Methods of treating autoimmune diseases comprising the administration of Anti-BCMA therapeutics

Abstract

Provided herein are methods of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-BCMA therapeutic.

Description

METHODS OF TREATING AUTOIMMUNE DISEASESBACKGROUND

[0001] Autoimmune diseases are generally defined as the inappropriate activation of the immune system by self-antigens leading to the targeting of healthy cells, inflammation, and tissue damage in a patient, and can have devastating short- and long-term consequences. Currently, the treatments available for patients diagnosed with autoimmune diseases are limited. Thus, there is a need for therapeutics that can be used to treat a range of autoimmune diseases. The embodiments provided for herein fulfil these needs as well as others.SUMMARY

[0002] Provided herein are methods of treating an autoimmune disease in a subject in need thereof. In some embodiments, the methods comprise administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-BCMA therapeutic. In some embodiments, the anti-BCMA therapeutic is a monospecific antibody, a bispecific antibody, a trispecific antibody, an antibody drug conjugate, an antibody fragment, or a cell comprising an antibody or an antibody fragment. In some embodiments, the anti-BCMA therapeutic is selected from the group consisting of SEA-BCMA, belantamab mafodotin, ispectamab debotansine, teclistamab, elranatamab, ABBV-383, alnuctamab, linvoseltamab, and ISB 2001.

[0003] In some embodiments, the pharmaceutical composition is administered to the subject one time. In some embodiments, the pharmaceutical composition is administered to the subject two or more times. In some embodiments, the pharmaceutical composition is administered to the subject for one cycle. In some embodiments, the pharmaceutical composition is administered to the subject for two or more cycles.

[0004] In some embodiments, the autoimmune disease is selected from the group consisting of Addison's disease, alopecia areata, Wegener's granulomatosis, ankylosing spondylitis, antibody-mediated rejection, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, autoimmune haemolytic anaemia (AIHA), autoimmune hearing loss, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, Behcets disease, bullous pemphigoid, catastrophic anti-phospholipid antibody syndrome, celiac sprue-dermatitis, chronicfatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, glomerulus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, hepatitis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, immune complex-mediated vasculitis, immune neutropenia, inflammatory bowel disease, insulin dependent diabetes, juvenile arthritis, lichen planus, limited scleroderma (CREST syndrome), lupus nephritis, Meniere's Disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, reactive arthropathies, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, serum sickness, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, and vitiligo.

[0005] In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is moderate to severe active rheumatoid arthritis. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows improvement in one or more of the following: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CD Al score, SDAI score, pain VAS score, FACIT-fatigue scorejoint pain severity score, PtGA of disease activity score, and SF-36 score. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies. In some embodiments, the autoantibodies are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof.

[0006] In some embodiments, the autoimmune disease is Sjogren's syndrome. In some embodiments, the Sjogren's syndrome is Primary Sjogren's syndrome. In some embodiments, thesubject, after administration of the anti-BCMA therapeutic, shows improvement in one or more of the following: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT-Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF-36, PROMIS-29 v2.0, Hospital Anxiety and Depression Scale (HADS), Work Productivity and Activity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies. In some embodiments, the autoantibodies are selected from the group consisting of: anti-La (SSB), anti-Smith, antinuclear antibodies (ANA), anti-phospholipid antibodies, anti-dsDNA antibodies, anti-nRNP (ribonucleoproteins) antibodies, anti-rheumatoid factor antibodies, anti-Ro antibodies, and combinations thereof.

[0007] In some embodiments, the autoimmune disease is systemic lupus erythematosus. In some embodiments, the is at least moderately active systemic lupus erythematosus. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows improvement in one or more of the following: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain-NRS), Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Form 36-Item (SF-36) questionnaire, physical activity, mobility, sleepjoint, and skin score. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies. In some embodiments, the autoantibodies are selected from the group consisting of: anti-Sm / RNP, anti-SSA / Ro, anti-SSB / La, anti-dsDNA, antinuclear antibodies (ANA), anti-Smith, anti-NMDAR, anti-02GPl, anti-phospholipid antibodies, anti-Clq, anti- Ribosomal P antibodies, and any combination thereof.

[0008] In some embodiments, the anti-BCMA therapeutic is teclistamab. In some embodiments, teclistamab is administered subcutaneously at a dose of about 1.5 mg / kg of the subject weekly. In some embodiments, a first step up dose of 0.06 mg / kg of the subject and a second step up dose of 0.3 mg / kg of the subject are administered to the subject prior to the first dose of about 1.5 mg / kg weekly. In some embodiments, teclistamab is administered to the subject for one week. In some embodiments, teclistamab is administered to the subject for two or more weeks.DETAILED DESCRIPTION

[0009] The present disclosure provides methods of treating autoimmune diseases in a subject in need thereof, comprising administering to the subject at least anti-BCMA therapeutic.

[0010] Several aspects and embodiments of the disclosure are described below, with reference to examples for illustrative purposes only. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the disclosure. One having ordinary skill in the relevant art, however, will readily recognize that the disclosure can be practiced without one or more of the specific details or practiced with other methods, protocols, reagents, cell lines and animals. The present disclosure is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and / or concurrently with other acts or events. Furthermore, not all illustrated acts, steps or events are required to implement a methodology in accordance with the present disclosure.

[0011] Any references in the description or in the claims to methods of treatment refer to the compounds, compositions, pharmaceutical compositions and medicaments for use in a method of treatment of the human (or animal) body by therapy (or for diagnosis).

[0012] Any references in the description or in the claims to methods of treatment refer to the use of the compounds, compositions, pharmaceutical compositions for the manufacture of a medicament for the treatment of the human (or animal) body by therapy (or for diagnosis).

[0013] In an attempt to help the reader of the present application, the description has been separated in various paragraphs or sections. These separations should not be considered as disconnecting the substance of a paragraph or section from the substance of another paragraph or section. To the contrary, the present description encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated.

[0014] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and / or as otherwise defined herein.

[0015] All references, including patents and patent publications, are incorporated by reference in their entirety.Definitions

[0016] The terminology used herein is for the purpose of describing particular aspects or embodiments only and is not intended to be limiting. As used herein, the indefinite articles “a”, “an” and “the” should be understood to include plural reference unless the context clearly indicates otherwise.

[0017] The term “about” or “approximately” includes being within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0018] Unless otherwise stated, any numerical value, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a dosage of 10 mg includes 9 mg to 11 mg. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0019] ‘ ‘About” when used in reference to numerical ranges, cutoffs, or specific values means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewherein the Specification in the context of an assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 10%, whichever is larger.

[0020] The term “antibody” is meant in a broad sense and includes monoclonal antibodies (including full length 4-chain antibodies or full length heavy-chain only antibodies which have an immunoglobulin Fc region), antibody compositions with poly epitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), as well as antibody fragments (e.g., Fab, F(ab’)2, and Fv). The term “immunoglobulin” (Ig) is used interchangeably with “antibody” herein. Antibodies contemplated herein include single-domain antibodies, such as heavy chain only antibodies. The terms “antibody” and “antibodies” refer to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), intrabodies, minibodies, diabodies and anti-idiotype (anti-Id) antibodies (including, e.g., anti-Id antibodies to antigen specific TCR), and epitope-binding fragments of any of the above. The terms “antibody” and “antibodies” also refer to covalent diabodies such as those disclosed in U.S. Pat. Appl. Pub. 2007 / 0004909 and Ig-DARTS such as those disclosed in U.S. Pat. Appl. Pub. 2009 / 0060910. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgMl, IgM2, IgAl and IgA2) or subclass. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (A), based on the amino acid sequences of their constant domains.

[0021] “Antigen binding fragment” or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, theVH and the VL, Fab, F(ab’)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, VH domains modified to function without a corresponding VL domain, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. W01998 / 44001, WO1988 / 01649, WO1994 / 13804 and W01992 / 01047.

[0022] The antibodies, polypeptides, and proteins of embodiments of the disclosure (including functional portions and functional variants) can be subject to post-translational modifications. They can be glycosylated, esterified, N-acylated, amidated, carboxy lated, phosphorylated, esterified, cyclized via, e.g., a disulfide bridge, or converted into an acid addition salt. In some embodiments, they are dimerized or polymerized, or conjugated.

[0023] The terms “B-cell maturation antigen” and “BCMA” as used herein include human B cell maturation antigen, also known as BCMA, CD269, and TNFRSF17 (UniProt Q02223), which is a member of the tumor necrosis receptor superfamily. The extracellular domain of human BCMA consists, according to UniProt of amino acids 1-54 (or 5-51).

[0024] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0025] “ CD3” refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta and CD3 gamma. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.

[0026] A “chimeric antigen receptor” or “CAR” is an artificially constructed hybrid protein or polypeptide containing the antigen binding domains of at least one antibody (or antibody fragment)linked to T-cell signaling domains. Characteristics of CARs can include their ability to redirect T- cell specificity and reactivity toward a selected target in a non-MHC-restricted manner, exploiting the antigen-binding properties of monoclonal antibodies. The non-MHC-restricted antigen recognition gives T cells expressing CARs the ability to recognize antigens independent of antigen processing, thus bypassing a major mechanism of tumor evasion. Moreover, when expressed in T- cells, advantageously, CARs do not dimerize with endogenous T cell receptor (TCR) a- and 0- chains. T cells expressing a CAR are referred to herein as CAR T cells, CAR-T cells or CAR modified T cells, and these terms are used interchangeably herein. The cell can be genetically modified to stably express at least one antigen-binding domain on its surface, conferring novel antigen specificity that is MHC independent. “BCMA CAR” refers to a CAR having an extracellular binding domain specific for BCMA. “Bi-epitope CAR” refers to a CAR having an extracellular binding domain specific for two different epitopes of an antigen, such as BCMA.

[0027] “ Combination” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0028] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs may be defined using various delineations such as Kabat (Wu et al. J Exp Med 132: 211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27: 55-77, 2003) and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). The correspondence between the various delineations and variable region numbering are described (see e.g., Lefranc et al. Dev Comp Immunol 27: 55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; Web resources, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat; Chothia; Martin; Lefranc et al.).Table 1. Kabat, IMGT, AbM, and Chothia numbering systems.

[0029] “Comprising” is intended to include examples encompassed by the terms “consisting essentially of’ and “consisting of’; similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of” Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0030] By “decrease” or “lower,” or “lessen,” or “reduce,” or “abate” refers generally to the ability of composition contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. In some embodiments, a “decrease” or “reduced” amount can be a “statistically significant” amount, and may include a decrease that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in-between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the response (reference response) produced by vehicle, a control composition, or the response in a particular cell lineage.

[0031] The term “effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[0032] By “enhance” or “promote,” or “increase” or “expand” or “improve” refers generally to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. A measurable physiological response may include an increase in T cellexpansion, activation, effector function, persistence, and / or an increase in cancer cell death killing ability, among others apparent from the understanding in the art and the description herein. In some embodiments, an “increased” or “enhanced” amount can be a “statistically significant” amount, and may include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, or more times (e.g., 500, 1000 times) (including all integers and decimal points in-between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the response produced by vehicle or a control composition. “Enhance” or “enhanced” also refers to enhancement in one or more functions of a test molecule when compared to a control molecule or a combination of test molecules when compared to one or more control molecules. “Enhanced” may be an enhancement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant enhancement.

[0033] The terms “express” and “expression” mean allowing for or causing the information in a gene or DNA sequence to become produced. For example, expression can take the form of producing a protein by activating the cellular functions involved in transcription and translation of a corresponding gene or DNA sequence. A DNA sequence is expressed in or by a cell to form an “expression product” such as a protein. The expression product itself, e.g., the resulting protein, may also be said to be “expressed” by the cell. An expression product can be characterized as intracellular, extracellular or transmembrane.

[0034] ‘ ‘Fc gamma receptor” (FcyR) refers to well-known FcyRI, FcyRIIa, FcyRIIb or FcyRIII.Activating FcyR includes FcyRI, FcyRIIa and FcyRIII.

[0035] The terms “fragment of an antibody”, “antibody fragment”, “functional fragment of an antibody”, and “antigen-binding portion” are used interchangeably herein to mean one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen (see, generally, Holliger et al., Nat. Biotech., 23(9): 1 126-1129 (2005)). The antigen recognition moiety of the CAR encoded by the nucleic acid sequence disclosed herein can contain any BCMA-binding antibody fragment. The antibody fragment desirably comprises, for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (iv) a single chain Fv (scFv), which is a monovalent molecule consisting of the twodomains of the Fv fragment (i.e., VL and VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain (see, e.g., Bird et al., Science, 242: 423- 426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA, 85: 5879-5883 (1988); and Osbourn et al., Nat. Biotechnol, 16: 778 (1998)) and (v) a diabody, which is a dimer of polypeptide chains, wherein each polypeptide chain comprises a VH connected to a VL by a peptide linker that is too short to allow pairing between the VH and VL on the same polypeptide chain, thereby driving the pairing between the complementary domains on different VH -VL polypeptide chains to generate a dimeric molecule having two functional antigen binding sites. Antibody fragments are known in the art and are described in more detail in, e.g., U.S. Patent Application Publication 2009 / 0093024 AL Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as the VH, the VL, the VH and the VL, Fab, Fab’, F(ab’)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, VH domains modified to function without a corresponding VL domain ns, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as VH and VL) may be linked together via a synthetic linker to form various types of single antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0036] A “full length antibody” is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant domain, the heavy chain constant domain comprised of subdomains CHI, hinge, CH2 and CH3. Each light chain is comprised of a light chain variable domain (VL) and a light chain constant domain (CL). The VH and the VL may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FW). Each VH and VL iscomposed of three CDRs and four FW segments, arranged from amino-to-carboxy-terminus in the following order: FW1, CDR1, FW2, CDR2, FW3, CDR3 and FW4.

[0037] ‘ ‘Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.

[0038] ‘Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the frameworks so that the frameworks may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0039] ‘ ‘Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and / orpurified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated antibody” refers to an antibody that is substantially free of other cellular material and / or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0040] ‘ ‘Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0041] ‘ ‘Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration may be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

[0042] The terms “nucleic acid”, “nucleotide”, and “polynucleotide” encompass both DNA and RNA unless specified otherwise. By a “nucleic acid sequence” or “nucleotide sequence” is meant the nucleic acid sequence encoding an amino acid; these terms may also refer to the nucleic acid sequence including the portion coding for any amino acids added as an artifact of cloning, including any amino acids coded for by linkers.

[0043] As used herein, the term “operatively linked,” and similar phrases, when used in reference to nucleic acids or amino acids, refer to the operational linkage of nucleic acid sequences or amino acid sequence, respectively, placed in functional relationships with each other. For example, an operatively linked promoter, enhancer elements, open reading frame, 5’ and 3’ UTR, and terminator sequences result in the accurate production of a nucleic acid molecule (e.g., RNA). In some embodiments, operatively linked nucleic acid elements result in the transcription of an open reading frame and ultimately the production of a polypeptide (i.e., expression of the open reading frame). As another example, an operatively linked peptide is one in which the functionaldomains are placed with appropriate distance from each other to impart the intended function of each domain.

[0044] ‘ ‘Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.

[0045] The phrase “pharmaceutically acceptable”, as used in connection with compositions described herein, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human). Preferably, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0046] “Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. In some embodiments, the pharmaceutically acceptable carrier is an excipient or diluent in a pharmaceutical composition.

[0047] The term “protein” or “polypeptide” is used herein encompasses all kinds of naturally occurring and synthetic proteins, including protein fragments of all lengths, fusion proteins and modified proteins, including without limitation, glycoproteins, as well as all other types of modified proteins (e.g., proteins resulting from phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, polyglutamylation, ADP- ribosylation, pegylation, biotinylation, etc.).

[0048] ‘ ‘Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0049] ‘ ‘Reduce” or “reduced” refers to a reduction in one or more functions of a test molecule when compared to a control molecule or a combination of test molecules when compared to one or more control molecules. “Reduced” may be a reduction of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant enhancement.

[0050] The term “refractory,” as used in connection to treatment with a particular treatment agent or medicament or line of therapy herein, refers to diseases or disease subjects that fail to respond to said treatment agent or medicament or line of therapy.

[0051] “Relapsed” refers to a disease that responded to treatment but then returns.

[0052] The term “single-domain antibody” or “sdAb” refers to a single antigen-binding polypeptide having three complementary determining regions (CDRs). The sdAb alone is capable of binding to the antigen without pairing with a corresponding CDR-containing polypeptide. In some cases, single-domain antibodies are engineered from camelid HCAbs, and their heavy chain variable domains are referred herein as “VHHs”. Some VHHs may also be known as “Nanobodies”. A camelid sdAb is one of the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993); Greenberg et al., Nature 374:168- 73 (1995); Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8: 1013-26 (2013)). AbasicVHH has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3- CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3.

[0053] As used herein, the terms “specifically binds”, “specifically recognizes”, or “specific for” refer to measurable and reproducible interactions such as binding between a target and an antigen binding protein (such as a CAR or a VHH), which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.

[0054] The term “specificity” refers to selective recognition of an antigen binding protein (such as a CAR or a VHH) for a particular epitope of an antigen. Natural antibodies, for example, are monospecific. The term “multispecific” denotes that an antigen binding protein (such as a CAR or antibody) has two or more antigen-binding sites of which at least two bind different antigenbinding specificities. “Bispecific” as used herein denotes that an antigen binding protein (such as a CAR or antibody) has two different antigen-binding specificities.

[0055] As used herein, the term “subject” refers to an animal. The terms “subject” and “patient” may be used interchangeably herein in reference to a subject. As such, a “subject” includes a human that is being treated for a disease, or prevention of a disease, as a patient. The methods described herein may be used to treat an animal subject belonging to any classification. Examples of such animals include mammals. Mammals, include, but are not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. The mammals may be of the order Carnivora, including felines (cats) and canines (dogs). The mammals may be of the order Artiodactyla, including bovines (cows) and swines (pigs) or of the order Perssodactyla, including equines (horses). The mammals may be of the order Primates, Ceboids,or Simoids (monkeys) or of the order Anthropoids (humans and apes). In some embodiments, the mammal is a human.

[0056] The terms “T cell” and “T lymphocyte” are interchangeable and used synonymously herein. As used herein, T cell includes thymocytes, naive T lymphocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. A T cell can be a T helper (Th) cell, for example a T helper 1 (Thl) or a T helper 2 (Th2) cell. The T cell can be a helper T cell (HTL; CD4+ T cell) CD4+ T cell, a cytotoxic T cell (CTL; CD8+ T cell), a tumor infiltrating cytotoxic T cell (TIL; CD8+ T cell), CD4+CD8+ T cell, or any other subset of T cells. Other illustrative populations of T cells suitable for use in particular embodiments include naive T cells and memory T cells. Also included are “NKT cells”, which refer to a specialized population of T cells that express a semi-invariant o.p T-cell receptor, but also express a variety of molecular markers that are typically associated with NK cells, such as NK1.1. NKT cells include NK1.1 + and NK1.1-, as well as CD4+, CD4-, CD8+ and CD8- cells. The TCR on NKT cells is unique in that it recognizes glycolipid antigens presented by the MHC I-like molecule CD Id. NKT cells can have either protective or deleterious effects due to their abilities to produce cytokines that promote either inflammation or immune tolerance. Also included are “gamma-delta T cells (y8 T cells),” which refer to a specialized population that to a small subset of T cells possessing a distinct TCR on their surface, and unlike the majority of T cells in which the TCR is composed of two glycoprotein chains designated a- and 0-TCR chains, the TCR in y8 T cells is made up of a y-chain and a 8-chain. T8 T cells can play a role in immunosurveillance and immunoregulation and were found to be an important source of IL- 17 and to induce robust CD8+ cytotoxic T cell response. Also included are “regulatory T cells” or “Tregs”, which refer to T cells that suppress an abnormal or excessive immune response and play a role in immune tolerance. Tregs are typically transcription factor Foxp3 -positive CD4+T cells and can also include transcription factor Foxp3- negative regulatory T cells that are IL-10-producing CD4+T cells.

[0057] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0058] The terms “treat” or “treatment” refer to therapeutic treatment wherein the object is to slow down or lessen an undesired physiological change or disease, or provide a beneficial or desired clinical outcome during treatment. Beneficial or desired clinical outcomes include alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., a cessation in the worsening) of the state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and / or remission (whether partial or total and whether detectable or undetectable). “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those subjects already with the undesired physiological change or disease as well as those subjects prone to having the physiological change or disease. Treatment may involve a treatment agent, also referred to herein as a “medicament” or “medication,” that may be intended to help achieve the beneficial or desired clinical outcome of interest by its action. Treatment agents or medicaments may be administered to a subject by many routes, including, for example, intravenous administration. The term “intravenous,” in connection to the administration of treatment agents or medicaments, refers to the administration of said treatment agents or medicaments within one or more veins.

[0059] The term “variable” refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain (i.e., variable domain) mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a 0-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the 0-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and contribute to the formation of the antigen binding site of antibodies (with the HVRs from the other chain, if the antibody is not a sdAb or HCAb) (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0060] The “variable region” or “variable domain” of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites. Heavy-chain only antibodies from the Camelid species have a single heavy chain variable region, which is referred to as “VHH” domain. VHH is thus a special type of variable region.

[0061] The dosing frequencies provided for herein are understood to be synonymous with standard terms in the art. For example, “weekly” dosing is understood to be synonymous with “QW”. For example, “biweekly” dosing is understood to be synonymous with “Q2W”. For example, “once every four weeks” is understood to be synonymous with “Q4W”. Unless explicitly stated to the contrary, “once every four weeks” and “monthly” are used interchangeably in the context of dosing frequencies. Accordingly, “monthly” or “once a month” is also understood to be synonymous with “Q4W” unless explicitly stated otherwise.

[0062] When referring to a dosage amount, “pg / kg” or “mg / kg” refers to the amount of an active agent, such as a bispecific antibody or antibody, in microgram (pg) or milligram (mg) administered to a subject per kilogram (kg) body weight of the subject.

[0063] Additionally, throughout this disclosure, various aspects and embodiments of the disclosure can be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99 % identity, includes something with 95 %, 96 %, 97 %, 98 % or 99 % identity, and includes subranges such as 96-99 %, 96-98 %, 96-97 %, 97- 99 %, 97-98 % and 98-99 % identity. This applies regardless of the breadth of the range.

[0064] The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda,MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbering can be found for example at ImMunoGeneTics website, at IMGT Web resources at IMGT Scientific charts.

[0065] The substitutions in the CH3 region are expressed as modified position(s) in the first CH3 domain of the first heavy chain / modified position(s) in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to a F405L mutation in the first CH3 region and K09R mutation in the second CH3 region. L351Y F405A Y407V / T394W refers to L351Y, F40FA and Y407V mutations in the first CH3 region and T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to mutation in which D399 may be replaced by F, H, K R or Q, and K409 may be replaced by A, G, R or H.

[0066] Conventional one and three-letter amino acid codes are used herein as shown in Table 2.Table 2. Amino acid abbreviations.Methods

[0067] The present application relates to methods and compositions for use in treating autoimmune diseases. In particular, disclosed herein are methods of treating an autoimmunedisease in a subject in need thereof, the method comprising administering an anti-BCMA therapeutic to the subject.

[0068] Autoimmune diseases are generally defined as the inappropriate activation of the immune system by self-antigens leading to the targeting of healthy cells, inflammation, and tissue damage in the subject. During this inflammatory process, B-cells are responsible for the production of autoantibodies, a hallmark marker of various autoimmune diseases. They are additionally involved in the production of pro-inflammatory cytokines and in the presentation of antigens to T-cells.

[0069] In some embodiments, autoimmune diseases include, but are not limited to Addison's disease, alopecia areata, Wegener's granulomatosis, ankylosing spondylitis, antibody-mediated rejection, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, autoimmune haemolytic anaemia (AIHA), autoimmune hearing loss, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, Behcets disease, bullous pemphigoid, catastrophic anti-phospholipid antibody syndrome, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, glomerulus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, hepatitis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, immune complex-mediated vasculitis, immune neutropenia, inflammatory bowel disease, insulin dependent diabetes juvenile arthritis, lichen planus, limited scleroderma (CREST syndrome), lupus nephritis, Meniere's Disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, reactive arthropathies, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, serum sickness, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, and vitiligo.

[0070] In some embodiments, B cells have been specifically implicated as having a role in rheumatoid arthritis (RA), primary Sjogren’s Syndrome (pSS), systemic lupus erythematosus(SLE), ANCA- associated vasculitis (AAV), and multiple sclerosis (MS). (Merino-Vico et al., Eur. J. Immunol., 53:e2149675 (2023), which is herein incorporated by reference in its entirety). As a non-limiting example, patients with RA commonly develop autoantibodies in the pre- clinical phase of the disease, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). (Nielen et al., Arthritis Rheum., 50(2):380-386 (2004), which is herein incorporated by reference in its entirety). Prior to the onset of clinically classifiable RA, the titer of ACPA antibodies was shown to spike. (Nielen et al., Arthritis Rheum., 50(2):380-386 (2004), which is herein incorporated by reference in its entirety). These observations indicate a role of B cells and autoantibodies in early pathogenesis and progression of RA. More recent studies have demonstrated that ACPA specific plasmablasts circulate in the peripheral blood of RA patients and in the synovium, B cells are predominately CD20'CD27hlplasmablast / plasma cells (50%) (Kerkman et al., Ann. Rheum. Dis., 72(7): 1259-1263 (2013) and Kerkman et al., Ann. Rheum. Dis., 75(12):2201-2207 (2016), each of which are herein incorporated by reference in their entirety).

[0071] Due to the incidence and role of autoantibodies, B cells may serve as a therapeutic target for the treatment of autoimmune diseases. Accordingly, a number of B cell depletion therapies (BCDT) have been or are being tested for the treatment of the disease. These include antibodies targeting CD20, CD22, CD40, CD 19, CD38 and inhibitors of BAFF and Bruton’s tyrosine kinase (BTK). (see, e.g., Lee et al., Nat. Rev. Drug Discov., 20(3):179-199 (2021) and Merino-Vico et al., Eur. J. Immunol., 53:e2149675 (2023), each of which are herein incorporated by reference in their entirety).

[0072] B-cell maturation antigen, also known as BCMA, CD269, TNFRSF17 (UniProt Q02223), is a member of the tumor necrosis receptor superfamily (Laabi et al. (1992) EMBO J 11(11): 3897-3904; Madry et al. (1998) Int Immunol 10(11): 1693-1702). BCMA is a nonglycosylated type I transmembrane protein, which is involved in B cell maturation, growth and survival. BCMA is a receptor for two ligands of the TNF superfamily: APRIL (a proliferation-inducing ligand, CD256, TNFSF13), the high-affinity ligand to BCMA and the B cell activation factor BAFF (THANK, BlyS, B lymphocyte stimulator, TALL-1 and zTNF4), the low-affinity ligand to BCMA. APRIL and BAFF show structural similarity and overlapping yet distinct receptor binding specificity. The negative regulator TACI also binds to both BAFF and APRIL. The coordinate binding of APRIL and BAFF to BCMA and / or TACI activatestranscription factor NF-KB and increases the expression of pro-survival Bcl-2 family members (e.g. Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Al) and down regulates expression of pro-apoptotic factors (e.g. Bid, Bad, Bik, Bim, etc.), thus inhibiting apoptosis and promoting survival. This combined action promotes B cell differentiation, proliferation, survival, and antibody production (as reviewed in Rickert RC et al., Immunol Rev (2011) 244 (1): 115-133).

[0073] As BCMA is expressed on plasmablasts and plasma cells and has a role in B cell differentiation, proliferation, survival, and antibody production, BCMA may be a promising therapeutic target in autoimmune diseases. For example, as discussed above for RA, ACPA specific plasmablasts were found to circulate in the peripheral blood of RA patients and in the synovium, B cells are predominately plasmablast / plasma cells (50%) (Kerkman et al., Ann. Rheum. Dis., 72(7): 1259-1263 (2013) and Kerkman et al., Ann. Rheum. Dis., 75(12):2201-2207 (2016), each of which are herein incorporated by reference in their entirety). Thus, targeting the plasmablasts and plasma cells that express BCMA may selectively deplete the population of cells implicated in the production of autoantibodies.

[0074] Various anti-BCMA therapeutics are known in the art and may be useful for the development of treatments for autoimmune diseases. However, any substance that inhibits BCMA may be suitable for the development of treatments of autoimmune diseases.

[0075] In some embodiments, the anti-BCMA therapeutic is an antibody. In some embodiments, the anti-BCMA therapeutic is a bispecific antibody. Various bispecific antibody formats include formats described herein and recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; IgG fusion molecules, wherein full length IgG antibodies are fused to an extra Fab fragment or parts of Fab fragment; Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; Fab fusion molecules, wherein different Fab-fragments are fused together; ScFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different single chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g. domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or bispecific antibodies generated by arm exchange. Exemplary bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), DuoBody (Genmab),Ts2Ab (Medlmmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idee) and TvAb (Roche), ScFv / Fc Fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), Bispecific T Cell Engager (BITE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies have been described, for example in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and in Nunez-Prado et al., (2015) Drug Discovery Today 20(5): 588-594.

[0076] In some embodiment, the anti-BCMA therapeutic is an antibody drug conjugate. In some embodiments, the anti-BCMA therapeutic is an antibody fragment. In some embodiments, the anti-BCMA therapeutic is a cell comprising an antibody or an antibody fragment, such as an anti-BCMA CAR-T cell product. In some embodiments, the anti-BCMA therapeutic is listed in Tables 3 and 4.Table 3. Inhibitors of BCMATable 4. Anti-BCMA Antibodies

[0077] In some embodiments, the anti-BCMA therapeutic is SEA-BCMA, a humanized nonfucosylated IgGl monoclonal anti-BCMA antibody.

[0078] In some embodiments, the anti-BCMA therapeutic is belantamab mafodotin (also known as Blenrep), an afucosylated monoclonal anti-BCMA antibody conjugated to the microtubule disrupter monomethyl auristatin-F (MMAF). In some embodiments, belantamab mafodotin is described in U.S. Patent No. 9,273,141, which is incorporated herein by reference in its entirety.

[0079] In some embodiments, the anti-BCMA therapeutic is ispectamab debotansine (also known as CC-99712), an anti-BCMA IgGl humanized antibody conjugated covalently to the dibenzocyclooctyne (DBCO) noncleavable linker maytansinoid warhead.

[0080] In some embodiments, the anti-BCMA therapeutic is teclistamab (also known as CC- 93269, BI 836909, JNJ-64007957, PF-06863135, or TECVAYLI®), an BCMA x CD3 bispecific antibody. Teclistamab and its methods of use are described, for example, in WO 2017 / 031104, WO 2019 / 220369 and WO 2021 / 228783, which are incorporated by reference herein. In some embodiments, the BCMAxCD3 bispecific antibody has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of teclistamab.

[0081] In some embodiments, the anti-BCMA anti-BCMA therapeutic is elranatamab (also known as ELREXFIO™), a humanized immunoglobulin 2-alanine kappa antibody derived fromtwo monoclonal antibodies, an anti-BCMA mAb and an anti-CD3 mAb. In some embodiments, elranatamab is described in U.S. Patent No. 9,969,809, which is incorporated herein by reference in its entirety.

[0082] In some embodiments, the anti-BCMA therapeutic body is ABBV-383 (also known as TNB-383B), a CD3 and BCMA T-cell engaging bispecific antibody.

[0083] In some embodiments, the anti-BCMA therapeutic is alnuctamab, a BCMAxCD3 bispecific monoclonal antibody.

[0084] In some embodiments, the anti-BCMA therapeutic is linvoseltamab, an investigational BCMAxCD3 bispecific antibody.

[0085] In some embodiments, the anti-BCMA therapeutic is ISB 2001, a T-cell engaging trispecific antibody that targets BCMA, CD38, and CD3.

[0086] In some embodiments, the anti-BCMA therapeutic is any anti-BCMA molecule disclosed in any of the patent publications listed in Table 4, all of which are incorporated by reference in their entirety.

[0087] In some embodiments, any anti-BCMA antibody described herein comprise certain substitutions in the antibody Fc region that enhance the antibody half-life. For example, exemplary substitutions are substitutions at amino acid positions 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430 (residue numbering according to the EU index) as described in U.S. Pat. No. 6,737,056. In some embodiments, the anti-BCMA therapeutic is any antibody described herein that is further modified by one or more modifications of its Fc region that enhance the half-life of the antibody.

[0088] In some embodiments, the anti-BCMA therapeutic is present in a pharmaceutical composition. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with the anti-BCMA therapeutic. The pharmaceutical composition may be in aqueous form for intravenous or subcutaneous administration. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition is suitable for subcutaneous administration.

[0089] In some embodiments, the pharmaceutical composition comprises one or more of sodium phosphate, sodium chloride, trehalose, or polysorbate.

[0090] In some embodiments, the pharmaceutical compositions that contain an anti-BCMA therapeutic may be formulated for intravenous administration, parenteral administration,subcutaneous administration, intramuscular administration, intra-arterial administration, intrathecal administration, or intraperitoneal administration. For injectable formulations, various effective pharmaceutical carriers are known in the art.

[0091] The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to the anti- BCMA therapeutic. The nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used.

[0092] In some embodiments, the anti-BCMA therapeutic or a pharmaceutical composition comprising the anti-BCMA therapeutic is administered as a single dose. As used herein, “dose” refers to a single administration of the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic. In some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is dosed based on the weight of the subject.

[0093] In some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered every week, every two weeks, or monthly. In some embodiments, the initial dose is different from the weekly or once every two weeks dose. In some embodiments, the dose is the same every time it is administered.

[0094] In some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered parenterally. In some embodiments, the anti-BCMA therapeutic pharmaceutical composition comprising the anti-BCMA therapeutic is administered intravenously or subcutaneously. In some embodiments, the anti-BCMA therapeutic pharmaceutical composition comprising the anti-BCMA therapeutic is administered intravenously. In some embodiments, the anti-BCMA therapeutic is administered subcutaneously.

[0095] In some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered to the subject in a safe and efficacious manner to treat the autoimmune disease. While dosing regimens can vary, in some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered to the subject one time, or two or more times, as needed. In some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered in a dosing cycle which can comprise step-up dosing, one or more priming doses,maintenance doses, or other repeated doses. Thus, in some embodiments, the anti-BCMA therapeutic or pharmaceutical composition comprising the anti-BCMA therapeutic is administered to the subject for one cycle, or for two or more cycles, as needed. In certain embodiments, a cycle is 28 days. In alternative embodiments, a cycle is 21 days.

[0096] In some embodiments, teclistamab can be administered for the treatment of an autoimmune disease with step-up doses followed by 1.5 mg / kg weekly doses; for example, a first dosing cycle can comprise a first step up dose of 0.06 mg / kg on day 1, and a second step up dose of 0.3 mg / kg on day 4, followed by a 1.5 mg / kg dose on day 7. In some embodiments, no more teclistamab is administered to the subject for the treatment of the autoimmune disease. In some embodiments, additional 1.5 mg / kg weekly doses of teclistamab are administered as needed to achieve an efficacious response in the subject. In some embodiments, the 1.5 mg / kg weekly dose is administered for one week, two weeks, three weeks, four weeks, or more.

[0097] According to certain embodiments, a method of treating an autoimmune disease in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-BCMA therapeutic. In some embodiments, the anti-BCMA therapeutic is an antibody. In certain embodiments, the anti- BCMA therapeutic is a monospecific antibody, a bispecific antibody, a trispecific antibody, an antibody drug conjugate, an antibody fragment, or a cell comprising an antibody or an antibody fragment. In some embodiments, the anti-BCMA therapeutic is selected from the group consisting of SEA-BCMA, belantamab mafodotin, ispectamab debotansine, teclistamab, elranatamab, ABBV-383, alnuctamab, linvoseltamab, and ISB 2001. In some embodiments, the pharmaceutical composition is administered to the subject one time, two or more times, for one cycle, or for two or more cycles (e.g., wherein a cycle is 28 days).

[0098] In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is moderate to severe active rheumatoid arthritis. In some embodiments, the method comprises administering a pharmaceutical composition comprising an anti-BCMA therapeutic to the subject. In some embodiments, the anti-BCMA therapeutic is as provided for herein. In some embodiments, the anti-BCMA therapeutic is teclistamab.

[0099] In some embodiments, the subject treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis, shows an improvement as a result of treatment with an anti-BCMA therapeutic in one or more of the following assays, scores or criteria, which can be used to evaluatethe improvement or condition of a subject with rheumatoid arthritis. In some embodiments, the subject shows improvement in one or more of the following: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CDAI score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score.

[0100] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis has or shows a reduction in one or more immunoglobulin isotypes or total IgG, as a result of treatment with an anti-BCMA therapeutic. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%. In some embodiments, the isotype of immunoglobulins reduced is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE, or any combination thereof. In some embodiments, the administration of the pharmaceutical composition to the patient shows a reduction in one or more immunoglobulin isotypes or total IgG in the patient. In some embodiments, the isotype is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%.

[0101] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis has or shows a reduction in autoantibodies as a result of treatment with an anti-BCMA therapeutic. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the autoantibodies reduced are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof. In some embodiments, the administration of the pharmaceutical composition to the patient shows a reduction in autoantibodies. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the autoantibodies reduced are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti- carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti- citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof.

[0102] In some embodiments, the autoimmune disease is Sjogren's syndrome. In some embodiments, the Sjogren's syndrome is Primary Sjogren's syndrome (pSjS). In some embodiments, the method comprises administering a pharmaceutical composition comprising an anti-BCMA therapeutic to the subject. In some embodiments, the anti-BCMA therapeutic is as provided for herein. In some embodiments, the anti-BCMA therapeutic is teclistamab.

[0103] In some embodiments, the subject treated for Sjogren's syndrome, or Primary Sjogren's syndrome (pSjS), shows an improvement as a result of treatment with an anti-BCMA therapeutic in one or more of the following assays, scores or criteria, which can be used to evaluate the improvement or condition of a subject with Sjogren's syndrome. In some embodiments, the subject shows improvement in one or more of the following: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT- Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF-36, PROMIS- 29 v2.0, Hospital Anxiety and Depression Scale (H DS), Work Productivity and Activity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria.

[0104] In some embodiments, the subject being treated for Sjogren's syndrome, or Primary Sjogren's syndrome (pSjS) has or shows a reduction in one or more immunoglobulin isotypes or total IgG, as a result of treatment with an anti-BCMA therapeutic. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%. In some embodiments, the isotype of immunoglobulins reduced is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE, or any combination thereof.

[0105] In some embodiments, the subject being treated for Sjogren's syndrome, or Primary Sjogren's syndrome (pSj S) has or shows a reduction in autoantibodies, as a result of treatment with an anti-BCMA therapeutic. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, orat least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the autoantibodies reduced are selected from the group consisting of: anti- La (SSB), anti-Smith, antinuclear antibodies (ANA), anti-phospholipid antibodies, anti-dsDNA antibodies, anti-nRNP (ribonucleoproteins) antibodies, anti-rheumatoid factor antibodies, anti-Ro antibodies, and any combination thereof.

[0106] In some embodiments, the autoimmune disease is systemic lupus erythematosus. In some embodiments, the systemic lupus erythematosus is at least moderately active systemic lupus erythematosus. In some embodiments, the method comprises administering a pharmaceutical composition comprising an anti-BCMA therapeutic to the subject. In some embodiments, the anti- BCMA therapeutic is as provided for herein. In some embodiments, the anti-BCMA therapeutic is teclistamab.

[0107] In some embodiments, the subject treated for systemic lupus erythematosus shows an improvement, as a result of treatment with an anti-BCMA therapeutic, in one or more of the following assays, scores or criteria, which can be used to evaluate the improvement or condition of a subject with systemic lupus erythematosus. In some embodiments, the subject shows improvement in one or more of the following: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain-NRS), Lunctional Assessment of Chronic Illness Therapy-Latigue (LACIT-Latigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Porm 36-Item (SF-36) questionnaire, physical activity, mobility, sleep joint, and skin score.

[0108] In some embodiments, the subject being treated for systemic lupus erythematosus, as a result of treatment with an anti-BCMA therapeutic, has or shows a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%. In some embodiments, the isotype of immunoglobulins reduced is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE, or any combination thereof.

[0109] In some embodiments, the subject being treated for systemic lupus erythematosus has or shows a reduction in autoantibodies, as a result of treatment with an anti-BCMA therapeutic. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the autoantibodies reduced are selected from the group consisting of: anti-Sm / RNP, anti-SSA / Ro, anti- SSB / La, anti-dsDNA, antinuclear antibodies (ANA), anti-Smith, anti-NMDAR, anti-02GPl, antiphospholipid antibodies, anti-Clq, anti-Ribosomal P antibodies, and any combination thereof.Additional Therapeutics

[0110] In some embodiments, the subject being treated for an autoimmune disease has been previously treated with a different therapeutic to treat the autoimmune disease. In some embodiments, the subject has previously been treated with glucocorticoids, immunosuppressives, pharmacological gland stimulant, topical ophthalmologic medication (other than artificial tears), hydroxychloroquine (or other antimalarial); NSAIDs, Methotrexate, Leflunomide, rituximab, anti- BAFF monoclonal antibody, or other B cell depleting therapeutic, anti-tumor necrosis factor (TNF) therapeutic, or other biologic medication (e.g., tocilizumab, alefacept, efalizumab, natalizumab, abatacept, anakinra, brodalumab, secukinumab, ixekizumab, or agents whose mechanism of action targets interleukin (IL) 1, IL-2, IL-6, IL- 17, cytotoxic T-lymphocyte- associated protein (CTLA) 4, or interferon pathway drugs), cyclosporine A, tacrolimus, pimecrolimus, JAK inhibitors (e.g., tofacitinib, baricitinib, or upadacitinib), or any combination thereof.

[0111] In some embodiments, the subject being treated for an autoimmune disease is treated with one or more co-treatments. In some embodiments, the subject being treated for an autoimmune disease is treated with one or more co-treatments simultaneously, about simultaneously, or sequentially, in addition to the anti-BCMA therapeutic. In some embodiments, the co-treatment is glucocorticoids, immunosuppressives, pharmacological gland stimulant, topical ophthalmologic medication (other than artificial tears), hydroxychloroquine (or other antimalarial); NSAIDs, Methotrexate, Leflunomide, rituximab, anti-BAFF monoclonal antibody, or other B cell depleting therapeutic, anti-tumor necrosis factor (TNF) therapeutic, or other biologic medication (e.g., tocilizumab, alefacept, efalizumab, natalizumab, abatacept, anakinra,brodalumab, secukinumab, ixekizumab, or agents whose mechanism of action targets interleukin (IL) 1, IL-2, IL-6, IL- 17, cytotoxic T-lymphocyte-associated protein (CTLA) 4, or interferon pathway drugs), cyclosporine A, tacrolimus, pimecrolimus, JAK inhibitors (e.g., tofacitinib, baricitinib, or upadacitinib), or any combination thereof.Enumerated Embodiments

[0112] The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.1. A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-BCMA therapeutic.2. The method of embodiment 1, wherein the anti-BCMA therapeutic is a monospecific antibody, a bispecific antibody, a trispecific antibody, an antibody drug conjugate, an antibody fragment, or a cell comprising an antibody or an antibody fragment.3. The method of embodiment 2, wherein the anti-BCMA therapeutic is selected from the group consisting of SEA-BCMA, belantamab mafodotin, ispectamab debotansine, teclistamab, elranatamab, ABBV-383, alnuctamab, linvoseltamab, and ISB 2001.4. The method of any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered to the subject one time.5. The method of any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered to the subject two or more times.6. The method of any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered to the subject for one cycle.7. The method of any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered to the subject for two or more cycles.8. The method of any one of embodiments 1 to 7, wherein the autoimmune disease is selected from the group consisting of Addison's disease, alopecia areata, Wegener's granulomatosis, ankylosing spondylitis, antibody-mediated rejection, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, autoimmune haemolytic anaemia (AIHA), autoimmune hearing loss, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, Behcets disease, bullous pemphigoid, catastrophic antiphospholipid antibody syndrome, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, glomerulus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, hepatitis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, immune complex-mediated vasculitis, immune neutropenia, inflammatory bowel disease, insulin dependent diabetes juvenile arthritis, lichen planus, limited scleroderma (CREST syndrome), lupus nephritis, Meniere's Disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, reactive arthropathies, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, serum sickness, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, and vitiligo.9. The method of any one of embodiments 1 to 8, wherein the autoimmune disease is rheumatoid arthritis.10. The method of embodiment 9, wherein the rheumatoid arthritis is moderate to severe active rheumatoid arthritis.11. The method of embodiment 9 or 10, wherein the subject, after administration of the anti- BCMA therapeutic, shows improvement in one or more of the following: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CD Al score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score.12. The method of any one of embodiments 9 to 11, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.13. The method of any one of embodiments 9 to 12, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.14. The method of embodiment 13, wherein the autoantibodies are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof.15. The method of any one of embodiments 1 to 8, wherein the autoimmune disease is Sjogren's syndrome.16. The method of embodiment 15, wherein the Sjogren's syndrome is Primary Sjogren's syndrome.17. The method of embodiment 15 or 16, wherein the subject, after administration of the anti- BCMA therapeutic, shows improvement in one or more of the following: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT-Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF- 36, PROMIS-29 v2.0, Hospital Anxiety and Depression Scale (HADS), Work Productivity andActivity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria.18. The method of any one of embodiments 15 to 17, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.19. The method of any one of embodiments 15 to 18, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.20. The method of embodiment 19, wherein the autoantibodies are selected from the group consisting of: anti-La (SSB), anti-Smith, antinuclear antibodies (ANA), anti-phospholipid antibodies, anti-dsDNA antibodies, anti-nRNP (ribonucleoproteins) antibodies, anti-rheumatoid factor antibodies, anti-Ro antibodies, and combinations thereof.21. The method of any one of embodiments 1 to 8, wherein the autoimmune disease is systemic lupus erythematosus.22. The method of embodiment 21 , wherein the is at least moderately active systemic lupus erythematosus.23. The method of embodiment 21 or 22, wherein the subject, after administration of the anti- BCMA therapeutic, shows improvement in one or more of the following: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain- NRS), Lunctional Assessment of Chronic Illness Therapy-Latigue (LACIT-Latigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Lorm 36-Item (SL-36) questionnaire, physical activity, mobility, sleepjoint, and skin score.24. The method of any one of embodiments 21 to 23, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.25. The method of any one of embodiments 21 to 24, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.26. The method of embodiment 25, wherein the autoantibodies are selected from the group consisting of: anti-Sm / RNP, anti-SSA / Ro, anti-SSB / La, anti-dsDNA, antinuclear antibodies (ANA), anti-Smith, anti-NMDAR, anti-02GPl, anti-phospholipid antibodies, anti-Clq, anti- Ribosomal P antibodies, and any combination thereof.27. The method of any proceeding embodiment, wherein the anti-BCMA therapeutic is teclistamab.28. The method of embodiment 27, wherein teclistamab is administered subcutaneously at a dose of about 1.5 mg / kg of the subject weekly.29. The method of embodiment 28, wherein a first step up dose of 0.06 mg / kg of the subject and a second step up dose of 0.3 mg / kg of the subject are administered to the subject prior to the first dose of about 1.5 mg / kg weekly.30. The method of any one of embodiments 27 to 29, wherein teclistamab is administered to the subject for one week.31. The method of any one of embodiments 27 to 29, wherein teclistamab is administered to the subject for two or more weeks.EXAMPLES

[0113] The following examples are provided to further describe some of the aspects and embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed aspects or embodiments.Example 1: Treatment of rheumatoid arthritis with an anti-BCMA therapeutic.

[0114] A subject with moderate to severe active rheumatoid arthritis will be administered a pharmaceutical composition comprising an anti-BCMA therapeutic at a dose and duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following rheumatoid arthritis scores: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CDAI score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score. Additionally, the subject will show a reduction in autoantibodies for rheumatoid arthritis.Example 2: Treatment of rheumatoid arthritis with teclistamab.

[0115] A subject with moderate to severe active rheumatoid arthritis will be administered teclistamab at a dosage of 1.5 mg / kg for a duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following rheumatoid arthritis scores: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CDAI score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score. Additionally, the subject will show a reduction in autoantibodies for rheumatoid arthritis.Example 3: Treatment of Sjogren's syndrome with an anti-BCMA therapeutic.

[0116] A subject with Primary Sjogren's syndrome will be administered a pharmaceutical composition comprising an anti-BCMA therapeutic at a dose and duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following Sjogren's syndrome scores: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT-Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF-36,PROMIS-29 v2.0, Hospital Anxiety and Depression Scale (HADS), Work Productivity and Activity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria. Additionally, the subject will show a reduction in autoantibodies for Sjogren's syndrome.Example 4: Treatment of Sjogren's syndrome with teclistamab.

[0117] A subject with Primary Sjogren's syndrome will be administered teclistamab at a dosage of 1.5 mg / kg for a duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following Sjogren's syndrome scores: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT-Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF-36, PROMIS-29 v2.0, Hospital Anxiety and Depression Scale (HADS), Work Productivity and Activity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria. Additionally, the subject will show a reduction in autoantibodies for Sjogren's syndrome.Example 5: Treatment of systemic lupus erythematosus with an anti-BCMA therapeutic.

[0118] A subject with at least moderately active systemic lupus erythematosus will be administered a pharmaceutical composition comprising an anti-BCMA therapeutic at a dose and duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following lupus scores: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAL2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain-NRS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Form 36-Item (SF-36) questionnaire, physical activity, mobility, sleep, joint, and skin score. Additionally, the subject will show a reduction in autoantibodies for systemic lupus erythematosus.Example 6: Treatment of systemic lupus erythematosus with teclistamab.

[0119] A subject with at least moderately active systemic lupus erythematosus will be administered teclistamab at a dosage of 1.5 mg / kg for a duration sufficient for the subject to have an efficacious response. The response will be characterized by the subject having an improvement in one or more of the following lupus scores: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain-NRS), Lunctional Assessment of Chronic Illness Therapy-Latigue (LACIT-Latigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Lorm 36-Item (SL-36) questionnaire, physical activity, mobility, sleep joint, and skin score. Additionally, the subject will show a reduction in autoantibodies for systemic lupus erythematosus.

Claims

What is claimed is:

1. A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-BCMA therapeutic.

2. The method of claim 1, wherein the anti-BCMA therapeutic is a monospecific antibody, a bispecific antibody, a trispecific antibody, an antibody drug conjugate, an antibody fragment, or a cell comprising an antibody or an antibody fragment.

3. The method of claim 2, wherein the anti-BCMA therapeutic is selected from the group consisting of SEA-BCMA, belantamab mafodotin, ispectamab debotansine, teclistamab, elranatamab, ABBV-383, alnuctamab, linvoseltamab, and ISB 2001.

4. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to the subject one time.

5. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to the subject two or more times.

6. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to the subject for one cycle.

7. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to the subject for two or more cycles.

8. The method of any one of claims 1 to 7, wherein the autoimmune disease is selected from the group consisting of Addison's disease, alopecia areata, Wegener's granulomatosis, ankylosing spondylitis, antibody-mediated rejection, antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis, antiphospholipid syndrome, autoimmune haemolytic anaemia (AIHA), autoimmune hearing loss, autoimmune hepatitis, autoimmune lymphoproliferative syndrome,Behcets disease, bullous pemphigoid, catastrophic anti-phospholipid antibody syndrome, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, glomerulus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, hepatitis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, immune complex-mediated vasculitis, immune neutropenia, inflammatory bowel disease, insulin dependent diabetes juvenile arthritis, lichen planus, limited scleroderma (CREST syndrome), lupus nephritis, Meniere's Disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, reactive arthropathies, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, serum sickness, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, and vitiligo.

9. The method of any one of claims 1 to 8, wherein the autoimmune disease is rheumatoid arthritis.

10. The method of claim 9, wherein the rheumatoid arthritis is moderate to severe active rheumatoid arthritis.

11. The method of claim 9 or 10, wherein the subject, after administration of the anti-BCMA therapeutic, shows improvement in one or more of the following: DAS28 (CRP) score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CD Al score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score.

12. The method of any one of claims 9 to 11, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.

13. The method of any one of claims 9 to 12, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.

14. The method of claim 13, wherein the autoantibodies are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof.

15. The method of any one of claims 1 to 8, wherein the autoimmune disease is Sjogren's syndrome.

16. The method of claim 15, wherein the Sjogren's syndrome is Primary Sjogren's syndrome.

17. The method of claim 15 or 16, wherein the subject, after administration of the anti- BCMA therapeutic, shows improvement in one or more of the following: Schirmer’s test for CRESS score, Unstimulated Salivary Flow test for CRESS, Physician’s Global Assessment (PGA), FACIT-Fatigue, Sjogren's Symptoms, Patient Global Impression of Severity (PGIS) of Sjogren’s Syndrome, Patient Global Impression of Change (PGIC) in Sjogren’s Syndrome, SF- 36, PROMIS-29 v2.0, Hospital Anxiety and Depression Scale (HADS), Work Productivity and Activity Impairment (WPAI), or Primary SjS diagnosis by 2016 ACR-EULAR Classification Criteria.

18. The method of any one of claims 15 to 17, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.

19. The method of any one of claims 15 to 18, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.

20. The method of claim 19, wherein the autoantibodies are selected from the group consisting of: anti-La (SSB), anti-Smith, antinuclear antibodies (ANA), anti-phospholipid antibodies, anti-dsDNA antibodies, anti-nRNP (ribonucleoproteins) antibodies, anti-rheumatoid factor antibodies, anti-Ro antibodies, and combinations thereof.

21. The method of any one of claims 1 to 8, wherein the autoimmune disease is systemic lupus erythematosus.

22. The method of claim 21, wherein the is at least moderately active systemic lupus erythematosus.

23. The method of claim 21 or 22, wherein the subject, after administration of the anti- BCMA therapeutic, shows improvement in one or more of the following: SLE Responder Index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG), British Isle Composite Lupus Assessment (BICLA), glucocorticoid taper, Lupus Multivariable Outcomes Score (LuMOS), Lupus Low Disease Activity State (LLDAS), Pain Numeric Rating Scale (Pain- NRS), Lunctional Assessment of Chronic Illness Therapy-Latigue (LACIT-Latigue), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), Lupus Quality of Life (LupusQoL), Short Lorm 36-Item (SL-36) questionnaire, physical activity, mobility, sleepjoint, and skin score.

24. The method of any one of claims 21 to 23, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in one or more immunoglobulin isotypes or total IgG.

25. The method of any one of claims 21 to 24, wherein the subject, after administration of the anti-BCMA therapeutic, shows a reduction in autoantibodies.

26. The method of claim 25, wherein the autoantibodies are selected from the group consisting of: anti-Sm / RNP, anti-SSA / Ro, anti-SSB / La, anti-dsDNA, antinuclear antibodies(ANA), anti-Smith, anti-NMDAR, anti-02GPl, anti-phospholipid antibodies, anti-Clq, anti- Ribosomal P antibodies, and any combination thereof.

27. The method of any proceeding claim, wherein the anti-BCMA therapeutic is teclistamab.

28. The method of claim 27, wherein teclistamab is administered subcutaneously at a dose of about 1.5 mg / kg of the subject weekly.

29. The method of claim 28, wherein a first step up dose of 0.06 mg / kg of the subject and a second step up dose of 0.3 mg / kg of the subject are administered to the subject prior to the first dose of about 1.5 mg / kg weekly.

30. The method of any one of claims 27 to 29, wherein teclistamab is administered to the subject for one week.

31. The method of any one of claims 27 to 29, wherein teclistamab is administered to the subject for two or more weeks.

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