Anti-CD38 antibodies for use in the treatment of antibody-mediated transplant rejection - Patents.com

Abstract

The present invention relates to the use of the anti-CD38 antibody felzartamab in the prevention and / or treatment of antibody-mediated rejection of transplants (ABMR). According to the present invention, felzartamab is effective against antibody-mediated renal transplant rejection.

Description

[Technical field]

[0001] The present disclosure relates to the field of organ transplantation (e.g., kidney transplantation). In particular, the present disclosure relates to anti-CD38 antibodies for use in treating patients with antibody-mediated transplant rejection (ABMR). The present disclosure provides methods for reducing antibody-secreting cells and for reducing antibody levels with specificity for one or more antigens present on a transplanted organ using anti-CD38 antibodies. In accordance with the present invention, anti-CD38 antibodies can be effective in treating and / or preventing ABMR, alone or in combination with one or more immunosuppressants. Anti-CD38 antibodies for use according to the present invention include felzartamab (MOR202). [Background technology]

[0002] Organ transplantation is a medical procedure in which an organ is removed from a subject's (donor) body and placed into a recipient's (host) body to replace a damaged or missing organ. Transplantation is the treatment of choice for patients with end-stage organ failure. Transplantation between two subjects of the same species is primarily performed to reduce organ rejection by the host's immune system (so-called allogeneic transplantation). However, the host's immune system can recognize and ultimately destroy even well-matched grafts.

[0003] Previously, it was supported that alloreactive T cells are solely responsible for graft damage due to T cell-mediated rejection (TCMR). On the other hand, anti-donor alloantibodies have been proven to be an additional important obstacle for long-term graft survival. This so-called antibody-mediated rejection (ABMR) often contributes to graft function loss after organ transplantation. Anti-donor specific antibodies (DSA), e.g. anti-human leukocyte antigen (HLA) antibodies, are the main triggers of chronic graft damage, probably in conjunction with antibody-mediated activation of cellular mechanisms (e.g. activation of natural killer cells). In kidney transplantation, ABMR is one of the main causes of allograft dysfunction and chronic allograft damage. Rejection of the transplanted kidney is usually caused by anti-HLA DSA and is associated with a progressive decrease in glomerular filtration rate (GFR), increased proteinuria, and renal failure.

[0004] There are many studies in the prior art evaluating various treatment strategies for ABMR. Known strategies include, for example: Immunosuppression with clolimus, mycophenolate mofetil and belatacept (CTLA-4 Fc-fusion) (Theruvath, TP et al., 2001, Transplantation, 72:77-83; Schwarz, C et al., 2015, Transplant International, 28:820-827), Immunomodulatory treatment including high-dose intravenous immunoglobulin with or without anti-CD20 rituximab (Fehr, T et al., 2009, Transplantation, 87:1837-1841), The proteasome inhibitor bortezomib (Walsh, RC et al., 2012, Kidney Int, 81:1067-1074) or Complement inhibitors (Eskandary, F et al., 2017, Am J Transplant, 18:916-926).

[0005] However, these strategies have not been sufficient to achieve significant improvements in long-term outcomes, and therapeutic options for long-term graft survival remain to be improved.

[0006] A promising target may be CD38, which is expressed primarily on immune and hematopoietic cells, with particularly high expression levels on antibody-producing plasma cells. Given the important role of allogeneic antibody-producing plasma cells in ABMR (when DSA is the cause of injury), effective plasma cell depletion by CD38 may be useful in transplant medicine to achieve sustained DSA reduction.

[0007] The concept of combating ABMR with anti-CD38 antibodies has been shown in the prior art with daratumumab. In a renal transplant rhesus monkey model, daratumumab reduced donor-specific antibodies and achieved long-term graft survival (Kwun, J et al., 2019, Journal of the American Society of Nephrology, 30:1206-1219). WO2020185672 (Cedars-Sinai) illustrates two cases of patients with anti-HLA antibodies and ABMR resistant to standard treatment who were treated with daratumumab and experienced an early reduction in anti-HLA antibody levels.

[0008] However, a drawback of this treatment was that CD4 and CD8 T cells were increased and regulatory B cells (B-regs) were depleted after daratumumab treatment. This may be due to the auxiliary effect of daratumumab on the depletion of regulatory T and B cells. Thus, targeting CD38 with daratumumab not only reduces plasma cell populations, but also depletes beneficial regulatory cell populations. The presence of regulatory T cells (Tregs) within the peripheral circulation and graft microenvironment may be important for inducing and maintaining long-term transplant tolerance.

[0009] Furthermore, there was no significant effect on the levels of anti-HLA class II antibodies, including DSA DQ5, while some class II antibodies rebounded and new HLA class II antibodies emerged. This may be due to the ability of daratumumab to deplete CD38+ natural killer (NK) cells, thus limiting ADCC. Figure 1 shows the effect of daratumumab compared to MOR202 and isatuximab on depleting NK cells in vitro.

[0010] In summary, these studies indicate that although early ABMR episodes are effectively controlled, the treatment options administered for early ABMR have limited impact on late / chronic episodes, which remain the primary contributors to late graft loss.

[0011] Therefore, there is a great need for novel strategies that target alloantibody reactivity to treat ABMR and prolong long-term graft survival.

[0012] The primary mechanism of action for MOR202-induced lysis of plasma cells is ADCC and ADCP, not CDC. CDC is believed to be the major contributor to infusion reactions. Thus, the main advantage compared to other CD38 antibodies is the lower risk of infusion reactions. Furthermore, MOR202 primarily depletes high CD38 cells, leaving behind a specific cell population with low CD38 levels in vitro. Specific regulatory cell subsets may be preserved following treatment with MOR202, improving graft survival.

[0013] The present disclosure provides the anti-CD38 antibody felzartamab for use in an efficient, safe, sustainable and well-tolerated strategy to treat ABMR, particularly late-onset and / or chronic ABMR. Repeated administration of felzartamab can combat ongoing ABMR tissue inflammation (i.e., increased CD4+CD8+ T cell counts) and graft injury, particularly inflammation in the microcirculation, B cell responses to HLA antigens, and, as a result, combat alloantibody / NK cell-triggered chronic graft injury. Summary of the Invention

[0014] The present invention provides the anti-CD38 antibody felzartamab for use in the treatment and / or prevention of antibody-mediated rejection of an organ transplant. Additionally, methods are provided for reducing or eliminating donor-specific antibodies (e.g., anti-HLA) and / or treating or reducing the severity of ABMR in a subject who has received a kidney transplant. The methods include administering to the patient an effective amount of the anti-CD38 antibody felzartamab. In some embodiments, the methods further include selecting a patient who is experiencing or has experienced ABMR of an organ transplant. In other embodiments, the methods further include selecting a patient who has anti-HLA antibodies specific for donor HLA in their serum. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows that MOR202 specifically kills CD38-high expressing MM plasma cell lines in vitro while sparing CD38-low expressing NK cells in comparison to daratumumab (Dara) and isatuximab. [Diagram 2] Figure 2 shows the scheme of the phase 2 pilot study of felzartamab in late-onset ABMR. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description of the Invention definition The term "CD38" refers to the protein known as CD38, which has the following synonyms: ADP-ribosyl cyclase 1, cADPR hydrolase 1, cyclic ADP-ribose hydrolase 1, T10. Human CD38 (UniProt P28907) has the following amino acid sequence: MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI (SEQ ID NO: 9)

[0017] CD38 is a type II transmembrane glycoprotein and an example of an antigen highly expressed on antibody-secreting cells, such as autoantibody-secreting plasmablasts and plasma cells. Functions attributed to CD38 include both receptor-mediated adhesion and signaling events as well as (ecto)enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as a substrate to form cyclic ADP-ribose (cADPR) and ADPR, and also to form 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 regulating NAD-induced cell death (NCID). In addition to signaling via Ca2+, CD38 signaling also occurs by crosstalk with antigen receptor complexes on T and B cells or with other types of receptor complexes, such as MHC molecules, and is thus involved in several cellular responses, but also in the switching and secretion of IgG antibodies.

[0018] The term "anti-CD38 antibody" as used herein 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 exerts a therapeutic effect on CD38 in any other manner. Any molecule that interferes with or inhibits the functionality of CD38 is included. The term "anti-CD38 antibody" includes, but is not limited to, an antibody that specifically binds to CD38, another protein scaffold that binds to CD38, a nucleic acid (including an aptamer) specific for CD38, or a small organic molecule specific for CD38.

[0019] Antibodies specific for CD38 are described, for example, in WO199962526 (Mayo Foundation), WO200206347 (Crucell Holland), U.S. Patent No. 2002164788 (Jonathan Ellis), WO2005103083, WO2006125640, WO2007042309 (MorphoSys), WO2006099875 (Genmab), and WO2008047242 (Sanofi-Aventis). Combinations of antibodies specific for CD38 and other agents are described, for example, in WO 200040265 (Research Development Foundation), WO 2006099875 and WO 2008037257 (Genmab), as well as WO 2010061360, WO 2010061359, WO 2010061358 and WO 2010061357 (Sanofi Aventis). 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 (UMC Utrecht), WO2019020643 (ENCEFA), WO2020185672 (Cedars-Sinai), and WO2020187718 (MorphoSys), which are incorporated by reference in their entireties.

[0020] 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 eliminates specific CD38 positive B cells, plasma cells, plasmablasts and any other CD38 positive antibody secreting cells. Such antibodies may be of any type, such as mouse, rat, chimeric, humanized or human antibodies.

[0021] As used herein, a "human antibody" or "human antibody fragment" is an antibody or antibody fragment having variable regions in which the framework and CDR regions are sequences of human origin. If the antibody contains a constant region, the constant region is also derived from such sequences. Human origin includes, but is not limited to, antibodies that contain human germline sequences or variants of human germline sequences, or consensus framework sequences derived from human framework sequence analysis, e.g., as described in Knappik et al. (2000) J Mol Biol 296:57-86). Human antibodies can be isolated, for example, from synthetic libraries or transgenic mice (e.g., XenoMouse). If the sequence of the antibody or antibody fragment is human, then the antibody or antibody fragment is human, regardless of the species from which the antibody was physically derived, isolated, or made.

[0022] The structures and locations of immunoglobulin variable regions, e.g., CDRs, may be defined using well-known numbering schemes, such as, for example, the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (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 103:111-115; 342:877-883, and Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-948.

[0023] A "humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having an antibody constant region derived from sequences of human origin, and only the antibody variable region or portion or CDRs of the antibody molecule are derived from another species. For example, a humanized antibody can be a CDR-grafted antibody, in which the CDRs of the variable region are of non-human origin, while one or more frameworks of the variable region are of human origin, and the constant region (if any) is of human origin.

[0024] The term "chimeric antibody" or "chimeric antibody fragment" is defined herein as an antibody molecule having an antibody constant region derived from or corresponding to sequences found in one species and an antibody variable region derived from another species. Preferably, the antibody constant region is derived from or corresponds to sequences found in humans and the antibody variable region (e.g., VH, VL, CDR or FR regions) is derived from sequences found in a non-human animal, such as mouse, rat, rabbit or hamster.

[0025] The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments with different antigen specificities. Furthermore, an isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemicals. Thus, in some embodiments, the antibody provided is an isolated antibody that is separated from antibodies with different specificities. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. An isolated antibody that specifically binds to a target epitope, isoform, or variant may, however, have cross-reactivity with other related antigens, e.g., from other species (e.g., species homologs).

[0026] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition that display a unique binding site having a unique binding specificity and affinity for a particular epitope.

[0027] Furthermore, as used herein, "immunoglobulin" (Ig) is hereby defined as a protein belonging to the classes IgG, IgM, IgE, IgA, or IgD (or any subclass thereof) and includes all conventionally known antibodies or functional fragments thereof.

[0028] 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, stabilization of spatial distribution, etc.). Examples of binding fragments include, but are not limited to, Fab fragments, i.e., monovalent fragments consisting of the VL, VH, CL and CH1 regions, F(ab)2 fragments, i.e., bivalent fragments containing two Fab fragments linked by a disulfide bond at the hinge region, Fd fragments consisting of the VH and CH1 regions, Fv fragments consisting of the VL and VH regions of a single arm of an antibody, dAb fragments consisting of the VH region, and separate complementarity determining regions (CDRs). Furthermore, the two regions of the Fv fragment, i.e., VL and VH, are encoded by separate genes, but can be recombinantly linked by a synthetic linker that allows the pair of VL and VH regions to generate a single protein chain that forms a monovalent molecule (known as single chain fragment (scFv)). Such single chain antibodies are intended to be encompassed by the term "antibody fragment". Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv. Antibody fragments can be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3). Antibody fragments can be incorporated into single chain molecules that contain a pair of tandem Fv segments (VH-CH1-VH-CH1) that form a pair of antigen-binding sites with complementary light chain polypeptides.

[0029] The present disclosure provides a method of treatment comprising administering a therapeutically effective amount of the disclosed anti-CD38 antibodies to a subject in need of such treatment. As used herein, a "therapeutically effective amount" or "effective amount" refers to the amount of an antibody specific for CD38 required to induce a desired biological response. According to the present disclosure, a therapeutically effective amount is the amount of an antibody specific for CD38 required to treat and / or prevent immune complex-mediated disease and symptoms associated with the disease. The effective amount for a particular individual may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route and dose of administration, and the severity of side effects (Maynard et al., (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001) Good Laboratory and Good Clinical Practice, London, UK).

[0030] As used herein, the terms "treat", "treating", "treatment" or the like refer to relieving symptoms, either temporarily or permanently, eliminating the cause of symptoms, or preventing or delaying the onset of symptoms of the indicated disorder or condition. These terms refer to therapeutic treatment and prophylactic or preventative measures. The purpose of treatment is to prevent or slow (alleviate) undesirable physiological changes or damage, or to cure the disease being treated. Beneficial or desired clinical results include alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not getting worse), delaying or slowing the progression of the disease, remission or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean extending the lifespan of a subject compared to the lifespan expected if the subject did not receive treatment. Those in need of treatment include those already with a condition or injury as well as those susceptible to the condition or injury or those in whom the condition or injury is to be prevented.

[0031] "Preventing" or "prevention" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a subject who has been exposed to a disease-causing agent or who may be susceptible to the disease prior to the onset of the disease). "Prevention" refers to a method that aims to avert the onset of a disease or a symptom of a disease or to delay the onset of a disease or a symptom of a disease.

[0032] "Administered" or "administration" includes, but is not limited to, administering an agent by an injectable form, such as, for example, intravenous, intramuscular, intradermal, or subcutaneous routes, or by mucosal routes, such as, for example, nasal drops or aerosols for inhalation, or by orally ingestible solutions, capsules, or tablets. Preferably, administration is by an injectable form.

[0033] Concurrent 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. Two or more active agents may be administered simultaneously in a single formulation, i.e., in a single pharmaceutical composition, but this is not required. The active agents may be administered in different formulations at different times. The combination therapy treatments (e.g., prophylactic or therapeutic agents) can be administered to a subject simultaneously or sequentially. The combination therapy treatments (e.g., prophylactic or therapeutic agents) can also be administered in cycles. Cycling therapy involves administering a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, and repeating this sequential administration, i.e., cycle. This is to reduce the development of resistance to one of the multiple therapies, avoid or reduce the side effects of one of the multiple therapies, and / or improve the efficacy of the multiple therapies. The terms "concomitantly" or "concurrently" are not limited to administration of therapies at exactly the same time; rather, the terms refer to administration of a pharmaceutical composition comprising an antibody or antibody fragment of the present disclosure in a sequence and at a time interval that allows the antibody of the present disclosure to work with the other therapy(s) in a more beneficial manner than if the antibody of the present disclosure was administered in any other sequence and at any other time interval with the other therapy(s).

[0034] "Subject" or "species" as used herein refers to all mammals, including rodents such as mice or rats, and primates such as cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), or humans (Homo sapiens). Preferably, the subject is a primate, and most preferably, a human.

[0035] As used herein, the term "subject in need thereof" or the like means a human or non-human animal patient exhibiting one or more symptoms or signs of antibody-mediated rejection of an organ transplant. Preferably, the subject is a primate, and most preferably, a human patient diagnosed with antibody-mediated rejection after kidney transplantation.

[0036] The term "antibody-mediated rejection (ABMR)" refers to a well-established entity that often occurs after organ transplantation (Tx) and includes clear diagnostic criteria according to the Banff classification, such as inflammation and morphological damage of the microenvironment, deposition of the complement cleavage product C4d along the (non-obligatory) graft endothelium, and detection of antibodies against donor antigens ("donor-specific antigens, DSA"). DSA can be (i) antibodies against the donor's HLA and / or (ii) non-HLA antibodies, and DSA may be divided into at least two major categories: alloantibodies against polymorphic antigens that differ between the recipient and the donor, and antibodies that recognize autoantigens or autoantibodies.

[0037] As used herein, the term "about" used in reference to a particular recited numerical value means that the value may vary from the recited value by up to 1%. 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.).

[0038] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, or, more specifically, in humans.

[0039] "Pharmaceutically acceptable solvent" refers to a diluent, adjuvant, excipient, or carrier with which an antibody or antibody fragment is administered.

[0040] Throughout this specification, unless the context requires otherwise, the words "comprise," "have," and "include," as well as variations of each of these words such as "comprises," "comprising," "has," "having," "includes," and "including," are meant to include the stated element or integer or group of elements or integers but not to exclude any other element or integer or group of elements or integers.

[0041] "Felzartamab" is an anti-CD38 antibody also known as "MOR202," "MOR03087," or "MOR3087." The terms are used interchangeably in this disclosure. MOR202 has an IgG1 Fc region.

[0042] The amino acid sequence of MOR202 HCDR1 according to Kabat is: SYYMN (SEQ ID NO: 1).

[0043] The amino acid sequence of MOR202 HCDR2 according to Kabat is: GISGDPSNTYYADSVKG (sequence number 2).

[0044] The amino acid sequence of MOR202 HCDR3 by Kabat is: DLPLVYTGFAY (sequence number 3).

[0045] The amino acid sequence of MOR202 LCDR1 according to Kabat is: SGDNLRHYYVY (sequence number 4).

[0046] The amino acid sequence of MOR202 LCDR2 according to Kabat is: GDSKRPS (sequence number 5).

[0047] The amino acid sequence of MOR202 LCDR3 is QTYTGGASL (SEQ ID NO:6).

[0048] The amino acid sequence of the MOR202 heavy chain variable region is QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (sequence number 7).

[0049] The amino acid sequence of the MOR202 light chain variable region is DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (sequence number 8).

[0050] The DNA sequence encoding the MOR202 heavy chain variable region is CAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATACCTATTATGCGGAT AGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA (SEQ ID NO: 10).

[0051] The DNA sequence encoding the MOR202 light chain variable region is GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGGCA TCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTGGCGGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 11).

[0052] Embodiment antibody In certain embodiments of the present disclosure, an antibody or antibody fragment specific for CD38 for use according to the present disclosure comprises a heavy chain variable region, a light chain variable region, a heavy chain, a light chain and / or CDRs comprising any of the amino acid sequences of the CD38-specific antibodies set forth in WO2007042309.

[0053] In one embodiment, an antibody or antibody fragment specific for CD38 for use according to the present disclosure 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.

[0054] In one embodiment, an antibody or antibody fragment specific for CD38 for use according to the present disclosure comprises an HCDR1 region of SEQ ID NO:1, an HCDR2 region of SEQ ID NO:2, an HCDR3 region of SEQ ID NO:3, an LCDR1 region of SEQ ID NO:4, an LCDR2 region of SEQ ID NO:5, and an LCDR3 region of SEQ ID NO:6.

[0055] In one embodiment, an antibody or antibody fragment specific for CD38 for use according to the present disclosure comprises a heavy chain variable region of SEQ ID NO:7 and a light chain variable region of SEQ ID NO:8.

[0056] In another embodiment, an anti-CD38 antibody or antibody fragment for use according to the present disclosure comprises a heavy chain variable region of SEQ ID NO:7 and a light chain variable region of SEQ ID NO:8, or a heavy chain variable region and a light chain variable region having at least 60%, at least 70%, at least 80%, at least 90% or at least 95% identity to the heavy chain variable region of SEQ ID NO:7 and to the light chain variable region of SEQ ID NO:8.

[0057] An exemplary antibody or antibody fragment for use according to the present disclosure comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 is the human anti-CD38 antibody known as MOR202 (felzartamab).

[0058] In one embodiment, the disclosure relates to a nucleic acid composition comprising a nucleic acid sequence or sequences encoding an antibody or antibody fragment specific for CD38 for use according to the disclosure, the antibody or antibody fragment comprising an HCDR1 region of SEQ ID NO:1, an HCDR2 region of SEQ ID NO:2, an HCDR3 region of SEQ ID NO:3, an LCDR1 region of SEQ ID NO:4, an LCDR2 region of SEQ ID NO:5, and an LCDR3 region of SEQ ID NO:6.

[0059] 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, the nucleic acid comprising a VH of SEQ ID NO:10 and a VL of SEQ ID NO:11.

[0060] In one embodiment, the disclosed antibodies or antibody fragments specific for CD38 for use according to the present disclosure are monoclonal antibodies or antibody fragments.

[0061] In one embodiment, the disclosed antibodies or antibody fragments specific for CD38 for use according to the present disclosure are human, humanized or chimeric antibodies.

[0062] In certain embodiments, an antibody or antibody fragment specific for CD38 for use according to the present disclosure is an isolated antibody or antibody fragment.

[0063] In another embodiment, the antibody or antibody fragment for use in accordance with the present disclosure is a recombinant antibody or antibody fragment.

[0064] In a further embodiment, the antibody or antibody fragment for use in accordance with the present disclosure is a recombinant human antibody or antibody fragment.

[0065] In a further embodiment, the recombinant human antibody or antibody fragment for use in accordance with the present disclosure is an isolated recombinant human antibody or antibody fragment.

[0066] In a further 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.

[0067] In one embodiment, the disclosed antibody or antibody fragment for use according to the present disclosure is of the IgG isotype. In a particular embodiment, the antibody is an IgG1.

[0068] In certain embodiments of the invention, the anti-CD38 antibody for use in accordance with the present disclosure is MOR202 (felzartamab).

[0069] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising felzartamab (MOR202) or a fragment thereof specific for CD38 and a pharma- ceutically acceptable carrier or excipient for use in accordance with the present disclosure.

[0070] In a specific embodiment, the antibody or antibody fragment specific for CD38 is an isolated monoclonal antibody or antibody fragment that specifically binds to human CD38.

[0071] Pharmaceutical Compositions When used as a medicine, the antibody or antibody fragment specific for CD38 is typically administered in a pharmaceutical composition. The composition of the present disclosure is preferably a pharmaceutical composition comprising felzartamab (MOR202) and a pharma- ceutically acceptable carrier, diluent or excipient for use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) reaction of an organ transplant in a subject in need thereof.

[0072] The pharma- ceutically acceptable carrier should be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (eg, by injection or infusion).

[0073] Pharmaceutical carriers enhance or stabilize the composition or facilitate preparation of the composition. Pharmaceutically acceptable carriers include physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity and absorption delaying agents, and the like. In many cases, it is preferable to include isotonicity agents in the composition, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride.

[0074] The pharmaceutical compositions of the present disclosure can be administered by a variety of routes known in the art. Selected routes of administration of an antibody or antibody fragment of the present disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example, by injection or infusion.

[0075] The 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.

[0076] An important aspect of the present disclosure is a pharmaceutical composition capable of mediating the killing of CD38-expressing, antibody-secreting cells (eg, plasmablasts, plasma cells, etc.) by ADCC and ADCP.

[0077] Treatment method In one 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 use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) reaction of an organ transplant in a subject in need thereof.

[0078] In certain embodiments, the transplant organ is one or more of the kidney, heart, liver, lung, pancreas, stomach, skin and intestine.

[0079] In one embodiment, there is provided an anti-CD38 antibody or antibody fragment, or a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, for use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) reaction of a renal transplant in a subject in need thereof.

[0080] In certain embodiments, the present disclosure provides an anti-CD38 antibody or antibody fragment comprising an HCDR1 region of SEQ ID NO:1, an HCDR2 region of SEQ ID NO:2, an HCDR3 region of SEQ ID NO:3, an LCDR1 region of SEQ ID NO:4, an LCDR2 region of SEQ ID NO:5, and an LCDR3 region of SEQ ID NO:6 for use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) response in an organ transplant.

[0081] In another aspect, the disclosure provides an anti-CD38 antibody or antibody fragment comprising a heavy chain variable region of SEQ ID NO:7 and a light chain variable region of SEQ ID NO:8 for use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) reaction of an organ transplant in a subject in need thereof.

[0082] In certain aspects, the present disclosure provides MOR202 (felzartamab) for use in treating, inhibiting and / or reducing the severity of an antibody-mediated rejection (ABMR) reaction of an organ transplant in a subject in need thereof.

[0083] In one embodiment, the present disclosure provides an anti-CD38 antibody or antibody fragment for use in depleting CD38-expressing, antibody-secreting cells (preferably plasma cells) in a subject experiencing an antibody-mediated rejection (ABMR) response after receiving an organ transplant.

[0084] In a preferred embodiment, the present disclosure provides an anti-CD38 antibody (e.g., MOR202) for use in reducing circulating anti-HLA and / or anti-non-HLA antibodies in a subject with an antibody-mediated rejection (ABMR) response after receiving an organ transplant.

[0085] In another embodiment, the present disclosure provides an anti-CD38 antibody (e.g., MOR202) for use in reducing deposition of anti-HLA and / or anti-non-HLA antibodies in a transplanted organ in a subject with an antibody-mediated rejection (ABMR) response after receiving an organ transplant.

[0086] In a further aspect, the disclosure provides a therapeutic agent comprising as an active ingredient an anti-CD38 antibody (such as MOR202) for use in reducing symptoms of ABMR in a subject after receiving a renal transplant, the symptoms being selected from (i) worsening renal function as measured by serum creatinine and estimated glomerular filtration rate (eGFR), (ii) the presence of donor-specific antigens, and / or (iii) renal capillaritis, inflammation and complement (C4d) deposition.

[0087] In another aspect, the disclosure provides prophylactic and / or therapeutic agents comprising an anti-CD38 antibody (e.g., MOR202) for use in restoring, ameliorating, or normalizing renal function as indicated by glomerular filtration rate (eGFR) based on the CKD-epi equation in a subject with antibody-mediated rejection (ABMR) after receiving a kidney transplant.

[0088] In a further aspect, the disclosure provides an anti-CD38 antibody (e.g., MOR202) for use in treating an ABMR response in an organ transplant in a subject in need thereof, wherein the anti-CD38 antibody (e.g., MOR202) is administered at least 2 times, at least 5 times, at least 7 times, or at least 9 times.

[0089] In another aspect, the disclosure provides an anti-CD38 antibody (e.g., MOR202) for use in treating an ABMR response in an organ transplant in a subject in need thereof, wherein the anti-CD38 antibody (e.g., MOR202) is administered 2, 5, 7 or 9 times.

[0090] In a specific embodiment, the dosage is 8 mg / kg or more, hi a particular embodiment, the dosage is 16 mg / kg.

[0091] In another embodiment, the disclosure provides an anti-CD38 antibody for use in treating ABMR of an organ transplant in a subject in need thereof, wherein the anti-CD38 antibody is administered every 2 weeks in cycle 1 (C1) and every 4 weeks in cycles 2-6 (felzartamab / placebo on days 0 and 14 (cycle 1), then every 4 weeks at weeks 4, 8, 12, 16, and 20 (cycles 2-6)).

[0092] In another embodiment, the disclosure provides an anti-CD38 antibody for use in treating ABMR, wherein the anti-CD38 antibody is administered intravenously.

[0093] In another embodiment, the disclosure provides an anti-CD38 antibody for use in treating ABMR, wherein the antibody is administered intravenously over a period of 2 hours.

[0094] In one embodiment, the anti-CD38 antibody (eg, MOR202) is administered before, simultaneously with, and / or after organ transplantation.

[0095] In another embodiment, a method of treating an individual in need of a transplant by administering to the individual an effective amount of felzartamab prior to, concurrently with, and / or after transplant.

[0096] In another aspect, the present disclosure provides use of an anti-CD38 antibody or antibody fragment in the preparation of a medicament for the treatment and / or prevention of antibody-mediated rejection (ABMR) reactions of an organ transplant in a subject in need thereof.

[0097] In another aspect, the present disclosure provides the use of an anti-CD38 antibody or antibody fragment comprising an HCDR1 region of SEQ ID NO: 1, an HCDR2 region of SEQ ID NO: 2, an HCDR3 region of SEQ ID NO: 3, an LCDR1 region of SEQ ID NO: 4, an LCDR2 region of SEQ ID NO: 5, and an LCDR3 region of SEQ ID NO: 6 in the preparation of a medicament for the treatment and / or prevention of antibody-mediated rejection (ABMR) reactions of an organ transplant in a subject in need of such treatment and / or prevention.

[0098] In another aspect, the disclosure provides the use of an anti-CD38 antibody or antibody fragment comprising a heavy chain variable region of SEQ ID NO:7 and a light chain variable region of SEQ ID NO:8 in the preparation of a medicament for the treatment and / or prevention of antibody-mediated rejection (ABMR) of an organ transplant in a subject in need thereof.

[0099] In a further aspect, the present disclosure provides the use of MOR202 (felzartamab) in the preparation of a medicament for the treatment and / or prevention of antibody-mediated rejection (ABMR) reactions of a renal transplant in a subject in need thereof.

[0100] In another aspect, the disclosure provides the use of MOR202 (felzartamab) or a pharmaceutical composition comprising MOR202 (felzartamab), in combination with another therapeutic agent, in the preparation of a medicament for the treatment and / or prevention of antibody-mediated rejection (ABMR) reactions of an organ transplant in a subject in need thereof.

[0101] In some embodiments, there is provided a use of MOR202 in combination with a steroid for the treatment and / or prevention of ABMR in a subject in need thereof. In other embodiments, MOR202 is administered in combination with a proteasome inhibitor (e.g., bortezomib or carfilzomib) for use in the treatment and / or prevention of ABMR.

[0102] In one aspect, the present disclosure provides a method for treating and / or preventing an antibody-mediated rejection (ABMR) reaction of an organ transplant in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody. In certain embodiments, the antibody-mediated rejection (ABMR) reaction is directed against the transplanted kidney.

[0103] In some embodiments, the present disclosure provides a method for preventing and / or treating a subject suffering from an antibody-mediated rejection (ABMR) reaction of an organ transplant, the subject being refractory to treatment with corticosteroids or calcineurin inhibitors or other immunosuppressant therapies, including B cell depletion therapies (e.g., with rituximab or any other anti-CD20 antibody, or anti-BAFF antibody), the method comprising administration of an effective amount of an anti-CD38 antibody or antibody fragment.

[0104] In one aspect, the disclosure provides methods of using anti-CD38 antibodies or antibody fragments to achieve prophylactic or therapeutic effects in patients susceptible or vulnerable to antibody-mediated rejection (ABMR) reactions after receiving an organ transplant.

[0105] In another aspect, the disclosure provides a method of reducing the frequency of occurrence of an antibody mediated rejection (ABMR) reaction and / or symptoms of an antibody mediated rejection (ABMR) reaction, ameliorating an antibody mediated rejection (ABMR) reaction and / or symptoms of an antibody mediated rejection (ABMR) reaction, suppressing an antibody mediated rejection (ABMR) reaction and / or symptoms of an antibody mediated rejection (ABMR) reaction, alleviating an antibody mediated rejection (ABMR) reaction and / or symptoms of an antibody mediated rejection (ABMR) reaction, and / or delaying the onset, development or worsening of an antibody mediated rejection (ABMR) reaction and / or symptoms of an antibody mediated rejection (ABMR) reaction in a subject, the method comprising administering to the subject an effective amount of an anti-CD38 antibody. Specifically, the antibody mediated rejection (ABMR) reaction is following a kidney transplant.

[0106] In a preferred embodiment, the present disclosure provides a method for treating patients with elevated DSA levels associated with an antibody-mediated rejection (ABMR) response.

[0107] In other aspects, the disclosure provides methods for treating and / or preventing diseases caused by the presence of donor specific antigens. In yet other aspects, the disclosure provides methods for treating and / or preventing conditions associated with the presence of anti-donor HLA antibodies. In further aspects, the disclosure provides methods for treating and / or preventing conditions associated with the presence of anti-donor antibodies that are not directed against HLA.

[0108] In other embodiments, the present disclosure provides methods of reducing inflammation and C4d complement deposition in a subject suffering from antibody-mediated rejection (ABMR), the methods comprising administering an effective amount of an anti-CD38 antibody or antibody fragment, or one or more pharmaceutical compositions described herein. For example, the methods provided herein comprise administering an anti-CD38 antibody to a patient with elevated levels of anti-HLA antibodies. In other aspects, the methods provided herein comprise administering an anti-CD38 antibody to a patient with elevated levels of C4d complement deposition in a transplanted organ.

[0109] In one embodiment, the reduction (change) in anti-HLA levels in serum of a subject suffering from antibody-mediated rejection (ABMR) after administration of an anti-CD38 antibody or antibody fragment, or one or more pharmaceutical compositions described herein, is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to baseline.

[0110] In another aspect, the disclosure provides a method for preventing decline in renal function in an individual with antibody-mediated rejection (ABMR), the method comprising administration of an effective amount of an anti-CD38 antibody or antibody fragment, or one or more pharmaceutical compositions described herein.

[0111] In a further embodiment, the present disclosure relates to a method of treating antibody-mediated rejection (ABMR) in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and depletes CD38-expressing cells.

[0112] In a preferred embodiment, the present disclosure relates to a method of treating ABMR in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and depletes CD38-expressing, antibody-secreting cells, while sparing regulatory T cell and / or B cell populations.

[0113] In another embodiment, the disclosure relates to a method of treating ABMR in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and depletes CD38-expressing, antibody-secreting cells, but not to the extent that regulatory T cells.

[0114] In certain preferred embodiments, the present disclosure relates to a method of treating antibody-mediated rejection (ABMR) in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and depletes CD38-expressing, antibody-secreting cells, wherein the antibody exhibits significantly greater specific cell killing of antibody-secreting cells than NK cells.

[0115] In one embodiment, the disclosure relates to a method of treating antibody-mediated rejection (ABMR) in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment that binds to and depletes CD38-expressing, antibody-secreting cells, wherein specific cell killing of 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%, and specific cell killing of non-antibody-secreting NK cells is less than 30%, less than 25%, less than 20%, or less than 15%, as determined by a standard ADCC assay.

[0116] In one embodiment, the disclosure relates to a method of treating antibody-mediated rejection (ABMR) in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, wherein the subject has received standard therapies including one or more of immunoglobulin administration (IVIG), rituximab administration, and plasma exchange (PLEX), and the subject's response to the standard therapies is ineffective.

[0117] In another embodiment, the subject to be treated is further resistant or has acquired resistance to immunosuppressive therapy with one or more of eculizumab, thymoglobulin, bortezomib, carfilzomib, basiliximab, mycophenolate mofetil, tacrolimus, and corticosteroids.

[0118] In another embodiment, the present disclosure relates to a method of treating antibody-mediated rejection (ABMR) in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, wherein the subject has not received any prior standard of care treatment.

[0119] In a further embodiment, the disclosure relates to a method of treating ABMR in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, wherein administration of the anti-CD38 antibody does not significantly alter the absolute numbers of regulatory CD4+, CD25+, CD127- T cells.

[0120] In another embodiment, the present disclosure relates to a method of treating ABMR in a subject, comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, wherein the ratio of CD8+ T cells / Tregs is not significantly increased following antibody administration.

[0121] In another embodiment, the disclosure relates to a method of treating ABMR in a subject comprising administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody or antibody fragment, wherein administration of the anti-CD38 antibody or antibody fragment reduces class I and / or class II anti-HLA antibody levels. Anti-HLA class I antibodies include anti-HLA-A, -B, and -C. Anti-HLA class II antibodies include anti-HLA-DR, -DQ (e.g., anti-DQ5), and -DP.

[0122] In a preferred embodiment, the method for treating ABMR is in a human subject and comprises the administration of a pharmaceutical composition comprising MOR202 (felzartamab), which administration reduces class II anti-HLA antibody levels, preferably anti-DQ5 antibody levels. In a preferred embodiment, nine doses of MOR202 are administered. EXAMPLES

[0123] Example 1: Felzartamab in late antibody-mediated renal transplant rejection 1.1 Study design This is an investigator-initiated pilot trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of felzartamab, a fully human anti-CD38 monoclonal antibody, in kidney transplant recipients with late-active or chronic active ABMR.

[0124] The study is designed as a randomized, controlled, double-blind, phase 2 pilot study. The primary endpoints are safety and tolerability. A simplified flow chart of the study is shown in Figure 2.

[0125] 1.2 Study population Approximately 20 kidney transplant recipients with circulating anti-HLA DSA and biopsy features of late-onset (>180 days post-transplant) active ABMR (according to the Banff 2019 scheme) at biopsy indication (index biopsy: performed in clinical routine for patients with positive DSA results and slowly deteriorating graft function and / or proteinuria after transplantation). Other main inclusion criteria were age >18 years, graft functioning >180 days post-transplant, and estimated GFR (eGFR by CKD-EPI equation) ≥20 ml / min / 1.73 m 2 Inclusion and exclusion criteria are detailed in Table 1.

[0126] TIFF2024507986000002.tif242170

[0127] 1.3 Medication Subjects will be randomized 1:1 to receive either felzartamab (16 mg / kg, intravenous) or placebo using a web-based randomization platform (www.meduniwien.ac.at / randomizer). Based on the results of PK modeling in an ongoing Phase Ib / IIa clinical trial in an autoimmune disease (membranous nephropathy, ClinicalTrials.gov, NCT04145440), patients will receive felzartamab as an infusion for 6 months. Because transplant patients are on immunosuppressive baseline treatment with multiple compounds (as opposed to patients with membranous nephropathy), and therefore at higher risk for infection, an extended dosing interval (every 2 weeks instead of every week) is planned for the first cycle. Instead of 9 doses, 7 doses of felzartamab will be administered intravenously at 16 mg / kg for 6 treatment cycles of 28 days each. Dosing will occur every 2 weeks in cycle 1 (C1) and every 4 weeks in cycles 2-6 (felzartamab / placebo administered on days 0 and 14 (cycle 1), then every 4 weeks at weeks 4, 8, 12, 16, and 20 (cycles 2-6)).

[0128] In the favorable setting, subjects will be randomized to receive either felzartamab (16 mg / kg, intravenously) or placebo (0.9% saline) (1:1 randomization) for 6 months (felzartamab / placebo administered on days 0, 7, 14, 21 (Cycle 1) and then every 4 weeks at weeks 4, 8, 12, 16, and 20 (Cycles 2-6)). After 6 months (24 weeks) and 12 months (52 weeks), study participants will undergo follow-up transplant biopsies. The primary objective of the trial is to evaluate the safety, pharmacokinetics, and pharmacodynamics (peripheral blood PC and NK cell depletion) of the 6-month treatment course over a 12-month period.

[0129] Thus, nine infusions of felzartamab or placebo will be administered over six treatment cycles of 28 days each. Dosing will occur weekly in cycle 1 and every four weeks in cycles 2-6.

[0130] Felzartamab is supplied at 65 mg / mL in 10 mM histidine, 260 mM sucrose, 0.1% Tween 20, pH 6.0 for injection after reconstitution with 4.8 mL water (one vial contains 325 mg MOR202). Felzartamab is administered after dilution in 250 mL of 0.9% sodium chloride solution (final concentration should be 1-20 mg / mL). Placebo (0.9% sodium chloride) is administered in 250 mL of normal saline for infusion. Prepared infusions may be stored at 2°C-8°C for up to 24 hours, at room temperature for up to 4 hours out of the 24 hours, and at 15°C-25°C. Prior to administration, felzartamab / placebo infusion should reach room temperature by storing unrefrigerated for 30-60 minutes before use.

[0131] The first two felzartamab infusions should be slow (approximately 90 minutes) and, if no infusion reactions occur, the infusion time may be shortened to 1 hour or less (minimum 30 minutes) for subsequent infusions.

[0132] After 6 months (24 weeks) and 12 months (52 weeks), study participants will undergo follow-up graft biopsies. Randomization will be according to ABMR category (active ABMR vs. chronic / active ABMR) to ensure a balance of patients with these two tissue types between the two groups. The study will be designed as a double-blind trial to minimize bias.

[0133] Premedication To prevent infusion reactions, patients assigned to the felzartamab group will receive intravenous premedication before the first two felzartamab infusions (days 0 and 14). Patients in the placebo group will receive placebo (0.9% NaCl solution). Premedication will be administered 30 minutes before the felzartamab infusion and will consist of diphenhydramine (30 mg), paracetamol (1000 mg), and prednisolone (100 mg), each in a 100 mL volume. In the placebo group, patients will receive 3 x 100 mL NaCl 0.9%.

[0134] The following drugs are prohibited during this study: Other investigational drugs / treatments including rituximab, eculizumab, proteasome inhibitors, IVIG, plasma exchange or immunoadsorption, commercially available CD38 or anti-IL-6 / sIL-6R monoclonal antibody drugs such as daratumumab (Darcalex®) or tocilizumab (RoActemra® / Actemra®).

[0135] The following concomitant medications are permitted during this study: Long-term treatment with calcineurin inhibitors (CNIs, tacrolimus or cyclosporine A), mammalian target of rapamycin (mTOR) inhibitors (everolimus or rapamycin), mycophenolate mofetil (MMF) / mycophenolate sodium, and low-dose corticosteroids (prednisolone 5 mg / day).

[0136] Baseline immunosuppression: Once late-onset ABMR is diagnosed, all recipients of treatment with a calcineurin inhibitor [tacrolimus or cyclosporine A (CyA)] or an mTOR inhibitor (everolimus or rapamycin), but not azathioprine or mycophenolic acid (MPA), receive mycophenolate mofetil (or alternatively, enteric-coated mycophenolic acid (EC-MPA) initially at a dose of 2 × 500 mg (or 2 × 360 mg, respectively) per day, gradually increased to 2 × 1000 mg (or 2 × 720 mg) per day as tolerated, to avoid a decrease in immunosuppression. Tacrolimus is adjusted to reach target trough levels of 5-10 ng / mL and CyA to 80-120 ng / mL. Recipients weaned from steroids receive low-dose prednisolone (5 mg / day).

[0137] 1.4 Effectiveness evaluation The primary objective of this study is to evaluate the safety, pharmacokinetics and pharmacodynamics (depletion of peripheral blood PC and NK cells) of a 6-month treatment course over a 12-month period, and to provide efficacy data (rejection progression / activity, blood biomarkers) and potential associations of treatment with parameters reflecting clinical progression of graft dysfunction (e.g. renal function progression as described in Irish, W et al., 2020, Transplantation or iBOX score as described in Loupy, A et al., BMJ, 366:14923, 2019).

[0138] TIFF2024507986000003.tif187170TIFF2024507986000004.tif88170

[0139] Primary endpoints (see Table 2) include safety and tolerability, course of DSA (and in parallel total Ig and IgG subclass levels), dynamics of peripheral blood counts of PCs, NK cells, and T and B cell subpopulations (assessed by FACS), as well as biomarkers of rejection (CXCL9 and CXCL10 in blood and urine) and overall immunosuppression (torque teno virus load). In addition, kidney transplant biopsies at 6 and 12 months will be used to evaluate morphological (Banff criteria for rejection and chronic injury, immunohistochemistry to detect complement activation / deposition and characterization of cellular infiltrates including NK cells) and molecular rejection criteria (molecular ABMR score, microarray analysis using the Molecular Microscope® diagnostic system), including pathogenicity-based transcript (PBT) scores (cytotoxic T cell infiltration, gamma-interferon effect, natural killer cell load, epithelial cell damage) in biopsies at 6 and 12 months. Clinical endpoints were proteinuria as well as the slope of eGFR and iBox Clinical Prediction Score, both validated surrogate endpoints that accurately predict long-term graft survival.

[0140] Example 2: Experimental Method 2.1 HLA antibody detection To assess HLA antibody levels, serum samples are evaluated after completion of the study according to a published protocol (Doberer, K. et al.; J Am Soc Nephrol). Briefly, the LABscreen single-antigen flow bead assay (One Lambda) is applied for antibody detection. Serum samples are incubated with 10 mM EDTA to prevent complement interference. Data acquisition is performed with a LABScanTM 200 flow analyzer (Luminex Corporation). For longitudinal analysis of DSA / HLA antibody levels, the bead assay is performed retrospectively to avoid the influence of day-to-day variations in the test results. Donor specificity is defined according to serological and / or low- or high-resolution donor / recipient HLA-typing (HLA-A, -B, -Cw, -DR, -DQ, -DP). Test results are described as the mean fluorescence intensity (MFI) of immunodominant DSA. An MFI threshold of >1,000 is considered positive. The effect of felzartamab treatment on DSA levels is estimated by the percentage change in MFI. To more accurately quantify the changes in DSA levels, the method is followed by further dilution experiments as described in Doberer K et al., 2020, Transplantation. Briefly, a nonlinear calibration curve based on raw DSA MFI levels (immunodominant DSA) is obtained by serial dilution of individual patient sera collected before the start of treatment and at 24 weeks. According to the computerized calibration curve, the fold change in antibody levels is then calculated from the DSA MFI levels detected in the same experiment for undiluted 12-week, 24-week, and 52-week samples.

[0141] 2.2 Immunoglobulin levels Total IgG, IgM and IgG subclasses in the serum are assessed by applying the immunoturbidimetric method on a BN™ II analyzer (Siemens Healthineers).

[0142] 2.3 Transplant biopsy Follow-up biopsies will be performed at 24 and 52 weeks (end of study visit) after excluding coagulation abnormalities or platelet counts below 80%. Biopsies will be performed using an ultrasound-guided percutaneous technique under local anesthesia (lidocaine). Histomorphology will be evaluated applying standard methodology on paraffin-embedded sections. Embedded tissue blocks will undergo serial sectioning (5 mm thick), hematoxylin-eosin staining and periodic acid-Schiff staining for routine evaluation and staging of rejection. For immunohistochemical C4d staining, a polyclonal anti-C4d antibody (BI-RC4D, Biomedica) will be used, and minimal immunohistochemical staining (C4d Banff score ≥ 1) along the peritubular capillaries will be considered positive after the Banff scheme (Loupy, A et al., 2020, American Journal of Transplantation: ajt.15898). Biopsies are also evaluated by electron microscopy to detect multilayered lesions of the peritubular capillary basement membrane (MLPTC). In addition, all biopsies are analyzed using the internationally validated Molecular Microscope® diagnostic system MMDx platform with microarrays also proposed by the Banff scheme. A thoroughly validated molecular score based on machine learning derived lesion-based classification associated with rejection [ABMR, T-cell-mediated rejection (TCMR), total rejection], inflammation (global disturbance score) or chronic injury (atrophy / fibrosis score) is generated using a reference set of 1529 biopsies. All biopsy results are analyzed in terms of molecular results for classification of ABMR according to the Banff 2019 scheme. ABMR is defined based on both morphological (histomorphology, immunohistochemistry, electron microscopy) and thoroughly validated molecular criteria: (i) evidence of acute or chronic tissue injury, (ii) evidence of current / recent antibody interaction with the vascular endothelium, and (iii) serological evidence of DSA.

[0143] 2.4 Renal function eGFR was assessed using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula (mL / min / 1.73 m 2Protein excretion is described as spot urinary protein / creatinine ratio (mg / g).

[0144] 2.5. Immune biomarkers of rejection For chemokine detection, a Luminex-based protocol as described by Muhlbacher, J et al. (2020, Front Med, 7:114) is used. For quantification of chemokine (CXC motif) ligand (CXCL)9 and CXCL10, serum samples are adjusted to 10 mM EDTA to prevent complement interference. Undiluted samples are measured in duplicate using a multiplex Human ProcartaPlex Simplex immunoassay (Thermo Fisher Scientific) according to the manufacturer's instructions. Immunoassays are run on a Luminex 200 instrument (Luminex Corp.). Urinary results are normalized to creatinine excretion and expressed as pg(chemokine) / mg(creatinine). dd-cfDNA levels in recipient plasma samples, indicative of the degree of ongoing graft damage, are detected using standard techniques based on the detection of a predefined set of single nucleotide polymorphisms detected by next generation sequencing on an Illumina MiSeq sequencer (Illumina Inc).

[0145] 2.6 Immune Cell Monitoring and Leukocyte Subpopulations The mechanisms underlying chronic antibody-mediated rejection, especially the role of peripheral T and B cell subsets, remain poorly defined. Therefore, prospective monitoring of immune phenotype under treatment with felzartamab is a promising approach to elucidate the impact of immune regulatory pathways when targeting CD38. Furthermore, evaluation of plasma cell and NK cell counts allows monitoring the pharmacodynamic effect of anti-CD38 antibodies. For monitoring leukocyte (sub)populations, reproducible immune monitoring panels for phenotyping are used (e.g. DuraClone® for flow cytometry). The predefined assay tubes of the DuraClone kit include a layer containing a pre-made dried antibody panel. With up to 10 different monoclonal antibodies per tube, leukocyte (e.g. T cell, B cell, NK cell subsets) subpopulations present in whole blood samples can be identified.

[0146] For immune cell monitoring, cells from blood, lymph nodes, bone marrow, spleen, and transplant tissues are stained with the LIVE / DEAD Fixable Aqua Dead Cell Staining Kit (Life Technologies). Cells are then stained with one or more of the following human mAbs: CD3, CD4, CD8, CD14, CD20, CD25, CD27, CD28, CD38, CD56, CD95, CD127, CD159a, CD278 (ICOS), CD279 (PD-1), IgM, IgG, CXCR5, and, after fixation, Ki67 and FoxP3. Samples are collected on a flow cytometer and the percentages of CD38+ B and plasma cells, CD8+ T cells, and / or CD4+, CD25+, CD127- T cells are analyzed using standard software (e.g., FlowJo v9.6.).

[0147] 2.7 Gene expression analysis For gene expression analysis, 5 mL of blood was collected in PAXgene Blood RNA tubes and stored at -80°C until retrospective analysis. These tubes are designed to stabilize RNA in blood during long-term storage at ultra-low temperatures. Gene expression pattern analysis (microarray analysis) will be performed on peripheral blood to evaluate the effect of felzartamab on antibody-producing cells, analyzing genes annotated as part of B cell receptor signaling.

[0148] 2.8 Quantification of Torque Teno Virus (TTV) For TTV analysis, DNA is extracted from plasma samples using the NucliSENS easyMAG platform (bioMerieux) and eluted in 50 μL of elution buffer. TTV DNA is quantified by TaqMan real-time PCR, for example as described by Schiemann, M et al. (2017, Transplantation, 101:360-367). Quantitative PCR is performed in a volume of 25 μL using 2× TaqMan Universal PCR Master Mix containing 5 μL of extracted DNA, 400 nM of each primer, and 80 nM of probe. Thermal cycling begins with 50° C. for 3 min, followed by 95° C. for 10 min, then 45 cycles of 95° C. for 15 s, 55° C. for 30 s, and 72° C. for 30 s, performed using a CFX96 real-time system (Bio-Rad). Results are recorded as copies / mL.

[0149] 2.9 Vaccine titer progression Mumps, measles and rubella (MMR) specific serum IgG titers are analyzed by standard ELISA techniques.

[0150] 2.10 Collection of Biological Materials (Other than Routine Monitoring) Plasma (10 mL; chemokine, TTV challenge), serum (10 mL; HLA antibody testing), whole blood (10 mL; flow cytometry, RNA for gene expression analysis) and urine (10 mL) will be collected before study initiation (day 0), after 6 months and after 12 months (3 × 30 mL peripheral blood). Finally, serum will be obtained at every visit (5 mL peripheral blood per visit, 18 visits in total) for measurement of felzartamab concentrations and ADA.

[0151] Example 3: Safety and Efficacy of MOR202 to Prevent and Treat ABMR in Non-Human Primates Receiving Kidney Transplants 3.1 Experimental NHP models This study will investigate the safety and efficacy of desensitization to MOR202 to prevent ABMR and acute post-transplant ABMR in a highly sensitized non-human primate kidney transplant model (see Kwun J. et al., J Am Soc Nephrol. 2019 Jul;30(7):1206-1219). Additionally, we will evaluate the long-term efficacy of MOR202 to prevent rebound donor-specific antibodies (DSA) and late / chronic ABMR.

[0152] 3.1.1 CD38 expression Plasma cells from the BM, spleen, lymph nodes, and blood of recipient animals will be analyzed for CD38 expression levels and cross-reactivity with MOR202. Erythrocyte CD38 expression levels will be determined to estimate the risk of anemia.

[0153] 3.1.2 Desensitization with MOR202 For allosensitization, male rhesus macaques (Macaca mulatta) are sensitized to an MHC-mismatched donor by placing two successive skin grafts 8 weeks apart as described in Burghuber CK et al., Am J Transplant 19:724-736. Approximately 8-12 weeks after the second skin graft, the monkeys are treated with 16 mg / kg MOR202 for 4 weeks. Alloantibody levels are measured. Desensitization levels are compared to the results of a desensitization strategy using proteasome inhibitors (bortezomib / carfilzomib) alone or in combination with costimulatory blockade (Kwun J. et al., Blood Adv. 2017 Nov 14;1(24):2115-2119). CMV titers are measured before and after completion of drug therapy. For immune cell monitoring, cells from blood, lymph nodes, bone marrow, spleen, and transplanted tissue are evaluated by flow cytometry.

[0154] 3.1.3 Efficacy of MOR202 to prevent and treat ABMR following desensitization therapy Animals receive kidney transplants from the same skin graft donors and receive MOR202 weekly for 4 weeks in addition to anti-rejection immunosuppression with rATG, tacrolimus, and steroids. Kidney transplants are performed essentially as described by Burghuber CK et al. (Am J Transplant. 2016;16(6):1726-1738). For depletion of plasma cell populations, sensitized rhesus macaques are treated weekly with MOR202. Control animals received no treatment prior to kidney transplantation. Circulating B and T cell populations are assessed by FACS, as CD38 is expressed on hematopoietic and non-hematopoietic cells, including activated B and T cell populations. These include circulating B cells, IgG+ B cells, and memory B cells (IgG+CD27+CD20+), as well as naive (CD28+CD95-), central memory (CD28+CD95+), and effector memory (CD28-CD95int) subsets of CD4 and CD8 T cells.

[0155] Renal biopsies are taken at 1, 3, 6 months and at sacrifice, analyzed by (immunohistology) and scored according to Banff criteria. Donor-specific antibodies (DSA) are measured weekly thereafter after transplantation. Animals with rebound DSA showing elevated serum creatinine are also treated with MOR202 for 1 month. Cellular and humoral immune responses are analyzed, including follicular helper T cells, plasma cells (BM, LN, and blood), and plasmablasts (blood and LN). Additional renal transplant biopsies are taken as necessary. H&E, PAS, and C4d staining are performed to monitor for occult rejection and C4d deposition.

[0156] 3.1.4 DSA Monitoring DSA levels are measured serially weekly by flow crossmatch using donor lymphocytes and recipient serum as described by Burghuber CK et al. (Am J Transplant 19:724-736). Briefly, donor PBMCs or splenocytes are incubated with recipient serum, washed, and stained with FITC-labeled anti-monkey IgG, anti-CD20 mAb, and anti-CD3 mAb. The mean fluorescence intensity (MFI) of anti-monkey IgG in T cells or B cells is measured and expressed as the MFI change from the pre-sensitization time point. To detect cross-reactive antibodies, NHP serum alloantibodies may also be measured using a human solid-phase Luminex assay using single HLA antigen beads (LABScreen Single Antigen; One Lambda).

Claims

1. 1. An anti-CD38 antibody or antibody fragment for use in the treatment and / or prevention of antibody-mediated rejection of a transplanted organ in a human subject, comprising: The antibody is an anti-CD38 antibody or antibody fragment comprising an HCDR1 region of amino acid sequence SEQ ID NO:1, an HCDR2 region of amino acid sequence SEQ ID NO:2, an HCDR3 region of amino acid sequence SEQ ID NO:3, and an LCDR1 region of amino acid sequence SEQ ID NO:4, an LCDR2 region of amino acid sequence SEQ ID NO:5, and an LCDR3 region of amino acid sequence SEQ ID NO:

6.

2. 2. The anti-CD38 antibody or antibody fragment for use according to claim 1, wherein the transplant organ is a kidney, heart, liver, lung, pancreas, stomach, skin or intestine transplant.

3. An anti-CD38 antibody or antibody fragment for use as described in claim 2, wherein the antibody or antibody fragment comprises a heavy chain variable (VH) region of SEQ ID NO: 7 and a light chain variable (VL) region of SEQ ID NO:

8.

4. An anti-CD38 antibody or antibody fragment for use as described in claim 3, wherein the antibody or antibody fragment is of the IgG1 isotype.

5. An anti-CD38 antibody or antibody fragment for use as described in claim 4, wherein the antibody or antibody fragment is a human antibody.

6. An anti-CD38 antibody or antibody fragment for use as described in claim 5, wherein the antibody or antibody fragment is felzartamab.

7. An anti-CD38 antibody or antibody fragment for use according to any of claims 1 to 6, wherein the antibody or antibody fragment depletes plasma cells by antibody-dependent cellular cytotoxicity (ADCC) and / or antibody-dependent cellular phagocytosis (ADCP).

8. An anti-CD38 antibody or antibody fragment for use according to any of claims 1 to 6, wherein the antibody or antibody fragment reduces the level of CD38+ antibody-secreting cells in a human subject.

9. An anti-CD38 antibody or antibody fragment for use according to any of claims 1 to 6, wherein the antibody or antibody fragment reduces levels of HLA antibodies in a human subject.

10. An anti-CD38 antibody or antibody fragment for use as described in claim 9, wherein the antibody or antibody fragment reduces the levels of class I and / or class II anti-HLA antibodies in a human subject.

11. An anti-CD38 antibody or antibody fragment for use as described in claim 10, wherein the anti-antibody or antibody fragment reduces anti-DQ5 antibody levels in a human subject.

12. An anti-CD38 antibody or antibody fragment for use according to any one of claims 1 to 6, wherein the treatment and / or prevention comprises intravenously administering the antibody or antibody fragment at a dose of 16 mg / kg.

13. An anti-CD38 antibody or antibody fragment for use as described in claim 12, wherein the antibody or antibody fragment is administered at least twice, at least five times, at least seven times, or at least nine times.

14. The anti-CD38 antibody or antibody fragment for use according to any of claims 1 to 6, wherein the antibody-mediated rejection of a renal transplant in a subject is characterized by an estimated glomerular filtration rate (eGFR) of ≧20 ml / min / 1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.

15. An anti-CD38 antibody or antibody fragment for use as described in claim 1, wherein the antibody depletes CD38-expressing, antibody-secreting cells in a human subject.

16. An anti-CD38 antibody or antibody fragment for use as described in claim 1, wherein the antibody reduces levels of circulating or deposited donor-specific antigen in a human subject.

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