In another embodiment, the present disclosure provides an antibody or antibody fragment specific for CD38, which depletes 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 subjects 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 subjects with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

[0197] In certain aspects, the present disclosure provides a prophylactic and / or therapeutic agent for reducing serum anti-PLA2R autoantibody levels in subjects with aMN, said agent 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 autoantibodies that accumulate in the kidneys of subjects 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 subjects 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 subjects 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, remitting, or normalizing kidney function, as indicated by the glomerular filtration rate (eGFR), based on the CKD-epi formula in subjects with aMN, said agent comprising an anti-CD38 antibody as an active ingredient.

Examples

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

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

[0204] 1.1. Test design The following bioanalytical evaluation was part of an open-label, multi-site, dose-escalating clinical trial to investigate the safety and preliminary efficacy characteristics of the human anti-CD38 antibody MOR03087 in adult subjects with relapsed / refractory multiple myeloma. The purpose of this experiment was a quantitative measurement of anti-tetanus toxoid (anti-TT) IgG antibody titers in human serum samples obtained during the trial to demonstrate that the monoclonal anti-CD38 antibody (MOR03087 = MOR202) is effective in reducing 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 Analysis up to -75 ± 15 °C, the serum samples were stored. For the measurement of anti-tetanus toxoid IgG in the samples, a commercially available immunoassay kit (VaccZyme™, binding site, product code MK010) was used. Before sample analysis, the quality of the assay was examined at the bioanalytical test site 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), 1.27 / 0.28 IU / mL (batch 5). During the validation experiment, according to the results of the validation experiment, three additional concentration levels were evaluated: ULOQ (7 IU / mL), LLOQ (0.01 IU / mL), 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 using the ready-to-use kit. One set of calibration standards consisted of 0.01, 0.03, 0.09, 0.26, 0.78, 2.33, 7 IU / mL.

[0206] 1.2.1. Measurement performance As provided in the assay kit, together with one set of calibration standard samples and two sets of QC samples, the samples were analyzed in duplicate during the experiment (one experiment = one 96-well plate). For the performance of anti-TT IgG ELISA, no sample treatment was required. The samples were measured after dilution with the sample diluent (minimum required dilution 1:101).

[0207] 1.2.2. Principle of the test The VaccZyme (trademark) anti-tetanus toxoid IgG enzyme immunoassay kit is a two-step enzyme-linked immunosorbent assay. The wells separated into 12 strips of 8 wells were coated with tetanus toxoid from Clostridium tetani. Standard substances, controls, and diluted serum samples were added to the wells, and antibodies that recognize the tetanus toxoid antigen bind during the first incubation. After washing the wells to remove all unbound proteins, a purified peroxidase-labeled rabbit anti-human IgG (gamma chain specific) complex is added. The complex binds to the captured human antibody, and an additional washing step removes the excess unbound complex. The bound complex is visualized using the 3,3’,5,5’-tetramethylbenzidine (TMB) substrate that gives a blue reaction product, the intensity of which is proportional to the antibody concentration in the sample. Phosphoric acid is added to each well to stop the reaction. This produces a yellow endpoint color, which is read at 450 nm.

[0208] 1.2.3. Data evaluation Using 4-parameter logistic, data organization of the output from the microplate reader was performed using Magellan (trademark) software version 6.6 from TECAN Austria GmbH. The optical densities of the quality controls and test samples were converted to concentrations (IU / mL) using the standard curve. Extrapolation was performed (extrapolation factor 1.1) to enable calculation of concentrations close to the upper and lower limits of quantification. All measured and calculated concentration data were reported with three significant figures.

[0209] 1.2.4. Results Human serum samples were analyzed in 22 assay runs. Accuracy and precision data between assays were evaluated from the calibration reference samples in the 22 approved assay runs. Accuracy (expressed as bias) and precision (coefficient of variation; expressed as CV) data are shown in Table 2.

[0210]

Table 4

[0211] Accuracy and precision data between assays were evaluated from up to 22 sets of QC samples during 22 approved 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) of serum samples from 74 subjects for whom at least one of the baseline and "Cycle, Day 15" or "Cycle 2, Day 15" data points was available are shown in Table 4. Since these co-medication factors lead to biased results, subjects who received co-medication during the clinical trial (such as IVIG administration or booster vaccination) were not included in the analysis.

[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 at day 0 (before MOR202 treatment, shown as "baseline" in Table 4), day 15 (cycle 1), and day 43 (= cycle 2, day 15) after MOR202 administration were analyzed. At day 15 of cycle 1, after MOR202 treatment, most subjects showed a significant decrease in anti-TT antibody titers compared to the baseline at day 0. The % change in anti-TT concentration of the "baseline" sample obtained at day 0 is shown in Figure 5 compared to the sample obtained at day 15 of cycle 1 (shown as "cycle 1, day 15"). The % change in anti-TT concentration of the "baseline" sample obtained at day 0 is shown in Figure 6 compared to the sample obtained at day 15 of cycle 2 (shown as "cycle 2, day 15"). In many of the MOR202-treated subjects, the anti-TT antibody titers further decreased (i.e., 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] In summary, these data clearly show that MOR202 is effective in reducing serum antibody titers. Therefore, effective treatment and / or prevention of autoimmune-mediated AD using anti-CD38 antibodies (such as MOR202) is highly plausible.

[0222] Example 2: Determination of M-protein levels 2.1. Test design Capillary electrophoresis (CE) assays, particularly serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP), were used to quantitatively determine the M-protein levels in serum samples of multiple myeloma patients (enrolled in the study of Example 1).

[0223] 2.2. Principle of capillary electrophoresis - test Charged molecules are separated by their electrophoretic migration at specific pH values in an alkaline buffer. Separation occurs according to the electrolyte pH and electroosmotic flow. Dilute each sample in a dilution buffer and fill the capillary with the separation buffer; then inject the sample by suction to the anode end of the capillary. After that, perform high-pressure protein separation. Subsequently, at the anode end of the capillary, directly detect and quantify different protein fractions at specific wavelengths.

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

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

[0226] The effect of MOR202 on the decrease of 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 decrease of M-protein after MOR202 administration (Figures 7-9) provides further evidence that MOR202 is effective in the decrease of antibody titer.

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

[0228] 3.2 Results The results [%] of specific cell death against MOR202, daratumumab, and isatuximab in NCI-929 and NK cells are shown in Figure 10.

[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 purpose of this study was 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] The administration of MOR202 is based on the results of the clinical trial of Example 1 and the PK / PD modeling approach in multiple myeloma (MM). Therefore, MOR202 was administered in a dose escalation scheme of 0.1 - 16 mg / kg i.v. once a week (QW) or every two weeks (Q2W), including the loading dose on Day 4 of Cycle 1. MOR202 was applied either as a single agent (monotherapy) or in combination with any of DEX, POM / DEX, or LEN / DEX. The overall treatment duration was based on the clinical response in continuous treatment for up to 3 years or less. Based on this result, a population-based PK / PD model was established considering the different target expression rates between MM subjects and aMN subjects. Using this model, drug exposure as expected in this trial was mimicked (i.e., administered at 16 mg / kg: 4xQW, followed by 5xQ4W), and considering the same treatment period, this result was compared with the data of the trial in Example 1. In the trial of Example 1 at 16 mg / kg QW, including the loading dose on Day 4, 6 patients were administered for at least 24 weeks. This should result in 2.4-fold excess in MOR202 exposure compared to the predicted dose and administration regimen in the current trial at a similar maximum serum concentration. The purpose of the clinical trial is to evaluate the safety and efficacy of the human anti-CD38 antibody MOR202 in patients with anti-PLA2R positive membranous nephropathy (aMN) who are either naive to immunosuppressive therapy or who did not respond to immunosuppressive therapy (IST) including rituximab (anti-CD20) therapy.

[0231] Example 5: M-PLACE: A Phase Ib / IIa Multi-center Open-label Trial for the Treatment of Two Cohorts of aMN Patients with MOR202 (NCT04145440) A Phase Ib / IIa open-label multi-center joint clinical trial has been initiated to evaluate the safety and efficacy of the human anti-CD38 antibody MOR202 in anti-PLA2R antibody-positive membranous nephropathy (aMN) with an estimated enrollment of 30 participants, and recruitment is ongoing at at least 14 sites in 6 locations in the United States and Europe. ClinicalTrials.gov identifier (NCT number): NCT04145440.

[0232] 5.1. Trial Design The purpose of this trial is 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 rationale for the main treatment is the reduction of disease-specific anti-PLA2R antibodies in membranous nephropathy (MN) through targeted depletion of autoantibody-producing plasma cells by the anti-CD38 antibody MOR202.

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

[0235] Important inclusion criteria: · Urine protein / creatinine ratio ≥ 3.0 g / g (when measured from 24-hour urine collection) · In kidney biopsy obtained within the last 6 months before the start of screening, estimated glomerular filtration rate ≥ 50 mL / min / 1.73m 2 or > 30 and < 50 mL / min / 1.73m 2 and interstitial fibrosis and tubular atrophy score < 25%. · In supportive treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker for at least 4 weeks before screening, a stable dose has been reached. · Systolic BP ≤ 150 mmHg and diastolic BP ≤ 100 mmHg · Vaccinated against pneumococcus within the last 3 years before the date of signing the informed consent (subjects may be vaccinated during screening to meet this criterion; the interval until the first dose of MOR202 must be at least 14 days). · Cohort 1a (newly diagnosed patients): Serum anti-PLA2R antibody ≥ 150.0 response units (RU) / mL measured by Euroimmun ELISA screening. · Cohort 1b, recurrence target: Complete immunological and / or clinical remission must have occurred according to the doctor's judgment, and serum anti-PLA2R antibody ≥ 50.0 RU / mL as measured by Euroimmun ELISA screening. · Cohort 2: Failure of previous treatment, i.e., the subject did not achieve complete immunological and / or clinical remission according to the doctor's judgment during or after the recognized IST containing cyclosporine A, tacrolimus, mycophenolate mofetil, ACTH or alkylating agent (e.g., cyclophosphamide) or rituximab. Serum anti-PLA2R antibody ≥ 20.0 RU / mL as measured by Euroimmun ELISA screening.

[0236] Important inclusion criteria: · Hemoglobin < 90 g / L · Thrombocytopenia: Platelets < 100.0 x 10 9 / L · Neutropenia: Neutrophils < 1.5 x 10 9 / L · Leukopenia: White blood cells < 3.0 x 10 9 / L · Hypogammaglobulinemia: Serum immunoglobulin ≤ 5.0 g / L · Secondary causes of MN (e.g., systemic lupus erythematosus, drug therapy, malignant tumor) · Concurrent kidney diseases other than MN (e.g., diabetic kidney disease, lupus nephritis, IgA nephropathy).

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

[0238] Cohort 2 includes approximately 10 aMN patients who did not respond immunologically to their last pre-treatment line and thus require second or third line IST, which is considered refractory. Failure of pre-treatment, i.e., the subject did not achieve a decrease in serum anti-PLA2R antibody titer 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 treatment initiation.

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

[0240] Monotherapy with MOR202 for both cohorts is over 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 must be stored at 2 - 8°C until use. For drug preparation, each vial must be reconstituted with 4.8 mL of water for injection (WFI). After reconstitution, each vial contains 325 mg of MOR202 (MOR03087) in a 5 mL extractable volume (65 mg / mL). For infusion, it is diluted in 250 mL of 0.9% sodium chloride solution.

[0242] The entire subject population is treated over 24 weeks in 6 cycles of 28-day treatment cycles. Overall, nine doses of MOR202 are administered on the following treatment days: Cycle 1, Days 1, 8, 15, and 22 and Day 1 of Cycles 2-6 (Figure 11). In the first treatment cycle, MOR202 is administered once weekly at 16 mg / kg (i.e., a total of 4 doses for Cycle 1). In treatment Cycles 2-6, MOR202 is administered once every 4 weeks at 16 mg / kg on the first day of each cycle (i.e., C2D1, C3D1, ···; a total of 5 doses over Cycles 2-6).

[0243] The first MOR202 i.v. infusion is slow (approximately 90 minutes at about 3 mL / min). If no acute infusion reaction occurs, the infusion time can be shortened to 1 hour or subsequent infusions can be shortened, but only to the shortening steps outlined in Table 5. The infusion time should not be shorter than 30 minutes. Premedication of the subject with antihistamines and antipyretics (e.g., paracetamol / acetaminophen) for the prevention of infusion-related reactions (IRR) is recommended. As outlined in Table 5, for the first 3 applications, co-medication with i.v. dexamethasone (or an equivalent glucocorticoid administered i.v.) approximately 30 minutes before the start of the MOR202 infusion is essential for the prevention of IRR.

[0244]

Table 12

[0245] 5.3. Evaluation of Safety, Immunogenicity, and Pharmacokinetics Safety is evaluated in terms of physical examination, vital signs, oxygen saturation, electrocardiogram, hematological and biochemical tests, adverse events, and immunogenicity. Adverse events are classified according to the NCI CTCAE, version 4.03. To monitor immunogenicity and pharmacokinetics, the presence of anti-MOR202 antibodies (anti-drug antibodies) and the serum concentration of MOR202 are evaluated at selected time points during a series of tests, respectively.

[0246] 5.4. Efficacy Evaluation The main efficacy evaluations include the following: (i) Serum anti-PLA2R antibody levels measured by ELISA to track a series of immune responses before, during, and after MOR202 treatment. (ii) Proteinuria based on UPCR from 24h 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 formula. (iv) Urinary sodium excretion determined from 24h urine.

[0247] 5.5. Biomarkers The presence and titer of anti-PLA2R antibody (i.e., the kinetics of anti-PLA2R antibody titer) at selected time points are measured for all subjects during a series of tests. 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 evaluated by ELISA. Quantitative NK cells, B cells, T cells (including regulatory T cells), plasmablasts, and plasma cell numbers at selected time points can be determined by peripheral blood flow cytometry or ELISPOT assay.

[0248] 5.6. KDQOL-36 The Kidney Disease Quality of Life (KDQOL-36™) survey is used for the evaluation of quality of life (QoL) defined as the score change from baseline in patients with autoimmune membranous nephropathy treated with MOR202.

[0249] Example 6: Determination of anti-PLA2R antibody levels Quantitatively measure the anti-phospholipase A2 receptor (PLA2R) antibody levels in human serum samples by a one-specificity ELISA (single antigen, enzyme immunoassay with Euroimmune, Order No. EA1254-G) according to the manufacturing instructions. Briefly, use a polystyrene microplate strip coated with purified PLA2R antigen as the solid phase. Prepare a 1:101 serum dilution and incubate it on the antigen bound to the wells of the microplate. If the sample is positive, the specific antibodies in the diluted serum sample will bind to the PLA2R antigen coupled to the solid phase. Wash away the unbound antibodies and, in a further step, detect the bound anti-PLA2R specific antibodies with peroxidase-labeled anti-human IgG. The bound antibodies are 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. A composition for use in the treatment of anti-M-type phospholipase A2 receptor (anti-PLA2R) and / or anti-thrombospondin type 1 domain-containing 7A (anti-THSD7A) positive membranous nephropathy, comprising an antibody or antibody fragment specific for CD38, wherein the antibody comprises 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.

2. The composition according to claim 1, for use in the treatment of anti-PLA2R positive membranous nephropathy.

3. The composition according to claim 1, for use in the treatment of anti-THSD7A positive membranous nephropathy.

4. The composition according to any one of claims 1 to 3, wherein the antibody or antibody fragment depletes plasma cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cell phagocytosis (ADCP).

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

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

7. The composition according to any one of claims 1 to 6, wherein administration of the antibody or antibody fragment to a subject leads to a decrease in the titer of endogenous autoantibodies in the subject.

8. The composition according to claim 7, wherein the endogenous autoantibody titer comprises anti-PLA2R and / or anti-THSD7A autoantibodies.

9. The composition according to claim 7, wherein the endogenous autoantibody titer comprises anti-PLA2R autoantibodies.

10. The composition according to claim 7, wherein the endogenous autoantibody titer comprises anti-THSD7A autoantibodies.

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

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

13. The composition according to any one of claims 1 to 12, 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. The composition according to claim 2, wherein the antibody is MOR202.

15. The composition according to any one of claims 1 to 14, which is administered in combination with a further therapeutic agent.

16. The composition according to claim 15, wherein the further therapeutic agent is a drug for the prevention and / or treatment of an autoimmune disease mediated by autoantibodies.

17. The composition according to claim 15, wherein the further therapeutic agent is an immunosuppressive drug or a proteasome inhibitor.

18. The composition according to claim 17, wherein the immunosuppressive drug is dexamethasone, azathioprine, mycophenolic acid, or methotrexate.

19. The composition according to claim 17, wherein the proteasome inhibitor is bortezomib.

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

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

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