CN116635422A - Anti-CD38 antibody and use thereof - Google Patents

Abstract

The present invention relates to the use of anti-CD 38 antibodies or antibody fragments for the prevention and/or treatment of diseases directly caused by immune complex deposition. According to the present invention, anti-CD 38 antibodies are effective in treating IgA nephropathy (IgAN).

Description

Anti-CD38 antibodies and uses thereof

Technical Field

The present invention relates to a CD38-specific antibody or antibody fragment for use in treating and/or preventing diseases caused by immune complex (IC) deposition. In particular, the present invention provides a method for reducing IC by (i) depleting immunoglobulin-secreting cells and/or (ii) depleting antibody-secreting cells using an anti-CD38 agent, wherein the antibodies secreted by these cells are directed against immunoglobulins. According to the present invention, anti-CD38 antibodies alone or in combination with one or more immunosuppressive drugs can effectively treat and/or prevent IgA nephropathy (IgAN) and lupus nephritis (LN). The anti-CD38 antibodies used according to the present invention include, but are not limited to, MOR202 (Fezetuzumab).

Background Art

Immune complex-mediated diseases

Immune complexes (ICs) are often the causative agent of certain diseases. It is well known that ICs formed between circulating antigens (e.g., antibodies) and bivalent antibodies are the major pathogenic mechanism leading to glomerular and vascular lesions, such as in glomerulonephritis and arteritis. Tissue damage caused by ICs is usually mediated by activation of the complement system, production of chemokines, and/or attraction of immune cells. The term "immune complex-mediated disease" is widely used to refer to diseases in which circulating ICs are thought to play a dominant role. Although most IC-mediated diseases are caused by deposition of complexes from the circulation, complexes formed locally in tissues can also produce damage. Disease-causing ICs can contain antibodies that bind to self-antigens or foreign antigens. The pathological features of IC-mediated diseases reflect the site of IC deposition and are not determined by the cellular source of the antigen. Therefore, IC-mediated diseases often affect multiple organs, although some organs are particularly susceptible, such as the kidneys and joints. The term "immune complex-mediated disease" implies that ICs are the primary mediators of damage. However, circulating complexes may also be present in other diseases where the pathogenic mechanism is more important, and in some cases, these complexes do not seem to be of much significance. Importantly, IC-mediated damage as used herein refers only to situations in which the complex is formed at an extracellular site, in the circulation, or locally within a tissue. This definition does not include damage caused by antibodies that bind to cell surface antigens, which is typically a type II immune response. For example, diseases caused by autoantibodies to the basement membrane (e.g., anti-glomerular basement membrane disease, anti-PLAR membranous glomerulonephritis) are not classified as IC-mediated diseases herein. The present disclosure relates to circulating ICs in a type III immune response. Typically, large ICs aggregate, or insoluble ICs are cleared by the mononuclear phagocyte system in the liver and spleen, but small soluble ICs tend to be deposited in tissues. IC deposition is affected by systemic factors, the physicochemical properties of ICs, and tissue-specific hemodynamics, and may be triggered by changes in vascular permeability induced by cytokines and/or lipid mediators. Many times, circulating ICs are first located within blood vessels and then translocated to extravascular tissues.

Depletion of anti-CD20-resistant B cells

B cell depletion with the anti-CD20 antibody rituximab (RTX) is widely used to treat autoimmune diseases, including IC-mediated diseases. However, the proportion of patients who achieve long-term remission after anti-CD20 antibody treatment varies greatly depending on the disease and clinical context, and many patients frequently relapse after anti-CD20 B cell depletion therapy (Lafayette RA et al. (2017) J Am Soc Nephrol.; 28(4): 1306-1313).

Three scenarios could explain these relapses: (i) new tolerance breakdown could recruit newly formed naive B cells into the autoimmune repertoire; (ii) autoreactive memory B cells resistant to RTX could be reactivated; and (iii) long-lived antibody-secreting plasma cells could lead to the survival of immune complexes in their niche.

The present disclosure provides improved options for treating and/or preventing IC-mediated diseases, particularly IgA nephropathy and lupus nephritis.

IgA nephropathy

IgA nephropathy (IgAN), also known as Berger's disease, is the most prevalent chronic glomerular disease worldwide. The name of the disease derives from the deposition of immunoglobulin A (IgA) in the glomerular mesangium. Subclass IgA1 is one of the two immunoglobulin types (the other is IgD) that is O-glycosylated on some serine and threonine residues in the proline-rich hinge region. Abnormal glycosylation of IgA1 appears to lead to aggregation of IgA1 molecules in certain tissues, especially the glomerular mesangium. In IgAN, the trigger and site of production of galactose-deficient IgA1 (Gd-IgA1) are unclear. Plasma cells, including long-lived plasma cells, may be the main source of antibodies corresponding to Gd-IgA1. A central finding in patients with IgAN is the presence of circulating and glomerular ICs containing Gd-IgA1 and autoantibodies (mainly IgG) against hinge region O-glycans and C3. These ICs are of nephrogenic origin and contribute to glomerular inflammation and mesangial proliferation. Ultimately, activation of the renin angiotensin system (RAS) and complement system promotes glomerular sclerosis and tubulointerstitial fibrosis, leading to loss of renal function. Approximately 25–30% of IgAN patients progress to end-stage renal disease (ESRD) within 20–25 years of onset (KDIGO Clinical Practice Guideline on Glomerular Diseases, 2020). The main risk factors for progression to ESRD are persistent proteinuria, hypertension, and decreased glomerular filtration rate (GFR) (Fellstroem BC et al. (2017) Lancet; 389(10084):2117-2127).

Treatment of IgAN focuses on non-immunosuppressive strategies as the standard of care to slow the rate of disease progression: blood pressure control, RAS inhibition, and lifestyle changes (i.e., weight loss, exercise, smoking cessation, and dietary sodium restriction, among others). Multiple studies have demonstrated that persistent proteinuria is the most powerful predictor of long-term renal outcomes, and that reductions in proteinuria are associated with improved renal outcomes regardless of the nature of the intervention, thus establishing proteinuria reduction as a valid surrogate marker of improved renal outcomes in IgAN (Thompson A et al. (2019) Clin J Am Soc Nephrol; 14:469-481). The typical goal for proteinuria reduction in these trials was <1 g/day. Therefore, reduction of proteinuria to this level is a reasonable goal for intervention in IgAN patients who remain at high risk for progressive chronic kidney disease. For patients who have persistent proteinuria exceeding 1 g/day and a GFR greater than 50 mL/min per 1.73 ^m2 after 6 months of optimized RAS blockade, treatment with high-dose systemic corticosteroids for 6 months is recommended. However, the clinical benefit is uncertain, and the use of high-dose systemic corticosteroids is associated with an increased risk of adverse events and sequelae, such as serious infection, hypertension, weight gain, diabetes, and osteoporosis (Pozzi C (2016) J Nephrol. (1): 21-5). Systemic corticosteroids should be used with extreme caution or avoided altogether in patients with GFR less than 30 mL/min, diabetes, obesity, latent infection (e.g., viral hepatitis, tuberculosis), secondary disease (e.g., cirrhosis), active peptic ulcer, or uncontrolled psychiatric illness. Clinical trials of azathioprine, calcineurin inhibitors, and rituximab for the treatment of IgAN have not provided documented evidence of efficacy (Pozzi C (2016) J Nephrol. (1): 21-5; Rauen T et al. (2020) Kidney Int. 98 (4): 1044-1052). Mycophenolate mofetil (MMF) was reported to reduce proteinuria and stabilize GFR in Chinese patients (Tang et al. (2005) Kidney Int. 68:802–812.), but not in Caucasian patients (Frisch G et al (2005) Nephrol Dial Transplant; 20:2139–2145).

Although evidence of the efficacy of RTX in some glomerular diseases is promising, early results in IgAN are not encouraging. For example, in a randomized controlled trial of rituximab in IgAN with proteinuria and renal dysfunction (NCT00498368), treatment with RTX failed to significantly reduce proteinuria or benefit renal function (Lafayette RA et al. (2017) J Am Soc Nephrol.; 28(4): 1306-1313).

Therefore, there is a need for improved treatment options with a more favorable risk-benefit ratio and universal efficacy for patients with IgAN.

Lupus nephritis

Lupus nephritis (LN) is an inflammation of the kidney that occurs as a consequence of systemic lupus erythematosus (SLE) and occurs in 20%-60% of SLE patients. Histopathologically, LN is a glomerulonephritis with IC deposits due to the formation of autoantibodies against nuclear antigens. Further pathological changes may include glomerulointerstitial nephritis and vascular changes with IC deposits and microangiopathy in the vessels. LN can be divided into at least six categories based on disease severity. Class I disease (micro-mesangial glomerulonephritis) presents with normal clinical urinalysis and an unremarkable appearance under the microscope, but shows mesangial deposits when analyzed by electron microscopy. Class II disease (mesangial proliferative glomerulonephritis) is characterized by mesangial hypercellularity and matrix expansion. Hematuria may occur with or without proteinuria. Class III disease (focal glomerulonephritis) is characterized by sclerotic lesions involving less than 50% of the glomeruli, which may be segmental or global, with intracapillary or extracapillary proliferative lesions. Clinically, there is hematuria, proteinuria, hypertension, and elevated serum creatinine. Class IV disease (diffuse proliferative nephritis) is the most severe and most common subtype. More than 50% of the glomeruli are affected, either segmentally or globally, with intracapillary or extracapillary proliferative lesions. Clinically, hematuria and proteinuria occur, often accompanied by nephrotic syndrome, hypertension, hypocomplementemia, elevated anti-dsDNA antibody titers, and elevated serum creatinine. Class V disease (membranous glomerulonephritis) is characterized by diffuse thickening of the glomerular capillary walls. Clinically, stage V presents with signs of nephrotic syndrome. Stage V can also lead to thrombotic complications such as renal vein thrombosis or pulmonary embolism. Class VI or advanced sclerosing LN presents with systemic sclerosis involving more than 90% of the glomeruli. This stage is characterized by slowly progressive renal dysfunction.

Drug regimens prescribed for LN include cyclophosphamide plus corticosteroids, MMF, azathioprine plus corticosteroids, and tacrolimus. Regimens containing cyclophosphamide have a high incidence of adverse events, such as serious infections, alopecia, and infertility. In addition, the response to treatment is often slow, and even when remission is achieved, the risk of relapse remains considerable. MMF has emerged as a less toxic alternative to cyclophosphamide, and it appears that MMF and cyclophosphamide plus corticosteroids are equally effective in achieving disease remission. Lupus nephritis (LN) is often resistant to standard immunosuppressive therapy, and relapses are common after achieving clinical remission.

Overall, LN remains a serious disease condition, leading to end-stage renal disease in 15% of patients after 10 years. There is a great need for improved treatment options (eg, steroid sparing) for patients suffering from LN.

Summary of the invention

The present invention provides CD38 specific antibodies or antibody fragments, which are used to treat and/or prevent autoimmune diseases with immune complex deposition as the main pathological mechanism. In particular, anti-CD38 antibodies or antibody fragments are used to treat and/or prevent IgA nephropathy and/or lupus nephritis. Preferably, anti-CD38 antibodies or antibody fragments are used to treat and/or prevent IgA nephropathy.

In addition, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a CD38-specific antibody or antibody fragment for treating and/or preventing IgA nephropathy.

Felzartamab (MOR202) is a known monoclonal human anti-CD38 antibody that targets antibody-secreting cells, such as plasmablasts and plasma cells, primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). In clinical trials of MOR202, effective killing of neoplastic, neoplastic, malignant plasma cells (i.e., multiple myeloma cells) as well as benign plasma cells has been demonstrated. In patients with multiple myeloma (MM), depletion of plasma cells by MOR202 resulted in a significant reduction in M-protein. Compared to other anti-CD38 antibodies, MOR202 is expected to retain cells that express low CD38 (e.g., NK cells), thus providing the best safety profile.

The effect of MOR202 on plasma cells was demonstrated by assessing serum anti-tetanus toxoid (anti-TT) antibody titers as a marker of depletion of specific plasma cells. After MOR202 administration, serum anti-TT antibody levels were significantly reduced compared to the baseline before MOR202 administration (WO2020187718), indicating a direct effect of MOR202 treatment on specific antibody concentrations (Figure 1).

MOR202 administration also effectively reduced circulating and deposited ICs, primarily in the glomeruli of IgAN patients' kidneys, thereby improving renal function and health status in these patients.

DETAILED DESCRIPTION

Figure 1

Proof of mechanism is supported by a reduction in anti-tetanus toxoid titers, which is a surrogate marker for effects on plasma cells.

definition

The term "CD38" refers to the protein called CD38, with the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclo ADP-ribose hydrolase 1, T10. Human CD38 (UniProt P28907) has the following amino acid sequence:

MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSK IFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI(SEQ ID NO.:9)

CD38 is a type II transmembrane glycoprotein and is an example of an antigen that is highly expressed on antibody-secreting cells, including plasmablasts and plasma cells that secrete autoantibodies. Functions attributed to CD38 include receptor-mediated adhesion and signaling events and (exo)enzymatic activity. As an extracellular enzyme, CD38 uses NAD+ as a substrate to form cyclic ADP-ribose (cADPR) and ADPR, and can also form nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to be second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 regulates extracellular NAD+ concentrations by regulating NAD-induced cell death (NCID), thereby regulating cell survival. In addition to signaling through Ca2+, CD38 signaling occurs through cross-talk with antigen-receptor complexes on T and B cells or other types of receptor complexes (such as MHC molecules), and in this way participates in several cellular responses, and also participates in the conversion and secretion of IgG antibodies.

As used herein, the term "anti-CD38 antibody" includes anti-CD38 binding molecules in the broadest sense; including any molecule that specifically binds to CD38 or inhibits the activity or function of CD38, or a molecule that exerts a therapeutic effect on CD38 by any other means. Including any molecule that interferes with or inhibits the function of CD38. The term "anti-CD38 antibody" includes, but is not limited to, antibodies that specifically bind to CD38, optional protein scaffolds that bind to CD38, CD38-specific nucleic acids (including aptamers), or CD38-specific organic small molecules.

Antibodies specific for CD38 are described, for example, in WO199962526 (Mayo Foundation); WO200206347 (Crucell Holland); US2002164788 (Jonathan Ellis); WO2005103083, WO2006125640, WO2007042309 (MorphoSys), WO2006099875 (Genmab) and WO2008047242 (Sanofi-Aventis). For example, WO200040265 (Research Development Foundation); WO2006099875 and WO2008037257 (Genmab); and WO2010061360, WO2010061359, WO2010061358 and WO2010061357 (Sanofi Aventis) describe combinations of CD38-specific antibodies and other agents. CD38-targeting antibodies are widely used in multiple myeloma (reviewed in Frerichs KA et al. 2018, Expert Rev Clin Immunol; 14(3): 197-206). Further uses of anti-CD38 antibodies are described, for example, in WO2015130732, WO2016089960, WO2016210223 (Janssen), WO2018002181 (UMCUtrecht), WO2019020643 (ENCEFA) and WO2020187718 (MorphoSys), all of which are incorporated herein by reference in their entirety.

Preferably, the anti-CD38 antibody used herein is a specific antibody 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 specific CD38-positive B cells, plasma cells, plasmablasts, and any other CD38-positive antibody-secreting cells. Such antibodies can be of any type, such as mouse, rat, chimeric, humanized or human antibodies.

As used herein, "human antibodies" or "human antibody fragments" are antibodies or antibody fragments having variable regions in which the framework and CDR regions are derived from human sequences. If the antibody contains a constant region, the constant region is also derived from such a sequence. Human sources include, but are not limited to, human germline sequences, or mutant forms of human germline sequences, or antibodies containing a consensus framework sequence derived from human framework sequence analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296: 57-86). Human antibodies can be isolated, for example, from a synthetic library or a transgenic mouse (e.g., Xenomouse). If the sequence of an antibody or antibody fragment is human, then the antibody or antibody fragment is human, regardless of which species the antibody is physically derived, isolated or prepared from.

The structure and position of immunoglobulin variable domains, e.g., CDRs, can be defined using well-known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (see, e.g., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S. Department of Health 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.

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

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

The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments having different antigenic specificities. In addition, the isolated antibody or antibody fragment may be substantially free of other cellular material and/or chemical composition. Therefore, in some aspects, the antibody provided is an isolated antibody that has been separated from antibodies having different specificities. The isolated antibody may be a monoclonal antibody. The isolated antibody may be a recombinant monoclonal antibody. However, an isolated antibody specifically bound to an epitope, isotype or variant of a target may have cross-reactivity with other related antigens, for example, from its species (e.g., species homologs).

As used herein, the term "monoclonal antibody" refers to an antibody molecule preparation of single molecular composition. A monoclonal antibody composition displays a unique binding site and has a unique binding specificity and affinity for a specific epitope.

Furthermore, as used herein, "immunoglobulin" (Ig) is defined herein as a protein belonging to the IgG, IgM, IgE, IgA or IgD class (or any subclass thereof), including all conventionally known antibodies and functional fragments thereof.

As used herein, the phrase "antibody fragment" refers to one or more parts of an antibody that retain the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, stabilizing spatial distribution). Examples of binding fragments include, but are not limited to, Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab)2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bond in the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of an antibody; dAb fragments, which consist of a VH domain; and separated complementarity determining regions (CDRs). In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, using recombinant methods, they can be connected by synthetic linkers to make them a single protein chain, in which the VL and VH regions are paired to form monovalent molecules (referred to as "single-chain fragments (scFv)"). Such single-chain antibodies are encompassed within the term "antibody fragment". Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs and bis-scFvs. Antibody fragments can be transplanted into scaffolds based on polypeptides such as fibronectin type III (Fn3). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv fragments (VH-CH1-VH-CH1), forming a pair of antigen binding sites together with complementary light chain polypeptides).

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

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

"Preventing" or "prevention" refers to reducing the risk of acquiring or developing a disease or condition (i.e., preventing a subject who may be exposed to a disease-causing agent or who is predisposed to the disease before the disease develops from developing at least one clinical symptom of the disease). "Prevention" refers to methods intended to prevent the occurrence of a disease or its symptoms or to delay the occurrence of a disease or its symptoms.

"Administered" or "administration" includes, but is not limited to, delivering a drug by injection, e.g., intravenous, intramuscular, intradermal or subcutaneous routes, or by mucosal routes, e.g., as a nasal spray or inhaled aerosol or as an ingestible solution, capsule or tablet. Preferably, administration is by injection.

Co-administration includes any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen, which is obvious to the technician. Although two or more medicaments can be administered simultaneously in a single formulation, i.e., as a single pharmaceutical composition, this is not essential. The medicament can be administered with different formulations and different times. The therapy (e.g., preventive or therapeutic agent) of the combination therapy disclosed herein can be administered to the subject simultaneously or sequentially. The therapy (e.g., preventive or therapeutic agent) of the combination therapy disclosed herein can also be cyclically administered. Cyclic therapy includes administering a first therapy (e.g., a first preventive or therapeutic agent) for a period of time, then administering a second therapy (e.g., a second preventive or therapeutic agent) for a period of time, and repeating this sequential administration, i.e., circulation, so as to reduce the resistance development to one of the therapies (e.g., medicament), avoid or reduce the side effects of one of the therapies (e.g., medicament), and/or improve the efficacy of the therapy.

The therapies (e.g., preventive or therapeutic agents) of the combination therapy of the present disclosure can be administered to the subject simultaneously. The term "simultaneously" is not limited to administering the therapy (e.g., preventive or therapeutic agent) at exactly the same time, but means that the pharmaceutical composition comprising the antibody or antibody fragment of the present disclosure is administered to the subject in a certain order and time interval, so that the antibody of the present disclosure can act together with other therapies to provide more benefits than administration in other ways.

As used herein, "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 fascicularis), or humans (Homo sapiens). Preferably, the subject is a primate, most preferably a human.

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

As used herein, the term "immune complex-mediated disease" refers to a group of diseases characterized by immune complex deposition. For example, IC-mediated diseases can include type III (immune complex) hypersensitivity reactions, in which IgG or IgM antibodies develop against circulating antigens and often affect one or more tissues such as the skin, joints, blood vessels, or glomeruli of the kidney. Examples of immune complex (IC)-mediated diseases are shown in Table 1, but are not limited to the listed diseases.

Table 1. Examples of immune complex (IC) mediated diseases

As used herein, the term "about" when used to refer to a particular listed value means that the value may differ from the listed value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

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

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

Throughout the specification, unless the context requires otherwise, the words “comprise,” “have,” and “include” and their respective variations such as “comprises,” “comprising,” “has,” “having,” “includes” and “including” are understood to mean the inclusion of stated elements or integers or groups of elements or integers but not the exclusion of any other elements or integers or groups of elements or integers.

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

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

SYYMN (SEQ ID NO: 1)

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

GISGDPSNTYYADSVKG(SEQ ID NO:2)

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

DLPLVYTGFAY (SEQ ID NO: 3)

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

SGDNLRHYYVY (SEQ ID NO: 4)

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

GDSKRPS (SEQ ID NO:5)

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

The amino acid sequence of the variable heavy chain domain of MOR202 is:

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS(SEQ ID NO:7)

The amino acid sequence of the variable light chain domain of MOR202 is:

DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ(SEQ ID NO:8)

The DNA sequence encoding the variable heavy chain domain of MOR202 is:

CAGGTGCAATTGGTGGAAAGCGGCGGCGCCTGGTGCAACCGGGCGGCAGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGCCAAGCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACCTATTATGCGGATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCT GCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA (SEQ ID NO: 10).

The DNA sequence encoding the variable light chain domain of MOR202 is:

GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGGCGGATTATTATTG CCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGCGGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 11).

Implementation

Antibody

In certain embodiments of the present disclosure, the CD38-specific antibody or antibody fragment used according to the present disclosure comprises a variable heavy chain variable region, a variable light chain variable region, a heavy chain, a light chain and/or CDRs, comprising any amino acid sequence of a CD38-specific antibody as shown in WO2007042309.

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

In one embodiment, the CD38-specific antibody or antibody fragment for use according to the present disclosure comprises a HCDR1 region of SEQ ID NO: 1, a HCDR2 region of SEQ ID NO: 2, a HCDR3 region of SEQ ID NO: 3, a LCDR1 region of SEQ ID NO: 4, a LCDR2 region of SEQ ID NO: 5, and a LCDR3 region of SEQ ID NO: 6.

In one embodiment, the CD38-specific antibody or antibody fragment for use according to the present disclosure comprises a variable heavy chain region of SEQ ID NO:7 and a variable light chain region of SEQ ID NO:8.

In another embodiment, an anti-CD38 antibody or antibody fragment for use in accordance with the present disclosure comprises a variable heavy chain region of SEQ ID NO:7 and a variable light chain region of SEQ ID NO:8, or a variable heavy chain region and a variable light chain region that are at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identical to the variable heavy chain region of SEQ ID NO:7 and the variable light chain region of SEQ ID NO:8.

An exemplary antibody or antibody fragment for use in accordance with the present disclosure that contains a variable heavy chain region comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain region comprising the amino acid sequence of SEQ ID NO:8 is the human anti-CD38 antibody known as MOR202 (fizerizumab).

In one embodiment, the present disclosure relates to a nucleic acid composition comprising a nucleic acid sequence or multiple nucleic acid sequences encoding the CD38-specific antibody or antibody fragment for use according to the present disclosure, 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.

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

In one embodiment, the CD38-specific antibody or antibody fragment used according to the present disclosure is a monoclonal antibody or antibody fragment.

In one embodiment, the CD38-specific antibody or antibody fragment used according to the present disclosure is a human, humanized or chimeric antibody.

In certain embodiments, the CD38-specific antibodies or antibody fragments for use according to the present disclosure are isolated antibodies or antibody fragments.

In another embodiment, the antibody or antibody fragment for use according to the present disclosure is a recombinant antibody or antibody fragment.

In another embodiment, the antibody or antibody fragment for use according to the present disclosure is a recombinant human antibody or antibody fragment.

In another embodiment, the recombinant human antibody or antibody fragment for use according to the present disclosure is an isolated recombinant human antibody or antibody fragment.

In another embodiment, the recombinant human antibody or antibody fragment or the isolated recombinant human antibody or antibody fragment for use according to the present disclosure is monoclonal.

In one embodiment, the antibody or antibody fragment for use according to the present disclosure is of the IgG isotype. In a specific embodiment, the antibody is IgG1.

In a specific aspect of the invention, the anti-CD38 antibody for use according to the present disclosure is MOR202 (Fezotuzumab).

In one embodiment, the present disclosure relates to a pharmaceutical composition comprising CD38-specific fuzetuzumab (MOR202) or a fragment thereof and a pharmaceutically acceptable carrier or excipient for use according to the present disclosure.

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

Pharmaceutical composition

When used as a medicament, the CD38-specific antibody or antibody fragment is usually administered in a pharmaceutical composition. The composition of the present disclosure is preferably a pharmaceutical composition comprising Fizetumomab (MOR202) and a pharmaceutically acceptable carrier, diluent or excipient for the treatment of IgA nephropathy (IgAN) and/or lupus nephritis (LN).

The pharmaceutically acceptable carrier should be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (eg, by injection or infusion).

Pharmaceutical carriers enhance or stabilize the composition, or facilitate the preparation of the composition. Pharmaceutically acceptable carriers include physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols such as mannitol, sorbitol and sodium chloride.

The pharmaceutical compositions of the present disclosure can be administered by various routes known in the art. Selected routes of administration of the antibodies or antibody fragments of the present disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion.

The CD38-specific antibody or antibody fragment is preferably formulated as an injectable composition. In a preferred aspect, the anti-CD38 antibody of the present disclosure is administered intravenously. In other aspects, the anti-CD38 antibody of the present disclosure is administered subcutaneously, intraarticularly, or intraspinally.

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

Treatment

In one embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment, or a pharmaceutical composition comprising the anti-CD38 antibody or antibody fragment, for use in treating an immune complex-mediated disease in a subject.

In one embodiment, an anti-CD38 antibody or antibody fragment, or a pharmaceutical composition comprising the anti-CD38 antibody or antibody fragment is provided for use in treating immune complex-mediated renal diseases.

In one embodiment, the immune complex mediated disease is selected from IgA nephropathy, lupus nephritis, Henoch-Schwann syndrome, ) Purpura nephritis, poststreptococcal glomerulonephritis, or drug-induced immune complex-mediated diffuse proliferative glomerulonephritis.

In a specific embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment, or a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, for preventing and/or treating IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In another embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment, or a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, for preventing and/or treating galactose-deficient IgA1 antibody (Gd-IgA1) and anti-galactose-deficient IgA1 antibody (anti-GD-IgA1)-positive IgA nephropathy.

In a specific embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment comprising a HCDR1 region of SEQ ID NO: 1, a HCDR2 region of SEQ ID NO: 2, a HCDR3 region of SEQ ID NO: 3, a LCDR1 region of SEQ ID NO: 4, a LCDR2 region of SEQ ID NO: 5, and a LCDR3 region of SEQ ID NO: 6, for preventing and/or treating IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In another aspect, the present disclosure provides an anti-CD38 antibody or antibody fragment comprising a variable heavy chain region of SEQ ID NO: 7 and a variable light chain region of SEQ ID NO: 8 for use in preventing and/or treating IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In a specific aspect, the present disclosure provides MOR202 (fizertumab) for use in preventing and/or treating IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In one embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment for use in depleting antibody-secreting cells (preferably plasma cells) expressing CD38 in a subject suffering from IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In a preferred embodiment, the present disclosure provides an anti-CD38 antibody (eg, MOR202) for use in reducing circulating immune complexes and/or immune complex deposition in a subject suffering from IgAN.

In a specific embodiment, the present disclosure provides an anti-CD38 antibody (e.g., MOR202) for reducing serum Gd-IgA1 and anti-GD-IgA1 antibodies (i.e., ab titers) and/or immune complex levels in subjects with IgAN. On the other hand, the present disclosure provides an anti-CD38 antibody (e.g., MOR202) for reducing Gd-IgA1 and anti-GD-IgA1 immune complexes deposited in the kidneys of subjects with IgAN.

In another aspect, the present disclosure provides a therapeutic agent comprising an anti-CD38 antibody (eg, MOR 202) as an active ingredient for reducing proteinuria in a subject suffering from IgAN.

In some aspects, the proteinuria refers to proteinuria up to 6.0 g/day, preferably up to 5.0 g/day, more preferably up to 4.0 g/day (total protein based on 24-hour urine collection). In some aspects, the subject with IgAN has persistent proteinuria. In some embodiments, the persistent proteinuria is persistent proteinuria based on UPCR>1 mg/mg of 24-hour urine collection, or the persistent proteinuria is persistent proteinuria based on UPCR>0.75 mg/mg of 24-hour urine collection, wherein at least once within 12 months prior to administration or use of the anti-CD38 antibody (e.g., MOR 202), it has been determined that the subject with IgAN has UPCR>1 mg/mg based on 24-hour urine collection. In some embodiments, the proteinuria is characterized by a urine-protein creatinine ratio (UPCR) based on 24-hour urine collection of at least 0.75 mg/mg, preferably at least 1.0 mg/mg, more preferably at least 1.5 mg/mg, more preferably at least 2.0 mg/mg. In some embodiments, the proteinuria is characterized by a urine-protein-creatinine ratio (UPCR) of up to 6.0 mg/mg, preferably up to 5.0 mg/mg, more preferably up to 4.0 mg/mg based on a 24-hour urine collection.

Preferably, after administration or use of the anti-CD38 antibody, proteinuria is reduced to less than 1 g/day.

In another aspect, the present disclosure provides a preventive and/or therapeutic agent comprising an anti-CD38 antibody (eg, MOR202) for restoring, improving or normalizing renal function indicated by eGFR based on the CKD-epi equation in a subject with IgA nephropathy (IgAN).

In another aspect, the present disclosure provides an anti-CD38 antibody (eg, MOR 202) for use in treating IgAN and/or LN, wherein the anti-CD38 antibody (eg, MOR 202) is administered in at least 2 doses, at least 5 doses, or at least 9 doses based on the patient's body weight.

In another aspect, the present disclosure provides an anti-CD38 antibody (eg, MOR 202) for use in treating IgAN and/or LN, wherein the anti-CD38 antibody (eg, MOR 202) is administered in 2 doses, 5 doses, or 9 doses according to the patient's body weight.

In another aspect, the present disclosure provides use of an anti-CD38 antibody or antibody fragment in the preparation of a medicament for treating and/or preventing immune complex-mediated diseases, preferably IgA nephropathy (IgAN) and/or lupus nephritis (LN), more preferably Gd-IgA1 and anti-GD-IgA1 positive IgAN.

In other aspects, the present disclosure provides use of an anti-CD38 antibody or antibody fragment in the preparation of a medicament for treating and/or preventing IgA nephropathy (IgAN) and/or lupus nephritis (LN), wherein the anti-CD38 antibody or antibody fragment comprises a HCDR1 region of SEQ ID NO: 1, a HCDR2 region of SEQ ID NO: 2, a HCDR3 region of SEQ ID NO: 3, a LCDR1 region of SEQ ID NO: 4, a LCDR2 region of SEQ ID NO: 5, and a LCDR3 region of SEQ ID NO: 6.

In other aspects, the present disclosure provides use of an anti-CD38 antibody or antibody fragment comprising a variable heavy chain region of SEQ ID NO: 7 and a variable light chain region of SEQ ID NO: 8 in the preparation of a medicament for treating and/or preventing IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In another aspect, the present disclosure provides use of MOR202 (fizertumab) in the preparation of a medicament for treating and/or preventing IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In other aspects, the present disclosure provides use of MOR202 (fizetumomab) in the preparation of a method for treating and/or preventing Gd-IgA1 and GD-IgA1 positive IgA nephropathy (IgAN).

In other aspects, the present disclosure provides the use of MOR202 (fizertumab) or a pharmaceutical composition comprising MOR202 (fizertumab) in combination with another therapeutic agent in the preparation of a medicament for treating and/or preventing IgA nephropathy (IgAN) and/or lupus nephritis (LN).

In one aspect, the present disclosure provides a method of treating and/or preventing an immune complex-mediated disease, comprising administering an anti-CD38 antibody to the subject. In a specific embodiment, the immune complex-mediated disease is IgA nephropathy.

In another aspect, the present disclosure provides a method of treating and/or preventing Gd-IgA1 and anti-GD-IgA1 positive IgA nephropathy (IgAN) in a subject, the method comprising administering an anti-CD38 antibody to the subject.

In some embodiments, the present disclosure provides a method for preventing and/or treating a subject with Gd-IgA1 and anti-GD-IgA1 positive IgA nephropathy, wherein the subject is resistant to treatment with other immunosuppressive therapies, including corticosteroids or calcineurin inhibitors or B cell depletion therapy (e.g., with rituximab or any other anti-CD20 antibody, or anti-BAFF antibody), the method comprising administering an effective amount of an anti-CD38 antibody or antibody fragment.

In one aspect, the disclosure provides methods of using anti-CD38 antibodies or antibody fragments to achieve prophylactic or therapeutic benefit in patients suffering from IgA nephropathy, particularly Gd-IgA1 and anti-GD-IgA1 positive IgA nephropathy.

In another aspect, the present disclosure provides a method of using an anti-CD38 antibody to treat and/or prevent symptoms mediated by IgA nephropathy, particularly Gd-IgA1 and anti-GD-IgA1 positive IgA nephropathy.

In another aspect, the present disclosure provides a method for reducing the incidence of immune complex deposition-mediated disease symptoms, improving immune complex deposition-mediated disease symptoms, inhibiting immune complex deposition-mediated disease symptoms, alleviating immune complex deposition-mediated disease symptoms and/or delaying the onset, development or progression of immune complex deposition-mediated diseases in a subject, the method comprising administering an effective amount of an anti-CD38 antibody to the subject. In particular, the immune complex-mediated disease is IgA nephropathy.

In preferred embodiments, the present disclosure provides methods of treating a patient having elevated levels of one or more immune complex deposition associated with a disease mediated by immune complex deposition.

In other aspects, the present disclosure provides a method for treating and/or preventing diseases caused by the presence of Gd-IgA1 and anti-GD-IgA1 immune complexes. In other aspects, the present disclosure provides a method for treating and/or preventing diseases associated with the presence of Gd-IgA1 and anti-GD-IgA1 immune complex deposits. In other aspects, the present disclosure provides a method for treating and/or preventing diseases associated with the presence of DNA and/or nuclear components and anti-DNA antibodies and/or anti-nuclear antibodies (ANA) immune complex deposits.

In other embodiments, the disclosure provides methods of reducing immune complexes in serum and/or tissues of a subject suffering from an immune complex-mediated disease, the methods comprising administering an effective amount of an anti-CD38 antibody or antibody fragment.

In a preferred embodiment, the present disclosure provides a method for reducing immune complexes in the serum of patients with IgA nephropathy and/or lupus nephritis, the method comprising administering an effective amount of an anti-CD38 antibody or antibody fragment as described herein, or one or more pharmaceutical compositions. For example, the methods provided herein include administering anti-CD38 antibodies to patients with elevated levels of Gd-IgA1 and anti-GD-IgA1 antibodies and their immune complexes. In other aspects, the methods provided herein include administering anti-CD38 antibodies to patients with elevated levels of anti-nuclear antibodies (ANA) and their immune complexes.

In one embodiment, following administration of an anti-CD38 antibody or antibody fragment, or one or more pharmaceutical compositions described herein, immune complexes in the serum of a subject with IgA nephropathy and/or lupus nephritis are reduced (changed) by 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.

In another embodiment, the present disclosure provides a method for treating and/or preventing proteinuria associated with IgA nephropathy and/or lupus nephritis in a subject, the method comprising administering an effective amount of an anti-CD38 antibody or antibody fragment described herein, or one or more pharmaceutical compositions.

In another aspect, the disclosure provides a method of preventing decline in renal function in an individual with IgA nephropathy and/or lupus nephritis, the method comprising administering an effective amount of an anti-CD38 antibody or antibody fragment, or one or more pharmaceutical compositions described herein.

In other embodiments, the present disclosure relates to a method of treating IgA nephropathy and/or lupus nephritis in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to CD38 expressing cells and causes depletion of such CD38 expressing cells.

In a preferred embodiment, the present disclosure relates to a method for treating IgA nephropathy and/or lupus nephritis in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, which binds to antibody-secreting cells expressing CD38 and causes depletion of such antibody-secreting cells expressing CD38, while retaining other (non-antibody-secreting) cells with low CD38 expression, such as NK cells and the like.

In a particularly preferred embodiment, the present disclosure relates to a method for treating IgA nephropathy and/or lupus nephritis in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, which binds to antibody-secreting cells expressing CD38 and causes depletion of such antibody-secreting cells expressing CD38, wherein the antibody has significantly higher specific cell killing of antibody-secreting cells than NK cells.

In one embodiment, the present disclosure relates to a method of treating IgA nephropathy and/or lupus nephritis in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and causes depletion of antibody-secreting cells expressing CD38, wherein the specific cell killing of the antibody-secreting cells is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% as determined in a standard ADCC assay, and wherein the specific cell killing of antibody non-secreting NK cells is less than 30%, less than 25%, less than 20% or less than 15%.

Example

Example 1: Evaluation of the efficacy and safety of the human anti-CD38 antibody fuzetozumab (MOR202) in subjects with IgA nephropathy (IgAN)

1.1 Study design

The aim of this study was to evaluate the efficacy and safety of the human anti-CD38 antibody frezetuzumab (MOR202) in patients with IgA nephropathy (IgAN). Table 2 summarizes the study objectives and endpoints.

Table 2. Study objectives and endpoints

1.2 Study population

Inclusion criteria

1. Patients aged ≥18 to ≤80 years.

2. Biopsy-confirmed diagnosis of IgAN.

3. Proteinuria ≥1.0g/d at the screening visit.

4. Treatment with maximal or maximum tolerated dose of angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker for ≥3 months with adequate blood pressure (recommended <125 mm Hg systolic and <75 mm Hg diastolic).

5. Women are eligible to participate only if they are not pregnant, not breastfeeding, and agree to follow contraception instructions during treatment and for at least 3 months after the last dose of feztomaxetine.

Renal biopsies were performed according to institutional practice and analyzed according to the MEST-C score for IgAN (see Table 3).

Table 3. Pathological variables used in the MEST-C score for IgAN (Trimarchi et al. 2017).

Exclusion criteria

Patients were excluded from the study if they met any of the following criteria:

1. Secondary form of IgAN in the presence of any other systemic disease that may lead to IgA deposition (e.g., lupus nephritis, Hennoch-Schwann syndrome, -Henoch) purpura, ankylosing spondylitis, dermatitis herpetiformis, chronic liver disease, inflammatory bowel disease, celiac disease).

2. Severe renal impairment, defined as estimated GFR < 30 mL/min (using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) or the need for dialysis or kidney transplantation.

3. Rapidly progressive IgAN variant, defined as a loss in eGFR of more than 30% per 3 months that is not explained by changes in renin angiotensin system (RAS) blockade.

4.Minor variants of IgAN.

5. Accompanied by other progressive glomerulonephritis or non-immune glomerular diseases such as diabetic nephropathy.

6. Kidney transplant recipients.

7. Systemic immunosuppression (e.g., mycophenolate mofetil [MMF], cyclophosphamide, biologics such as rituximab [RTX]), especially corticosteroid therapy exceeding 20 mg/day of prednisone equivalents for more than 7 consecutive days.

8. Any previous treatment with anti-CD38 antibodies.

9. Body mass index (BMI)>35kg/ ^m2 .

10.Hemoglobin <70g/L (4.9mmol/L).

11. Thrombocytopenia: Platelets <100.0x10 ⁹ /L.

12. Neutropenia: Neutrophils <1.5x10 ⁹ /L.

13. Leukopenia: White blood cells <3.0x10 ⁹ /L.

14. Type 1 diabetes.

15. Type 2 diabetes: Patients with type 2 diabetes may enter clinical trials only if their renal biopsy shows IgAN without evidence of diabetic nephropathy and their disease is under control, e.g.

a. Glycated hemoglobin (HbA1c) <8.0% or <64mmoL/mol.

b. No known diabetic retinopathy.

c. No known peripheral neuropathy.

16. Significant uncontrolled cardiovascular disease (including arterial or venous thrombotic or embolic events) or cardiac insufficiency (New York Heart Association [NYHA] class IV).

17. Clinically relevant findings on the 12-lead electrocardiogram (ECG) determined by the investigator at screening.

18. Have a clear history of cerebrovascular disease or sensory or motor neuron viral disease ≥ grade 3.

19. Aspartate aminotransferase or alanine aminotransferase >1.5x ULN, alkaline phosphatase >3.0x ULN.

20. Known or suspected allergy to feztomax and its excipients (L-histidine, sucrose, polysorbate 20).

21. Positive serological or virological markers for HIV, hepatitis C (patients with positive anti-hepatitis C virus [anti-HCV] antibodies but negative HCV RNA-PCR can be included), or active or latent hepatitis B (patients with positive hepatitis B surface antigen [HBsAg] are excluded. For patients with isolated positive hepatitis B core antibody [anti-HBc], hepatitis B virus (HBV) DNA must be undetectable by PCR before they can be included).

22. Any malignancy within 5 years before the start of screening, except for adequately treated cervical carcinoma in situ, basal or squamous cell carcinoma, or other non-melanoma skin cancer.

23. Any active infection (viral, fungal, bacterial) requiring systemic treatment.

1.3 Dosage

According to Table 4, patients will receive 9 infusions of fezinomab or placebo on days 1, 8, 15, 22, 29, 57, 85, 113, and 141.

Table 4. Dosing Arms

Felizumab will be dosed based on patient weight (Table 5). The absolute dose for intravenous (i.v.) administration will be determined based on the following information:

Table 5. Dosage of Fizetumomab (MOR202) by body weight

Weight [kg] ≤50 >50 to 70 >70 to 90 >90 Fizetumomab dose [mg] 650 975 1300 1625 Number of vials of Fizetumomab 2 3 4 5

Each patient received 650 mg-1625 mg of feztomax per dose i.v., based on their individual body weight. The dosing in this trial was based on the results of the FIH trial in MM (MOR202C101) and a PK/PD modeling approach (Raab M Set al. (2020) Lancet Haematol. 7(5): e381-e394 2020). A fixed dosing concept was used to simplify the dosing procedure within the 4 specified weight ranges. As shown in Table 6, the 4 dose levels for the 4 weight ranges were selected to be similar to the 16 mg/kg dose (i.e., the recommended dose in the FIH study MOR202C101).

Table 6: Comparison of fixed-dose and weight-based dosing of feztomax

Patients will receive an infusion of either frezetuzumab in 0.9% saline or placebo (0.9% saline alone). Premedication will be performed 2 hours to 30 minutes before each infusion to reduce the risk of IRR:

Take acetaminophen (paracetamol) 650-1000 mg orally.

Diphenhydramine 25-50 mg orally or i.v. or equivalent.

Administer i.v. corticosteroids according to Table 7.

If no IRR occurs, the infusion rate can be increased and glucocorticoid premedication can be reduced according to Table 7. For patients who do not experience ≥ Grade 2 IRRs/≥ Grade 1 cytokine release syndrome to frezetuzumab/placebo in the first three cycles, premedication in subsequent infusions is optional. Otherwise, premedication should continue in subsequent doses.

Table 7. Felizumab/placebo infusion rates and i.v. corticosteroid premedication

1.4 Efficacy evaluation

The planned time points for all efficacy assessments are provided in Example 1.1, and the efficacy goals and endpoints are shown in Table 2.

Definitions of efficacy parameters are shown in Table 8.

Table 8. Efficacy parameters

Proteinuria and UPCR are determined from a 24-hour urine sample. If the urine collection does not contain at least 5 mg creatinine/kg/day for women and at least 6 mg creatinine/kg/day for men, the urine collection needs to be repeated without undue delay.

Example 2: Evaluation of the efficacy and safety of human anti-CD38 antibody fuzetumab (MOR202) in subjects with lupus nephritis (LN)

2.1 Study design

The aim of this study is to evaluate the efficacy and safety of the human anti-CD38 antibody fezentuzumab (MOR202) in patients with lupus nephritis (LN). Patients will be randomized to receive one of 3 different dosing schedules of fezentuzumab (dosing arms M1, M2, or M3) or placebo. All patients will receive background LN treatment throughout the trial, including mycophenolate mofetil (MMF)/mycophenolic acid (MPA) and hydroxychloroquine (if not contraindicated and available) as well as angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). If the patient is doing well, corticosteroids will be tapered to minimal or eliminated.

Table 9. Study objectives and endpoints

2.2 Study population

Inclusion criteria

1. Patients aged ≥18 and ≤80 years.

2. According to the current EULAR/ACR 2019 criteria, it is classified as SLE.

3. Class III or IV LN as demonstrated by renal biopsy performed within 12 months prior to or during the screening period according to the International Society of Nephrology/Society of Renal Pathology 2003 classification. Patients may simultaneously demonstrate class V disease in addition to class III or IV disease.

4. Proteinuria ≥0.75g/24h at the screening visit.

5. Treatment with maximal or maximum tolerated dose of angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) for ≥3 months with adequate blood pressure <130 mm Hg systolic and <80 mm Hg diastolic.

6. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m ² .

Exclusion criteria

Patients were excluded from the trial if they met any of the following criteria:

1. The presence of rapidly progressive glomerulonephritis, defined as (a) the presence of crescents in ≥50% of glomeruli assessed by renal biopsy, or (b) a sustained doubling of serum creatinine within 12 weeks of screening, or (c) the investigator's opinion that the patient has rapidly progressive glomerulonephritis.

2. Kidney transplant recipients.

3. More than 50% of the glomeruli are sclerotic on renal biopsy, and the interstitial fibrosis and tubular atrophy score (IFTA) is <65%.

4. Oral or parenteral therapy before the start of screening: (a) use of alkylating agents (e.g., cyclophosphamide) or calcineurin inhibitors (CNIs) (e.g., tacrolimus, cyclosporine A) within 90 days before signing of the ICF, or (b) use of biologic drugs, including rituximab (RTX), within 180 days, or (c) use of any other oral/parenteral IST other than MMF/MPA or hydroxychloroquine (or other chloroquine compounds) within 180 days, or (d) induction therapy with MMF/MPA plus corticosteroids started more than 42 days before signing of the ICF.

5. Any previous treatment with anti-CD38 antibodies.

6. Hemoglobin <70 g/L, unless it is autoimmune hemolytic anemia caused by SLE.

7. Thrombocytopenia: Platelets <50.0x10 ⁹ /L.

8. Unstable disease with thrombocytopenia, or high risk of developing clinically significant bleeding or organ dysfunction requiring treatment such as plasma exchange or acute blood or platelet transfusion.

9. Neutropenia: Neutrophils <1.5x10 ⁹ /L.

10. Leukopenia: White blood cells <2.5x10 ⁹ /L.

11. B-cells <5x10 ⁶ /L.

12. Type 1 or type 2 diabetes.

13. Patients with significant uncontrolled cardiovascular disease (including arterial or venous thrombosis or embolic events) or heart failure (New York Heart Association [NYHA] class IV) as judged by the investigator.

14. Clinically relevant findings on the 12-lead electrocardiogram (ECG) determined by the investigator at screening.

15. Have a clear history of cerebrovascular disease or sensory or motor neuron viral disease ≥ grade 3.

16. Aspartate aminotransferase or alanine aminotransferase >1.5x ULN, alkaline phosphatase >3.0x ULN.

17. Known or suspected allergy to Fizetuzumab and its excipients (L-histidine, sucrose, polysorbate 20).

18. Intolerance or contraindications to systemic corticosteroids, MMF or MPA.

19. Positive serological or virological markers for HIV, hepatitis C (patients with positive anti-hepatitis C virus [anti-HCV] antibodies but negative HCV RNA polymerase chain reaction results can be included), or active or latent hepatitis B (patients with positive hepatitis B surface antigen [HBsAg] are excluded. For patients with isolated positive hepatitis B core antibody [anti-HBc], hepatitis B virus (HBV) DNA must be undetectable by PCR before they can be included).

20. For any other pre-existing symptoms or impairment of health or any residual toxicity from previous treatment, classified as ≥ Grade 3 (NCI-CTCAE, see Appendix 4): These patients may be included upon confirmation by the medical supervisor.

21. Any malignancy within 5 years before the start of screening, except for adequately treated cervical carcinoma in situ, basal or squamous cell carcinoma, or other non-melanoma skin cancer.

23. Any active infection (viral, fungal, bacterial) requiring systemic treatment.

24. Significant or uncontrolled medical illness in any organ system not related to SLE or LN that, in the opinion of the investigator, will preclude the patient's participation.

25. Currently active retinitis caused by SLE, poorly controlled epilepsy, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia.

2.3 Dosage

According to Table 4, patients will receive 9 infusions of fezinomab or placebo on days 1, 8, 15, 22, 29, 57, 85, 113, and 141.

Felizumab will be dosed based on patient weight. The absolute dose for intravenous (i.v.) administration will be determined according to Table 5. Each patient will receive 650 mg-1625 mg of Felizumab per i.v. dose, based on their individual weight.

The dosing in this trial is based on the results of the FIH trial in MM (MOR202C101) and the PK/PD modeling approach (Raab MS et al. (2020) Lancet Haematol. 7(5): e381-e3942020). A fixed dosing concept was used to simplify the dosing procedure within the four specified weight ranges. As shown in Table 6, the four dose levels in the four weight ranges were selected to be similar to the 16 mg/kg dose (i.e., the recommended dose in the FIH study MOR202C101).

Patients were treated with investigational medication (IMP) fezetuzumab/placebo (IMP) and background therapy for LN. IMP should be administered in the setting of possible resuscitation. The following medications should be administered 60-30 minutes prior to each infusion to reduce the risk of infusion-related reactions (IRRs):

- Oral acetaminophen (paracetamol) 650-1000 mg.

- Oral or i.v. diphenhydramine 25-50 mg or equivalent.

- Administer i.v. glucocorticoids according to Table 7.

If no IRR occurs, the infusion rate can be increased and glucocorticoid premedication can be reduced according to Table 7.

2.4 Efficacy evaluation

The planned time points for efficacy assessments are provided in Example 2.1, and the efficacy targets and endpoints are shown in Table 9. Definitions of efficacy parameters are shown in Table 8.

Example 3: Evaluation of Felizumab (MOR202) in vitro and in vivo using samples from IgA nephropathy (IgAN) and lupus nephritis (LN).

3.1 In vitro studies

The purpose of the in vitro study was to evaluate the ability of the human anti-CD38 antibody fezentuzumab (MOR202) to deplete CD38+ long-lived plasma cells. Plasma cells are likely to be the main cell type that secretes autoantibodies against self-antigens in IgAN and LN, leading to the formation of IC and glomerular inflammation. Since plasma cells are a very rare cell population in the peripheral blood of healthy people and IgAN and LN patients, it has proven to be unfeasible to establish in vitro assays using plasma cells directly from peripheral blood. Therefore, in a first step, an in vitro differentiation experiment as described by Cocco M et al. ((2012) J Immunol 189(12):5773-85) was used to differentiate the more abundant memory B cells (Bmem) into long-lived plasma cells. In brief, peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by density gradient centrifugation, and subsequently, Bmem were isolated from PBMCs by magnetic cell sorting. Bmem were cultured in the presence of different cytokine cocktails and supporting feeder cell lines for at least 16 days until complete differentiation was confirmed by flow cytometric staining.

The secretion of human IgG by differentiated plasma cells was confirmed by ELISA.Further ELISAs were performed to detect anti-GD-IgA1 and antinuclear antibodies, and the levels of these disease-specific autoantibodies secreted by plasma cells differentiated from IgAN and LN patient B cell samples were assessed, respectively.

In vitro differentiated patient-derived plasma cells are also tested in ADCC assays, where plasma cells as target cells are co-cultured with NK cells as effector cells, and incubated with fezetuzumab or isotype control antibodies. The percentage of CD38+ plasma cell depletion compared to the control by fezetuzumab is evaluated by flow cytometry. In addition, in vitro differentiated patient-derived plasma cells are co-cultured with NK cells and fezetuzumab or isotype control antibodies as described above, and ELISA is performed to measure the total human IgG and disease-specific autoantibody levels in the cell culture supernatant to prove that the plasma cells secreting antibodies after fezetuzumab treatment have been exhausted in culture, and the total antibody and disease-specific antibody levels have dropped sharply. In addition, a shortened differentiation protocol (adapted from Wang T et al., (2019) Front Immunol. 10: 1243) is used to confirm the ability of fezetuzumab to deplete CD38+ cells in vitro under different environments. Using this assay, patient PBMCs were co-cultured with TLR7/8 agonists, IL-2 and IFNα2b, and either fezinomab or an isotype control antibody. After a 5-6 day culture period, depletion of CD38+CD27+ cells by fezinomab was confirmed by flow cytometry, and reduced IgG secretion was confirmed by ELISA compared to cells treated with an isotype control antibody.

3.2 In vivo studies

The goal of the in vivo studies was to demonstrate in disease-relevant mouse models that fuzetuzumab has the potential to deplete autoantibody-secreting plasma cells, thereby reducing autoantibody titers and the intensity of autoimmune symptoms in vivo.

Because CD38 biology in rodents is very different than in humans, the studies involved immunocompromised mice transplanted with human immune components.

The lupus nephritis model is based on the well-established pristane-induced autoimmune model, but in immunocompromised NSG mice transplanted with human CD34+ cells from umbilical cord blood (Gunawan M et al. (2017) Sci Rep, 7(1):16642). The mice developed human SLE-like symptoms (production of human autoantibodies (nuclear antibodies), lupus nephritis and pulmonary serositis, lymphocytopenia). Results included a reduction in plasma cells in peripheral blood, spleen, and bone marrow (assessed by flow cytometry), as well as a reduction in pathogenic antinuclear antibodies in serum (measured by ELISA).

Since it is very difficult to establish an IgA nephropathy model in a humanized setting, the only viable option is to demonstrate the potential of feztomax to deplete human plasma cells that produce antibodies against galactose-deficient IgA (gdIgA) antibodies in vivo. The model is based on gdIgA vaccination in NSG-SGM3 mice, humanized with CD34+ cells. It has been reported that human CD38+ plasma cells can be present in this mouse strain (Jangalwe S et al. (2016) Immun Inflamm Dis 4(4): 427-440). Results include a reduction in plasma cells in peripheral blood, spleen, and bone marrow (assessed by flow cytometry), as well as a reduction in anti-gdIgA antibodies in serum (measured by ELISA).

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Claims (15)

CLAIMS 1. An anti-CD38 antibody or antibody fragment for use in treating an immune complex-mediated disease in a subject. 2. The anti-CD38 antibody or antibody fragment for use according to claim 1, wherein the immune complex mediated disease is renal disease. 3. The anti-CD38 antibody or antibody fragment used according to claim 2, wherein the disease mediated by the immune complex is selected from IgA nephropathy, lupus nephritis, Heno-Schulen Purpuric nephritis, poststreptococcal glomerulonephritis, or drug-induced immune complex-mediated diffuse proliferative glomerulonephritis. 4. The anti-CD38 antibody or antibody fragment for use according to claim 3, wherein the IgA nephropathy is galactose-deficient IgA1 antibody (Gd-IgA1 ) and anti-galactose-deficient IgA1 antibody (anti-GD-IgA1 ) positive IgA nephropathy. 5. The anti-CD38 antibody or antibody fragment used according to any one of the preceding claims, wherein said antibody comprises the HCDR1 region of the amino acid sequence SEQ ID NO:1, the HCDR2 region of the amino acid sequence SEQ ID NO:2, the amino acid sequence of SEQ ID NO HCDR3 region of :3, LCDR1 region of amino acid sequence SEQ ID NO:4, LCDR2 region of amino acid sequence of SEQ ID NO:5 and LCDR3 region of amino acid sequence of SEQ ID NO:6. 6. The anti-CD38 antibody or antibody fragment used according to claim 5, wherein said anti-CD38 antibody or antibody fragment comprises the variable heavy chain (VH) region of SEQ ID NO.:7 and the variable region of SEQ ID NO.:8 Light chain (VL) region. 7. An anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein the CD38-specific antibody or antibody fragment is IgGl. 8. An anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein the CD38-specific antibody or antibody fragment is a human antibody. 9. An anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein the antibody depletes plasma cells by ADCC and/or ADCP. 10. The anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein administration of the anti-CD38 antibody or antibody fragment results in a reduction of immune complexes. 11. The anti-CD38 antibody or antibody fragment for use according to any one of claims 4-10, wherein the immune complex comprises Gd-IgA1 and anti-Gd-IgA1 antibody. 12. The anti-CD38 antibody or antibody fragment for use according to claim 10 or 11, wherein the immune complexes are deposited in the glomeruli of the kidney. 13. An anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein said antibody or antibody fragment is administered according to the body weight of the subject. 14. The anti-CD38 antibody or antibody fragment for use according to claim 13, wherein said antibody or antibody fragment is administered according to Table 6 in at least 2 doses, at least 5 doses or at least 9 doses. 15. The anti-CD38 antibody or antibody fragment for use according to any one of the preceding claims, wherein the subject to be treated is characterized by proteinuria > 1.0 g/day at screening.