CD19 / CD38 multispecific antibodies for autoimmune and inflammatory therapies

Abstract

Provided herein are B cell depleting multispecific antibodies that bind CD19 and CD38, and effectively deplete auto-reactive CD19+CD38high / + B cells, CD19+CD38low B cells that rapidly differentiate into pathologic plasmablasts but preserve protective CD19-CD38high / + long lived plasma B cells and CD19+CD20+IgM+IgD+CD27- naïve B cells.

Description

CD19 / CD38 MULTISPECIFIC ANTIBODIES FOR AUTOIMMUNE AND INFLAMMATORY THERAPIES CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 709,892, filed on October 21, 2024, and U.S. Provisional Application Serial No. 63 / 827,715, filed on June 20, 2025, each of which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically and is hereby incorporated by reference in its entirety. Said copy, created on October 14, 2025, is named 51527-719-60 l_SEQ.xml and is 26000 bytes in size.BACKGROUND

[0003] Autoimmune disorders present significant challenges due to their complexity and variability. These conditions, which generally involve the immune system mistakenly attacking the body's own cells, are difficult to diagnose accurately because they often present with symptoms that overlap with other disorders. Even when properly diagnosed, developing effective and safe treatments remains a challenge. Additionally, as the underlying causes of many autoimmune diseases are still not fully understood, developing effective targeted therapies remains a substantial obstacle.SUMMARY

[0004] Despite advances in autoimmune and inflammatory therapies, a major bottleneck of such therapies can still be defined by safety concerns (e.g., from the depletion of a protective immune response). These challenges are notably present in B cell depleting therapies, such as monospecific therapies that target CD38 or CD 19 individually, whether antibodies or chimeric antigen receptor T cells (CAR T-cells). For example, monospecific anti-CD38 therapies do not differentiate between immunologically beneficial CD19'CD38hlghlong lived plasma B cells and pathogenic auto-reactive CD19+CD38hlghB cells or CD19lowCD38hlghB cells. Moreover, such monospecific anti-CD38 therapies are generally unable to target CD19+CD38lowB cells that rapidly differentiate into pathologic plasmablasts. Additionally, CAR T cells have a much higher incidence of systemic toxic side effects, such as cytokine release syndrome. Accordingly, there is an unmet need for the development of new B cell depleting therapies that effectively depletepathogenic auto-reactive CD19+CD38hlgh / +B cells, CD19+CD38lowB cells that rapidly differentiate into pathologic plasmablasts but preserve protective CD19'CD38hlghlong lived plasma B cells, preserve CD19+CD38‘ naive B cells, and have fewer toxic side effects. In other words, therapies are needed that result in less immunosuppression and greater protection from highly inflammatory side effects.

[0005] Provided herein are B cell depleting multispecific antibodies that bind CD 19 and CD38, and effectively deplete auto-reactive CD19+CD38hlgh / +B cells, CD19+CD38lowB cells, or CD19lowCD38hlghB cells that rapidly differentiate into pathologic plasmablasts, but preserve protective CD19'CD38hlgh / +long lived plasma B cells and CD19+CD20+IgM+IgD+CD27‘ naive B cells. The B cell depleting multispecific antibodies described herein also rapidly deplete pathogenic B cells by a variety of mechanisms including direct apoptosis, antibody dependent cell cytotoxicity (ADCC), cell dependent cytotoxicity (CDC), and antibody dependent cell phagocytosis (ADCP). This rapid depletion is achieved at reduced risk of cytokine release syndrome, as seen with CAR T cells, and spares beneficial B cell lineage subsets, such as CD19' CD38hlghlong lived plasma B cells and CD19+CD20+IgM+IgD+CD27‘ naive B cells enabling more effective and safer therapies for autoimmune diseases. Furthermore, the multispecific engagement of CD 19 and CD38 simultaneously allows for targeting of pathogenic B cell populations that express low amounts of either target such as CD19lowCD38hlghB cells that may be missed by monospecific binding. Additionally, the rapid and specific direct killing of the disclosed multispecific antibodies allow for the use of Fc regions with reduced effector function, thereby reducing or eliminating activation of complement, phagocytic cells, and NK cells.

[0006] In some embodiments, provided herein are methods of treating an autoimmune disorder or an inflammatory disorder in an individual, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby treating the autoimmune disorder. In certain embodiments, the autoimmune disorder is characterized by the presence of antibodies in the individual that bind double stranded deoxyribonucleic acid (dsDNA).

[0007] In some embodiments, provided are methods of reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby reducing the number of B cells in the individual that express CD 19 and CD38, wherein the B cells that express CD19 and CD38 comprise CD19+CD381ow B cells, CD19+CD38 high / + B cells, or both CD19+CD381ow B cells and CD19+CD38 high / + B cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does notsubstantially reduce the amount of CD19'CD38hlghB cells. In certain embodiments, the treating does not induce hypogammaglobulinemia. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19 CD38+B cells. In certain embodiments, “does not substantially reduce the amount of CD19'CD38hlgh / +B cells” refers to an antibody that, when administered, does not increase ADCP of CD19' CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced ADCP of CD19'CD38hlgh / +B cells when compared to daratumumab. The ADCP assay described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells. In certain embodiments, the administering does not induce hypogammaglobulinemia. In certain embodiments, the autoimmune disorder or the inflammatory disorder is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), anti -neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), or Type 1 diabetes (T1D). In certain embodiments, the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti-phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis.

[0008] In some embodiments, also provided herein are methods of treating lupus in an individual, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby treating lupus in the individual. In certain embodiments, treating the lupus comprises reducing an amount of antibodies that bind dsDNA in the individual. In certain embodiments, treating the lupus comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38. In certain embodiments, the B cells are CD19+CD38lowor CD19+CD38hlgh. In certain embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38lowB cells, or both CD19+CD38lowB cells and CD19+CD38lowB cells in the individual. In certain embodiments themultispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlgh. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not induce hypogammaglobulinemia.

[0009] The multispecific antibodies described herein effectively deplete CD19+CD38high / + B cells, CD19+CD38lowB cells, but preserve CD19'CD38hlgh / +B cells. In certain embodiments, the multispecific antibodies that bind CD19 and Cd38 (i) increase antibody-dependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; and (ii)(a) do not increase ADCP of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (ii)(b) result in reduced ADCP of CD19'CD38hlgh / +B cells when compared to daratumumab. The ADCP assays described in the Examples can be used to determine that a multispecific antibody or multispecific antibody fragment (i) kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, and / or (ii) does not substantially reduce the amount of CD19'CD38hlgh / +B cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of other CD19'CD38hlghimmune cells, such as CD38hlghregulatory T cells and CD38hlghmyeloid-derived suppressor cells (MDSCs).

[0010] In certain embodiments, the multispecific antibody or multispecific antibody fragment is a bispecific antibody or bispecific antibody fragment that binds CD19 and CD38. In certain embodiments, the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 comprises: an anti-CD38 heavy chain variable domain and an anti-CD38 light chain variable domain; and an anti-CD19 heavy chain variable domain and an anti -CD 19 light chain variable domain. In certain embodiments, the anti-CD38 heavy chain variable domain comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9, the anti-CD38 light chain variable domain comprises: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acidsequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25, the anti-CD19 heavy chain variable comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and the anti-CD19 light chain variable domain comprises: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

[0011] In certain embodiments, the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 is a common light chain bispecific antibody. In certain embodiments, the common light chain bispecific antibody comprises: an anti-CD38 heavy chain variable domain comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9, an anti-CD19 heavy chain variable comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and a common light chain variable domain comprising: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chaincomplementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

[0012] In certain embodiments, the anti-CD38 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 1, the anti-CD19 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 2, and common light chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 3. In certain embodiments, the common light chain bispecific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 4, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 5, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 6.

[0013] In certain embodiments, the multispecific antibody or multispecific antibody fragment comprises an afucosylated Fc region. In certain embodiments, the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increase affinity to FcRn. In certain embodiments, the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increases the plasma halflife of the multispecific antibody or multi specific antibody fragment (e.g., one or more of the alternation in Table 2). In certain embodiments, the one or more modifications relative to wildtype IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

[0014] Also provided herein are, in some embodiments, a common light chain multispecific antibody that binds CD19 and CD38, wherein the common light chain multispecific antibody comprises: (i) an anti-CD38 heavy chain amino acid sequence comprising SEQ ID NO: 26, (ii) an anti-CD19 heavy chain amino acid sequence comprising SEQ ID NO: 27, (iii) a first common light chain amino acid sequence comprising SEQ ID NO 28, and (iv) a second common light chain amino acid sequence comprising SEQ ID NO 28.Provided herein, in one aspect, is a method of treating an autoimmune disorder or an inflammatory disorder in an individual in need thereof. In some embodiments, the method comprises administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby treating the autoimmune disorder or aninflammatory disorder. In some embodiments, the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-nuclear antibodies (ANAs), antidouble stranded deoxyribonucleic acid (dsDNA) antibodies, anti-Ro / La antibodies, anti-Sm antibodies, anti-phospholipid antibodies, anti-ribonucleoprotein (RNP) antibodies, anti-glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) antibodies, anti-histones antibodies, antisynthetase (autoantibodies to aminoacyl -tRNA synthetases) antibodies, anti -centromere antibodies, anti-Scl-70 (anti -topoisomerase I) antibodies, anti-RNA polymerase III antibodies, anti-aminoacyl-tRNA synthetase (including anti-Jo-1) antibodies, anti-Mi-2 antibodies, antisignal recognition particle (SRP), anti -mitochondrial (AMAs) antibodies, anti-smooth muscle (ASMAs) antibodies, anti -neutrophil cytoplasmic antibodies, anti-thyroid antibodies antibodies, anti-transglutaminase antibodies, or a combination thereof. In some embodiments, the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-desmoglein-1 (Dsgl) antibodies, anti -acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSK) antibodies, anti -low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, anti-BP180 antibodies, anti-BP230 antibodies, anti-signal recognition particle (SRP) antibodies, anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, or a combination thereof. In some embodiments, the inflammatory disorder is characterized by the presence of antibodies in the individual that bind double stranded deoxyribonucleic acid (dsDNA). In some embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing the amount of the antibodies that bind dsDNA in the individual. In some embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38. In some embodiments, the B cells are CD19+CD381ow or CD19+CD38high. In some embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of CD19+CD381ow B cells, CD19+CD38 high / + B cells, or both CD19+CD381ow B cells and CD19+CD38high / + B cells in the individual. In some embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of memory B cells (CD 19+ CD20+ IgD CD27+) or plasmablasts (CD19+ CD20- CD27 high CD38high). In some embodiments, treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of long-lived plasma cells (CD19-CD38high B cells). In some embodiments, treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of naive B cells (CD 19+ CD20+ IgM+IgD+CD27 ). In some embodiments, treating the autoimmune disorder or the inflammatory disorder does notsubstantially reduce IgG levels in the individual. In some embodiments, administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19-CD38high B cells. In certain embodiments, administering the multispecific antibody or multispecific antibody fragment does not induce hypogammaglobulinemia. In some embodiments, the autoimmune disorder or the inflammatory disorder comprises systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), anti -neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), or Type 1 diabetes (T1D). In certain embodiments, the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti -phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis. In some embodiments, the autoimmune disorder comprises pemphigus, myasthenia gravis, or myositis. In some embodiments, the autoimmune disorder comprises pemphigus. In some embodiments, the pemphigus is pemphigus vulgaris. In some embodiments, the pemphigus is pemphigus foliaceus. In some embodiments, the autoimmune disorder comprises myasthenia gravis. In some embodiments, the autoimmune disorder comprises myositis. In some embodiments, the myositis is immune-mediated necrotizing myopathy. In some embodiments, the autoimmune disorder comprises pemphigus, myasthenia gravis, or myositis. In some embodiments, the autoimmune disorder comprises pemphigus. In some embodiments, the pemphigus is pemphigus vulgaris. In some embodiments, the pemphigus is pemphigus foliaceus. In some embodiments, the autoimmune disorder comprises myasthenia gravis. In some embodiments, the autoimmune disorder comprises myositis. In some embodiments, the myositis is immune-mediated necrotizing myopathy, and combinations thereof. In some embodiments, the myositis is dermatomyositis. In some embodiments, the myositis is anti-synthetase syndrome. In some embodiments, the autoimmune or inflammatory disorder comprises Lambert-Eaton syndrome, Goodpasture’s syndrome, Sjogren's syndrome, eosinophilic granulomatosis with polyangiitis (EGPA), ulcerative colitis, giant cell arteritis, Behcet's disease, Takayasu's arteritis, autoimmune polyendocrine syndrome,acute disseminated encephalomyelitis, anti-NMDA receptor encephalitis, chronic inflammatory demyelinating polyneuropathy, autoimmune pancreatitis, autoimmune oophoritis, autoimmune orchitis, stiff person syndrome, MOG antibody-associated disease (MOGAD), autoimmune autonomic ganglionopathy, autoimmune nodopathies, minimal change disease, focal segmental glomerulosclerosis, anti-LRP2 (anti-brush border) nephropathy, cryoglobulinemic vasculitis (type II / III), IgA vasculitis (Henoch-Schbnlein Purpura), autoantibody C3 glomerulopathy, immune thrombotic thrombocytopenic purpura (iTTP; anti-ADAMTS13), cold agglutinin disease (CAD), Evans syndrome, autoimmune pure red cell aplasia, chronic autoimmune neutropenia, hidradenitis suppurativa, dermatitismucous membrane pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, paraneoplastic pemphigus, pemphigoid gestationis, non-infectious uveitis, or thyroid eye disease, and combinations thereof.

[0015] Further provided herein, is a method of treating lupus in an individual. In some embodiments, the method comprises administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby treating lupus in the individual. In some embodiments, treating the lupus comprises reducing an amount of antibodies comprising anti-dsDNA in the individual. In some embodiments, treating the lupus comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38. In some embodiments, the B cells are CD19+CD38lowor CD19+CD38hlgh. In some embodiments, treating the lupus comprises reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells in the individual, optionally wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghcells. In certain embodiments, the method does not induce hypogammaglobulinemia.

[0016] Provided herein, in some embodiments, is a method of reducing the number of antibodies in an individual that bind dsDNA, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby reducing the number of antibodies in the individual that bind dsDNA. In some embodiments, the individual has an autoimmune disorder or an inflammatory disorder characterized by the presence of antibodies in the individual that bind dsDNA. In some embodiments, the individual has an increased number of antibodies in the individual that bind dsDNA.

[0017] Provided herein, in some embodiments, is a method of reducing (e.g., depleting) the number of B cells in an individual that express CD 19 and CD38. In some embodiments, the method comprises administering to the individual a multispecific antibody or multispecificantibody fragment that binds CD 19 and CD38, thereby reducing the number of B cells in the individual that express CD 19 and CD38. In some embodiments, the B cells that express CD 19 and CD38 comprise CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells. In some embodiments, administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD 19" CD38hlghB cells. In some embodiments, administering the multispecific antibody or multispecific antibody fragment reduces (e.g., depletes) the number of memory B cells (CD19+CD20+IgD CD27+) or plasmablasts (CD19+CD20 CD27hlCD38hl). In some embodiments, administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of long-lived plasma cells (CD19 CD38hlghB cells). In some embodiments, administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of Naive B cells. (CD19+CD20+IgM+IgD+CD27 ). In some embodiments, administering the multispecific antibody or multispecific antibody fragment does not substantially reduce IgG levels in the individual. In certain embodiments, administering the multispecific antibody or multispecific antibody fragment does not result in hypogammaglobulinemia. In some embodiments, the individual has a disorder characterized by immunoglobulin autoimmunity. In some embodiments, the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, in an in vitro assay: (i) increases antibody-dependent cellular phagocytosis (ADCP) of CD19+CD381ow B cells, CD19+CD38 high / + B cells, or both CD19+CD381ow B cells and CD19+CD38high / + B cells, compared to a human IgGl control or null control; (ii) does not increase ADCP of CD19-CD38high cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or results in reduced ADCP of CD19-CD38high cells when compared to daratumumab; and / or (iii) increases antibody-dependent cell cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or direct apoptosis of CD19+CD381ow B cells, CD19+CD38 high / + B cells, or both CD19+CD381ow B cells and CD19+CD38high / + B cells, compared to a human IgGl control or null control; and (iv) does not increase ADCC, CDC, or direct apoptosis of CD19-CD38high cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or results in reduced ADCC, CDC, or direct apoptosis of CD19-CD38high cells when compared to daratumumab. In some embodiments, the multispecific antibody or multispecific antibody fragment is a bispecific antibody or bispecific antibody fragment that binds CD19 and CD38. In some embodiments, the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 comprises: an anti-CD38 heavy chain variable domain and an anti-CD38 light chain variable domain; and an anti-CD19 heavy chain variable domain and an anti -CD 19 lightchain variable domain. In some embodiments, the anti-CD38 heavy chain variable domain comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9, the anti-CD38 light chain variable domain comprises: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25, the anti-CD19 heavy chain variable comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and the anti-CD19 light chain variable domain comprises: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 is a common light chain bispecific antibody. In some embodiments, the common light chain bispecific antibody comprises: an anti-CD38 heavy chain variable domain comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising anamino acid sequence set forth in SEQ ID NO: 9, an anti-CD19 heavy chain variable comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and a common light chain variable domain comprising: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the anti-CD38 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 1, the anti-CD19 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 2, and common light chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 3. In some embodiments, the common light chain bispecific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 4, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 5, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 6. In some embodiments, the anti-CD38 heavy chain variable domain and the anti-CD19 heavy chain variable domain each comprise a negatively-charged amino acid at heavy chain variable domain position 1 per Kabat numbering; the anti-CD38 heavy chain constant domain and the anti-CD19 heavy chain constant domain each lack a C-terminal lysine residue (K447 per EU numbering); and the common light chain bispecific antibody comprises an experimental isoelectric point (pl) of less than 9. In some embodiments, the common light chain bispecific antibody exhibits a Hydrophobicity (HIC) retention time of less than about 10 minutes. In some embodiments, the terminal lysine residue of K447 per EU numbering is absent. In some embodiments, the anti-CD19 heavy chain variable domain comprises a serine at position 84 and / or a leucine at position 108 according to Kabat numbering. In some embodiments, the common light chain variable region comprises a histidineat position 32 according to Kabat numbering. In some embodiments, the negatively-charged amino acid is glutamic acid. In some embodiments, the pl is between 8.7 and 9. In some embodiments, the multispecific antibody or multispecific antibody fragment comprises an afucosylated Fc region. In some embodiments, the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that decreases antibody dependent cell cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), or antibody dependent cell phagocytosis (ADCP). In some embodiments, one or more modifications relative to wild-type IgG comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S; P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof. In some embodiments, one or more modifications relative to wild-type IgG comprise L234A, L235E, G237A, A330S, P331S (AEASS). In some embodiments, the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increase affinity to FcRn. In some embodiments, the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increases the plasma half-life of the multispecific antibody or multispecific antibody fragment. In some embodiments, the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

[0018] Provided herein, in some embodiments, is a common light chain multispecific antibody that binds CD19 and CD38, wherein the common light chain multispecific antibody comprises: (i) an anti-CD38 heavy chain amino acid sequence comprising SEQ ID NO: 26, (ii) an anti-CD19 heavy chain amino acid sequence comprising SEQ ID NO: 27, (iii) a first common light chain amino acid sequence comprising SEQ ID NO 28, and (iv) a second common light chain amino acid sequence comprising SEQ ID NO 28. In some embodiments, the anti-CD38 heavy chain amino acid sequence, the anti-CD19 heavy chain amino acid sequence, or both comprises an Fc region comprises one or more modifications relative to wild-type IgG that increases the plasma half-life of the multi specific antibody or multispecific antibody fragment. In some embodiments, the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2. In some embodiments, the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2a. In some embodiments, the one or more modifications relative to wild-type IgG comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S;P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof. In some embodiments, one or more modifications relative to wild-type IgG comprise L234A, L235E, G237A, A330S, P331S (AEASS). In some embodiments, the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The novel features described herein are set forth with particularity in the appended claims. A better understanding of the features and advantages of the features described herein will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the features described herein are utilized, and the accompanying drawings of which:

[0020] FIGs. 1A-1B illustrate a trend for MBS- 1938-1 in reducing anti-dsDNA antibodies in prophylactic lupus model. Anti-dsDNA was measured after MRL / MpJ- / ’a.s / / "7J lupus mice received biweekly therapies. Shown are anti-dsDNA titers measured at week 12 (FIG. 1A) and week 14 (FIG. IB) across all groups.

[0021] FIGs. 2A-2B illustrate a trend of MBS-1938-1 in reducing anti-nuclear antibodies (ANAs) anti-dsDNA antibodies in a prophylactic lupus model. Anti-dsDNA antibodies (FIG.2A) were measured every 2-4 weeks after MRL / MpJ- / a.s / / "7J lupus mice received biweekly therapies. Anti-nuclear antigens (ANAs) (FIG. 2B) were measured post-week 16 in MRL / MpJ-FaslprH lupus mice, following biweekly therapies.*- p = 0.03, **- p = 0.001 Mann- Whitney test.

[0022] FIGs. 3A-3B illustrate a trend of MBS-1938-1 in blocking diabetes progression in a prophylactic NOD diabetes model. Blood glucose levels (FIG. 3A) were measured weekly after NOD / ShiLtJ Mice received treatment with MBS1 1938-1 (biweekly), isotype control (biweekly), or anti-CD40L (every three weeks). Shown are the blood glucose levels of individual mice in each group during the treatment course until at least 50% mice in the control groups reached diabetes onset. FIG. 3B shows survival curves of NOD / ShiLtJ Mice receiving the indicated antibody treatments, plotted at the end of the study.

[0023] FIG. 4 illustrates a schematic of CD 19 and CD38 expression on B cell lineage and the rational for treatment of autoimmune disease by B55-001 (heavy chain variable regions of SEQ ID NO 1 and 2; with common light chain of SEQ ID NO:3).

[0024] FIG. 5 illustrates potent killing of CD19+CD38hi cells (population #1) by B55-001. CD19+CD38hi Ramos cells were labeled and incubated with indicated therapies, followed byco-culturing with human macrophage effector cells. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells by flow cytometry. Assay was performed with macrophages from two healthy donors in triplicates. On the right is a schematic showing that population #1 is targeted by B55-001 antibody and other anti-CD38 monoclonal antibodies.

[0025] FIG. 6 illustrates effective elimination of CD19+CD381ow cells (population #2) by B55-001. CD19+CD381ow isolated B cells were labeled and incubated with indicated therapies, followed by co-culturing with human macrophage effector cells. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells. Assay was performed with macrophages from two healthy donors in triplicates. On the right is a schematic showing that population #2 is targeted by B55-001 antibody.

[0026] FIGs. 7 illustrate minimal killing of CD19-CD38hi cells (population #3) by B55-001. FIG. 7A shows that baseline levels of phagocytosis were mediated by B55-001. CD19-CD38hi NCL-H929 tumor cells were labeled and incubated with indicated therapies, followed by co-culturing with human macrophage effector cells. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells. Assay was performed with macrophages from two healthy donors in triplicates. On the right is a schematic showing that population #3 is targeted by other anti-CD38 monoclonal antibodies, but not by the B55-001 antibody. FIG. 7B shows dose-dependent cytotoxicity against NCI-H929 tumor cells by the indicated anti-CD38 monoclonal antibodies, but not by B55-001.

[0027] FIGs. 8A-8C illustrate greater cytotoxicity against CD19+CD38hi and CD19+CD381ow cells by afucosylated B55-001(BSM6F). Target cells (Raji, Ramos, or isolated B cells) were treated with indicated therapies, followed by co-culturing with effector cells. Bio-Glo was added to wells and luminescence measured. Shown are effector cell mediated cytotoxicity against Raji (FIG. 8A), Ramos (FIG. 8B), and isolated B cells (FIG. 8C).

[0028] FIGs. 9A-9C illustrate deeper B cell depletion and enhanced efficacy achieved by targeting both CD 19 and CD38, compared to targeting CD 19 alone. FIG. 9A shows potent direct apoptosis killing of CD191owCD38+ B cells mediated by B55-001 in CB17 / scid mice inoculated with SU-DHL-4 tumor. FIG. 9B shows a greater reduction in IgG anti-KLH titers mediated by mouse anti-CD19 / CD38 antibody (MBS1938-1) compared to anti-CD19 antibody in C57BL / 6 mice subcutaneously implanted with KLH. FIG. 9C shows a deeper depletion of antibody-secreting B cells mediated by mouse anti-CD19 / CD38 antibody (MBS1938-1) compared to anti-CD19 antibody in C57BL / 6 mice subcutaneously implanted with KLH.

[0029] FIG. 10 illustrates a schematic of direct apoptosis induced by B55-001.

[0030] FIGs. 11A-11B illustrate enhanced direct apoptosis mediated by B55-001 compared to the indicated anti-CD19 antibody or anti-CD38 antibody. FIG. 11A shows enhanced direct apoptosis across various tumor cell lines induced by B55-001 in comparison with anti-CD19. FIG. 11B shows higher levels of direct apoptosis across various tumor cell lines induced by B55-001 in comparison with anti-CD38.

[0031] FIGs. 12A-12D illustrate potent dose-dependent direct apoptosis induced by B55-001 antibody, in contrast to anti-CD19 and anti-CD38. FIG. 12A shows that incubation with B55-001 for 48 hours at the indicated concentrations resulted in a dose-dependent decrease in the percentage of viable WSU-DLCL2 tumor cells. FIG. 12B shows a dose-dependent decrease in the percentage of viable Raji tumor cells by administered B55-001 at the indicated concentration, after incubation for 48 hours. FIG. 12C shows a dose-dependent decrease in the percentage of viable Daudi tumor cells by administered B55-001 at the indicated concentration, after incubation for 48 hours. FIG. 12D shows a summary of rapid direct apoptosis mediated by B55-001 or the monospecific mAbs across the indicated B cell lymphoma cell lines. Cells were plated in triplicate (50,000 cells / well) and treated with the indicated antibodies at 30 pg / ml for 30 minutes. Viable cells were enumerated by flow cytometry following treatment. One-way ANOVA was performed comparing the following groups: B55-001 Fc-dead vs. all TAs, p<0.05 shown as ***; B55-001 vs. CD38 mAbs only, p<0.05 shown as *.

[0032] FIGs. 13A-13B illustrate that B55-001 treatment preserves CD38+ CD19- cells. FIG. 13A shows minimal ADCC induced by B55-001 against CD38+CD19- NCI-H929 cells.FIG. 13B shows modest ADCP induced by B55-001 against CD38+CD19- MOLP-8 cells.

[0033] FIGs. 14A-14B illustrate that B55-001 treatment preserves CD38+ CD19- immune cell subsets. FIG. 14A shows the relative proportion of viable immune cell subsets remaining after overnight incubation with B55-001. FIG. 14B shows the absolute count of alive CD19+CD38hi B cells after overnight incubation with B55-001.

[0034] FIGs. 15A-15B illustrate the pharmacokinetics of B55-001 in comparison with a control IgGl. FIG. 15A shows detected and model-predicted serum concentrations of B55-001 after IV administration in female CB-17 / SCID mice. FIG. 15B shows a summary of model-predicted pharmacokinetic parameters for B55-001.

[0035] FIGs. 16A-16B illustrate the extent of hemagglutination and hemolysis induced by B55-001. FIG. 16A shows the levels of hemagglutination induced by B55-001. FIG. 16B shows the levels of hemolysis induced by B55-001.

[0036] FIGs. 17A-17E illustrate the extent of B55-001 binding to the indicated human PBMC subsets. FIG. 17A shows the binding of B55-001 to platelets. FIG. 17B shows thebinding of B55-001 to RBCs. FIG. 17C shows the binding of B55-001 to T cells, NK cells, B cells, and monocytes. FIG. 17D shows representative FACS data of CD38 expression on RBCs from 3 individual donors. FIG. 17E shows representative FACS data of CD38 expression on various immune cell subsets from 1 donor.

[0037] FIGs. 18A-18B illustrate acute cytokine secretion by PBMCs following incubation with B55-001. FIG. 18A shows the levels of TNF-a produced by PBMCs following overnight incubation with soluble B55-001. FIG. 18B shows the levels of TNF-a produced by PBMCs following overnight incubation with coated B55-001.

[0038] FIGs. 19A-19B illustrate the efficacious dose of B55-001 in xenograft tumor models.FIG. 19A shows engrafted DoHH2 tumor progression suppression by B55-001 at indicated doses with 3-fold escalating concentration. FIG. 19B shows engrafted Ramos tumor progression suppression by escalating doses of B55-001.

[0039] FIGs. 20A-20F illustrate B55-001 -induced killing of target cells through Fc effector functions. FIGs. 20A-20B shows complement-dependent cytotoxicity (CDC) mediated by B55-001 in Daudi cells (FIG. 20A) and in SUDHL-4 cells (FIG. 20B). FIGs. 20C-20D shows antibody-dependent cellular cytotoxicity (ADCC) mediated by B55-001 in Daudi cells (FIG. 20C) and in SUDHL-4 cells (FIG. 20D). FIGs. 20E-20F shows antibody-dependent cellular phagocytosis (ADCP) mediated by B55-001 in Daudi cells (FIG. 20E) and in Raji cells (FIG.20F).

[0040] FIGs. 21A-21B illustrate the capacity of B55-001 to preserve naive B cells. FIG. 21A shows the depletion of naive B cells by the indicated antibodies after cryopreserved PBMCs (250,000 cells / well) were treated with 30 pg / ml of each antibody for 48 hours. Cells were seeded in triplicate and naive B cells were enumerated by flow cytometry following treatment. FIG. 21B shows the depletion of naive B cells by B55-001 in comparison with the isotype control.

[0041] FIGs. 22A-22B illustrate the potent depletion of plasmablasts mediated by effector cells in the presence of B55-001. FIG. 22A shows the depletion of plasmablasts after in vitro differentiated human B cells were co-cultured with CD3+ T depleted PBMCs at an E:T ratio of 4: 1 in the presence of the indicated antibodies, each at 30 pg / ml. Target cells were enumerated by flow cytometry following overnight antibody treatment. FIG. 22B shows the depletion of plasmablasts mediated by B55-001 in comparison with the isotype control.

[0042] FIGs. 23A-23B illustrate the direct apoptosis of plasmablasts mediated by B55-001.FIG. 23A shows the apoptosis in plasmablasts after in vitro differentiated human B cells were incubated with the indicated antibodies, each at 30 pg / ml, for 1.5 hours. Cells were labeled withCellTrace Violet (CTV) prior to antibody treatment and stained with propidium iodine (PI) prior to flow cytometry detection. Viable cells (CTV+PI-) were enumerated. FIG. 23B shows the direct apoptosis effect mediated by B 55-001 or its Fc-Dead variant in comparison with the isotype control.DETAILED DESCRIPTION

[0043] Provided herein are B cell depleting multispecific antibodies that bind CD 19 and CD38, and effectively deplete CD19+CD38hlgh / +B cells, CD19+CD38lowB cells, but preserve CD19'CD38hlgh / +B cells. Such bispecific antibodies that bind CD 19 and CD38 can be characterized by an antibody comprising a CD19-binding domain and a CD38-binding domain. For example, the CD19-binding domain can comprise a first heavy chain variable (VH) domain and light chain variable (VL) domain that binds CD 19 and a second heavy chain variable (VH) domain and light chain variable (VL) domain that binds CD38. The B cell depleting antibodies of the current disclosure are useful in the treatment of autoimmune and / or inflammatory diseases. Such autoimmune disorders may comprise lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), anti -neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), or Type 1 diabetes (T1D). In certain embodiments, the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti-phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis.

[0044] Antibody is used in the broadest sense and generally refers to and / or includes monoclonal antibodies, multi-valent antibodies, multispecific, antigen-binding fragments of antibodies that bind a CD 19 protein or CD38 protein. Antigen-binding fragments of antibodies (antigen-binding antibody fragments) generally refer to and / or include antibody-derived proteins that comprise a functional set of CDRs (e.g., a CDR-H1-3 and CDR-L1-3) that bind a CD 19 protein or CD38 protein and have a molecule weight less than a full-length IgG antibody (e.g., a molecular weight less than -150,00 Daltons). In certain embodiments, an antigen-bindingantibody fragment (e.g., a CD19- or CD38-binding fragment) includes fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab' fragments, Fv fragments, IgG (rlgG) fragments, and single chain antibody fragments, including single chain variable fragments (sFv or scFv).Antibodies and antigen-binding fragments of antibodies generally encompass genetically engineered, and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific antibodies, multi-valent antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. A full-length antibody, intact antibody, and / or whole antibody are interchangeable, and generally include and / or refer to an antibody having a structure substantially similar to a native antibody structure having heavy chains that contain an Fc region and / or include antibodies of any class or sub-class, including IgG and sub-classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and IgD.

[0045] Complementarity determining regions (CDRs) generally include amino acids within antibody variable regions that confer antigen specificity and / or binding affinity (e.g., to CD19 or CD38). In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). Framework regions (FRs) generally refer to and / or include non-CDR regions of the heavy and light chain variable regions. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0046] Variable regions (also referred to as variable domains) generally refer to and / or include the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen (e.g., a single variable domain comprises a CDR 1, CDR 2, and CDR 3). The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. In certain instances, a single VH or VL domain can be sufficient to confer antigen-binding specificity.

[0047] Fc region generally encompasses and / or refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. Generally, the Fc domain includes an immunoglobulin CH2 and CH3 domain (e.g., an IgG CH2 and CH3 domain). The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain, per EU numbering. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein,numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. In certain embodiments, the Fc region include IgG and sub-classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and / or IgD heavy chain constant regions and / or heavy chain constant regions derived from IgG and sub-classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and IgD.

[0048] Binding of antibodies to CD 19 or CD38 can be determined by bio-layer interferometry, surface plasmon resonance, isothermal titration calorimetry, and / or ELISA. Affinity generally refers to and / or includes the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen such as CD19 or CD38). Unless indicated otherwise, binding affinity generally refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of an antibody for an antigen (e.g., CD 19 or CD38) can generally be represented by the dissociation constant (KD). Affinity can be measured and determined by bio-layer interferometry, surface plasmon resonance, isothermal titration calorimetry, and / or ELISA.

[0049] The multispecific antibodies described herein effectively deplete CD19+CD38high / + B cells, CD19+CD38lowB cells, but preserve CD19'CD38hlgh / +B cells. In certain embodiments, the multispecific antibodies that bind CD19 and Cd38 (i) increase antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), CDC (complementdependent cytotoxicity), and / or direct apoptosis of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; and (ii)(a) do not increase ADCP and / or ADCC of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (ii)(b) result in reduced ADCP and / or ADCC of CD19'CD38hlgh / +B cells when compared to daratumumab. The ADCP, ADCC, CDC, or direct apoptosis assays described in the Examples can be used to determine that a multispecific antibody or multispecific antibody fragment (i) kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, and / or (ii) does not substantially reduce the amount of CD19'CD38hlgh / +B cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of other CD19' CD38hlghimmune cells, such as CD38hlghregulatory T cells and CD38hlghmyeloid-derived suppressor cells (MDSCs).

[0050] Exemplary CD38-binding CDRs include the CDRH1-3 of SEQ ID NOs: 7-9 and CDRL1-3 of SEQ ID NOs: 10-12. CD38-binding VHs include SEQ ID NO: 1 and CD19-binding VLs include SEQ ID NO: 3. In certain embodiments, a CD38-binding VH comprises a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 1, and the CD38-binding VL comprises a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3. In other embodiments, the CD38-binding CDRs and variable domains are selected from daratumumab, mezagitamab, felzartamab, and isatuximab.

[0051] Exemplary CD19-binding CDRs include the CDRH1-3 of SEQ ID NOs: 10-12 and CDRL1-3 of SEQ ID NOs: 13-15 or 23-25. CD19-binding VHs include SEQ ID NO: 2 and CD19-binding VLs include SEQ ID NO: 3 or 22. In certain embodiments, a CD19-binding VH comprises a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:2, and the CD19-binding VL comprises a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3 or 22. In other embodiments, the CD19-binding CDRs and variable domains are selected from Inebilizumab, Loncastuximab, SGN-CD19A, Tafasitamab, Taplitumomab, Blinatumomab, Coltuximab, and Denintuzumab.

[0052] As described herein, inhibitors of B-reg cells include bispecific antibodies that bind to CD19 and CD38. Bispecific antibodies can be conceived and designed to alter functionality or binding properties of the composite binding molecules or bispecific antibodies (see e.g., “Bispecific antibodies: a mechanistic review of the pipeline.” Nat Rev Drug Discovery. 2019 Aug; 18(8): 585-608) (see e.g., “The making of bispecific antibodies” MAbs. 2017 Feb-Mar; 9(2): 182-212). For example, the bispecific antibodies that bind CD19 and CD38 can be selected from any of the following non-limiting formats: a common light chain bispecific IgG, a Fab-Fc:scFv-Fc bispecific IgG, a Fab-Fc-Fab:Fc bispecific IgG, a Fab-Fc-scFv:Fab-Fc-scFv bispecific IgG, a Fab-Fc-scFv:Fc bispecific IgG, a Fab-Fc-Fab:Fab-Fc bispecific IgG, an scFv-Fab-Fc:scFv-Fab-Fc bispecific IgG, a Fab-Fab-Fc:Fab-Fab-Fc bispecific IgG, a Fab-Fc-Fab:Fab-Fc-Fab bispecific IgG, and a Fab-Fc-scFv:Fab-Fc bispecific IgG, wherein each bispecific antibody comprises at least one CD19-binding domain (e.g., Fab or scFv) and at least one CD38-binding domain (e.g., Fab or scFv). In certain embodiments, the CD38-binding domain is Daratumumab or CD38-binding fragment thereof (e.g., having the Daratumumab VH / VL or CDRs), Isatuximab or CD38-binding fragment thereof (e.g., having the Isatuximab VH / VL or CDRs), MOR202 or CD38-binding fragment thereof (e.g., having the MOR202 VH / VL or CDRs), TAK-079or CD38-binding fragment thereof (e.g., having the TAK-079VH / VL or CDRs), mezagitamab, or felzartamab. In certain embodiments, the CD19-binding domain is Blinatumomab or CD19-binding fragment thereof (e.g., having the Blinatumomab VH / VL or CDRs), or Tafasitamab or CD19-binding fragment thereof (e.g., having the Tafasitamab VH / VL or CDRs), or Inebilizumaor or CD19-binding fragment thereof (e.g., having the Inebilizuma VH / VL or CDRs), or FMC63 or CD19-binding fragment thereof (e.g., having the FMC63 VH / VL or CDRs). In certain embodiments, the CD38-binding domain comprises the CDRH1-3 of SEQ ID NOs: 7-9 and CDRL1-3 of SEQ ID NOs: 10-12. In certain embodiments, the CD38-binding domain comprises a VH comprising a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:1, and a VL comprising a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3. In certain embodiments, the CD19-binding domain comprises the CDRH1 -3 of SEQ ID NOs: 10-12 and CDRL 1-3 of SEQ ID NOs: 13-15 or 23-25. In certain embodiments, the CD19-binding domain comprises a VH comprising a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:2, and a VL comprising a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3 or 22.

[0053] In some embodiments, the bispecific antibody is a common light chain antibody. In certain embodiments, the common light chain antibody comprises:an anti-CD38 heavy chain variable domain comprising:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16, 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9,an anti-CD19 heavy chain variable comprising:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; anda common light chain variable domain comprising:a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementaritydetermining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, ora light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

[0054] In certain embodiments, the anti-CD38 heavy chain variable domain comprises the CDRH2 having the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the anti-CD38 heavy chain variable domain comprises the CDRH2 having the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the anti-CD38 heavy chain variable domain comprises the CDRH2 having the amino acid sequence set forth in SEQ ID NO: 17. In certain embodiments, the anti-CD38 heavy chain variable domain comprises the CDRH2 having the amino acid sequence set forth in SEQ ID NO: 18.

[0055] In certain embodiments, the anti-CD38 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 1, the anti-CD19 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 2, and the common light chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 3. In certain embodiments, the common light chain bi specific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 4, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 5, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 6.

[0056] In certain embodiments, the common light chain bispecific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 26, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 27, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 28.

[0057] In certain embodiments, the common light chain bispecific antibody further comprises a Hydrophobicity (HIC) retention time of less than about 10 minutes. In certain embodiments, the anti-CD19 heavy chain variable region comprises a serine at position 84 and / or a leucine at position 108 according to Kabat numbering. In certain embodiments, thecommon light chain variable region comprises a histidine at position 32 according to Kabat numbering. In certain embodiments, the pl is less than 9. In certain embodiments, the pl is between 8 and 9. In certain embodiments, the pl is between 8.5 and 9.0. In certain embodiments, the pl is between 8.7 and 9.0. In certain embodiments, the pl is between 8.8 and 9.0. In certain embodiments, the pl is 8.9.Fc Domains and CH regions

[0058] In some embodiments, the multispecific antibodies or multispecific antibody fragments (including single domain antibodies or antibody fragments) that binds CD 19 and CD38 includes a variant Fc region (CH2 and / or CH2 domain) alters the half-life (e.g., by increasing or decreasing FcRn binding) and / or effector function (e.g., ADCC, CDC, etc.) of the Fc region. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the immunoconjugate lacks FcyyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NEC cells, express FcyyRIII only, whereas monocytes express FcyyRI, FcyyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in US 5,500,362 (see e.g. Hellstrom, I. et al. Proc Natl Acad Sci USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc Natl Acad Sci USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med.166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc Natl Acad Sci USA 95:652-656 (1998). Clq binding assays may also be carried out to confirm that the immunoconjugate is unable to bind Clq and hence lacks CDC activity (see e.g., Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402). To assess complement activation, a CDC assay may be performed (see e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood 101:1045-1052 (2003); Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see e.g., Petkova, S.B. et al., Int'l. Immunol. 18(12): 1759-1769 (2006)).

[0059] The alterations of one or more amino acid residues in the Fc region can increase effector function associated with the Fc region, such as, the ability to fix complement, promote phagocytosis, or recruit other immune effector cells (e.g., NEC cells) to the heavy chain constant region. In certain embodiments, the alteration to one or more amino acid residues that increase the effector function of the Fc region is an alteration that increases complement dependent cytotoxicity (CDC), antibody -dependent cell-cytotoxicity (ADCC), antibody -dependent cellphagocytosis ADCP, or a combination thereof. In certain embodiment, the alteration to one or more amino acid residues that increase the effector function of the Fc region is selected from Table 1 and includes combinations thereof.Table 1: Exemplary Fc modifications that increaseeffector function (relative to wild-type IgG) (EUnumbering) _S298A / E333A / K334AS239D / I332EP247I / A339QF243L / R292P / Y300L / V305I / P396LS239D / I332E / A330LS239D / I332E / G236AK326W / E333SS267E / H268E / S324TG236AF243LS239D / A330L / I332Eafucosylation

[0060] Examples of alterations relative to wild-type IgG that increase FcRn binding and / or plasma half-life of an antibody are shown in Table 2. In some embodiments, alterations to one or more amino acid residues increase FcRn binding and / or plasma half-life is selected from Table 2 and includes combinations thereof.Table 2:Exemplary Fc modifications that increase FcRn binding and / or plasma half-life (relative to wild-typeIgG) (EU numbering)M252Y / S254T / T256E (YTE)N434A / N434WT307A / E380A / N434A (AAA)250Q / M428LP257I / Q311IP257I / N434HD376V / N434HM252Y / S254T / T256E / H433K / N434FL309D / Q311H / N434SQ331R / M428LG236A / S239D / I332EA330L

[0061] The alterations of one or more amino acid residues in the Fc region can decrease effector function associated with the Fc region, such as, the ability to fix complement, promote phagocytosis, or recruit other immune effector cells (e.g., NEC cells) to the heavy chain constant region. In certain embodiments, the alteration to one or more amino acid residues that decrease the effector function of the Fc region is an alteration that decreases complement dependent cytotoxicity (CDC), antibody -dependent cell-cytotoxicity (ADCC), antibody -dependent cellphagocytosis ADCP, or a combination thereof. In certain embodiments, the alteration to one or more amino acid residues that decrease the effector function is at amino acid L234, L235, G236, G237, P238, H268, N298, K322, P329, A330, P331, and combinations thereof according to EU numbering. In certain embodiments, the alteration to one or more amino acid residues that decrease the effector function comprise L234A, L235E, G237A, A330S, and P331S (AEASS) according to EU numbering. In certain embodiments, the Fc region is an IgG4. In certain embodiments, the alteration to one or more amino acid residues that decrease the effector function of the Fc region is selected from Table 2A and includes combinations thereof.Table 2A: Exemplary Fc modifications that decreaseeffector function (EU numbering for IgGl) _L234AL235AL235EG236RG237AP238SH268AK322AP329AP329GA330SP331SN298AL234, L235 (LALA)L234A, L235E (LALE)L234, L235, G237A (LALAGA)L234, L235, P329A (LALAPA)L234, L235, P329A (LALAPG)L234A, L235E, G237A, A330S, P331S (AEASS)Means for binding CD38 and CD 19

[0062] As described herein, means for binding CD38 include (i) the CD38-binding CDRs: CDRH1-3 of SEQ ID NOs: 7-9 and CDRL1-3 of SEQ ID NOs: 10-12, and (ii) the CD38-binding CDRs and variable domains of daratumumab, mezagitamab, felzartamab, isatuximab, MOR202, and TAK-079. As also described herein, means for Binding CD 19 include (i) CD 19-binding CDRs: CDRH1-3 of SEQ ID NOs: 10-12 and CDRL 1-3 of SEQ ID NOs: 13-15 or 23-25, and (ii) CD19-binding CDRs and variable domains of Inebilizumab, Loncastuximab, SGN-CD19A, Tafasitamab, Taplitumomab, Blinatumomab, Coltuximab, and Denintuzumab.CD38highB cells

[0063] A CD38 high phenotype (CD38high) can be indicated by a percentage of CD38 positive B Cells in the peripheral blood. In certain embodiments, assay results indicate a CD38 high phenotype if greater than about 1 %, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, or 4.0% of CD19+ CD20- cells in the peripheral blood are CD38 positive. Such positivity can be determined by flow cytometry or microscopy by comparison to a control (e.g., isotype matched control antibody of fluorescent bead controls). In certain embodiments, the CD38 high phenotype is indicated in a patient with a solid tumor. A CD38 high phenotype can also be indicated by a percentage of CD38 positive B Cells in a biopsy sample of a tumor. In certain embodiments, assay results indicate a CD38 high phenotype if greater than about 10 %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of CD 19+ CD20- cells in the peripheral blood are CD38 positive. Such positivity can be determined by flow cytometry or microscopy by comparison to a control (e.g., isotype matched control antibody of fluorescent bead controls). In certain embodiments, the CD38 high phenotype is indicated in a patient with a solid tumor. A CD38 high phenotype can be indicated by making a determination of absolute numbers of CD38 molecules on the surface of a B cell In certain embodiments, assay results indicate a CD38 high phenotype if greater than about 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, on average are present on B cells with that are positive for CD 19.CD38lowand CD38 B cells

[0064] A CD38 negative (CD38 ) phenotype can be identified by lack of detectable expression of CD38 by a standard assay such as flow cytometry. A CD38 low (CD38low) phenotype can be identified by low levels of expression of CD38 (e.g., CD38 expression less than compared to plasmablasts and / or short-lived plasma cells).CD19+and CD19~ B cells

[0065] A CD 19 negative (CD 19") phenotype can be identified by lack of detectable expression of CD 19 by a standard assay such as flow cytometry. A CD 19" or CD 19 low (CD19low) phenotype can be identified by low levels of expression of CD 19 (e.g., CD 19 expression less than compared to plasmablasts and / or short-lived plasma cells). A CD19 positive (CD19+) phenotype can be identified by the detectable expression of CD19 by a standard assay such as flow cytometry.Pharmaceutical compositions

[0066] In some embodiments, provided herein are pharmaceutical compositions and / or formulations comprising the bispecific antibody that binds CD19 and CD38. Pharmaceutical compositions include and / or refers a preparation that is in such form as to permit biological activity of the antibody or antibody fragment, and that contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier (e.g., an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to an individual). A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. The formulation of pharmaceutically active ingredients (e.g., an antibody or antibody fragment) with pharmaceutically acceptable carriers is known in the art, e.g.: Remington: The Science and Practice of Pharmacy (e.g. 21st edition (2005), and any later editions); Wang SS, Yan YS, Ho K. US FDA-approved therapeutic antibodies with high-concentration formulation: summaries and perspectives. Antib Ther. 2021 Nov 18;4(4):262-272. doi: 10.1093 / abt / tbab027. PMID: 34909579; and / or AA Elkordy.Formulation of Monoclonal Antibody Therapies. 2023. (978-0-12-823365-8). Non-limiting examples of additional ingredients include; buffers, diluents, solvents, tonicity regulating agents, preservatives, stabilizers, and chelating agents. One or more pharmaceutically acceptable carrier may be used in formulating the pharmaceutical compositions of the invention.

[0067] In certain embodiments, the pharmaceutical composition is a liquid formulation such as a liquid formulation. In certain embodiments, the liquid formulation is an aqueous formulation, i.e., a formulation comprising water. An aqueous formulation typically comprises at least 50% w / w water, or at least 60%, 70%, 75%, 80%, 85%, 90%, or at least 95% w / w of water.

[0068] Pharmaceutical compositions containing the multispecific antibodies described herein can be administered in the methods describe. Pharmaceutical compositions include and / orrefers a preparation that is in such form as to permit the biological activity of the photosensitizer alone or in the conjugate to be effective, and that contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier (e.g., an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to an individual). A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0069] In certain embodiments the multispecific antibodies of the current disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers and diluents can be included to increase shelf-life, stability, or the administrability of the antibody. Such compounds include salts, pH buffers, detergents, anti -coagulants, and preservatives. In certain embodiments, the antibodies of the current disclosure are administered suspended in a sterile solution. In certain embodiments, the solution comprises about 0.9% NaCl. In certain embodiments, the solution comprises about 5.0% dextrose. In certain embodiments, the solution further comprises one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxymethyl aminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and pol oxamer 188; polyol / disaccharide / polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA or EGTA.

[0070] In certain embodiments, the antibodies of the current disclosure can beshipped / stored lyophilized and reconstituted before administration. In certain embodiments, lyophilized antibody formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial comprised of glass or other suitable non-reactive material. The antibodies when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than 7.0. In certain embodiments, the pH can be between 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[0071] Also described herein are kits comprising one or more of the antibodies described herein in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier, and a device for administration.Methods

[0072] The multispecific antibodies described herein are useful in methods of depleting B cells associated with an auto immune response while preserving beneficial, long lived plasma cells that and naive B cells, for example, produce the protective antibodies generated by vaccines and infections. Accordingly, provided herein are methods depleting CD19+CD38hlghB cells and CD19+CD38lowB cells, but preserve protective CD19'CD38hlgh / +B cells and naive B cells. For example, in some embodiments, provided are methods of reducing (e.g., depleting) the number of B cells in the individual that express CD 19 and CD38, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby reducing the number of B cells in the individual that express CD19 and CD38, wherein the B cells that express CD19 and CD38 comprise CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD 19+CD38lowB cells and CD19+CD38high / +B cells.

[0073] In B cell-associated autoimmune and inflammatory disorders, CD19+CD38hlghB cells and CD19+CD38lowB cells (either each alone or in combination) are generally associated with the productive of autoreactive antibodies. In certain embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38.In certain embodiments the B cells are CD19+CD38lowor CD19+CD38hlgh. In certain embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD I 9 CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells in the individual. In some embodiments, the reduction in the number of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells in the individual is at least or about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99%.

[0074] In some embodiments, the reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells mediated by the multispecific antibodies in the individual is Fc-dependent. For example, in some embodiments, the multispecific antibodies disclosed herein can induce antibody-dependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38hlgh / +B cells and CD19+CD38lowB cells. In some embodiments, the multispecific antibodies disclosed herein can induce antibody-dependent cellular cytotoxicity (ADCC) of CD19+CD381OWB cells, CD19+CD38high / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells. In some embodiments, the multispecific antibodies disclosed herein caninduce complement-dependent cytotoxicity (CDC) of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells.

[0075] CD38 is expressed on B cells and is associated with the B cell receptor complex (BCR) which includes CD19 and CD81. In B cells, CD38 is involved in the modulation of CD19 / CD81 complex and thereby influence the balance between B cell survival and apoptosis. In some embodiments, the binding of the multispecific antibodies disclosed herein can induce direct apoptosis of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells.

[0076] In certain embodiments, “reducing (e.g., depleting) the number of CD19+CD38lowB cells, CDI 9 CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells” refers to an antibody that, when administered, increases antibody-dependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38 high / + gceps an(j CD19+CD381OWB cells, compared to a human IgGl control or null control. The ADCP assays described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells.

[0077] In some embodiments, “reducing (e.g., depleting) the number of CD19+CD38lowB cells, CDI 9 CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells” refers to an antibody that, when administered, increases antibody -dependent cellular cytotoxicity (ADCC) of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells, compared to a human IgGl control or null control. The ADCC assays described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD 19+CD38lowB cells and CD19+CD38high / +B cells.

[0078] In some embodiments, “reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells” refers to an antibody that, when administered, increases complement-dependent cytotoxicity (CDC) of CD19+CD381OWB cells, CD19+CD38high / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells, compared to a human IgGl control or null control. The CDC assays described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD 19+CD38lowB cells and CD19+CD38high / +B cells.

[0079] In some embodiments, “reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD I 9 CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells”refers to an antibody that, when administered, increases the direct apoptosis of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38high / +B cells and CD19+CD38lowB cells, compared to a human IgGl control or null control. The measurement of the direct apoptosis described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment kills (reduced the number or depletes) CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD 19+CD38lowB cells and CD19+CD38high / +B cells.

[0080] As described herein, it is beneficial to preserve CD19 CD38hlghB cells and CD 19" CD38+B cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19 CD38+B cells. In some embodiments, treatment with the multispecific antibody or multispecific antibody fragment results in less than about a 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, reduction in the number of CD19 CD38+B cells. Accordingly, treatment with the multispecific antibody or multispecific antibody fragment preserves at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the number of CD19 CD38+B cells.

[0081] As described herein, it is beneficial to preserve naive B cells characterized as CD19+CD20+IgM+IgD+CD27‘ cells. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not substantially reduce the number of naive B cells. In some embodiments, treatment with the multispecific antibody or multispecific antibody fragment results in less than about a 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, reduction in the number of CD19+CD20+IgM+IgD+CD27‘ B cells. Accordingly, treatment with the multispecific antibody or multispecific antibody fragment preserves at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the number of CD19+CD20+IgM+IgD+CD27 B cells.

[0082] In certain embodiments, the multispecific antibody or multispecific antibody fragment does not induce hypogammaglobulinemia when administered to an individual. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the serum IgG level in an individual to less than about 8 g / L. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the serum IgG level in an individual to less than about 7 g / L. In certain embodiments, the multispecific antibody or multi specific antibody fragment does not reduce the serum IgG level in an individual to less thanabout 6 g / L. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the serum IgG level in an individual to less than about 5 g / L. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the serum IgG level in an individual to less than about 4 g / L. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the serum IgG level in an individual to less than about 3 g / L. In certain embodiments, the multispecific antibody or multi specific antibody fragment does not reduce the serum IgG level in an individual to less than about 2.5 g / L.

[0083] In certain embodiments, “does not substantially reduce the amount of CD19' CD38hlgh / +B cells” refers to an antibody that, when administered, does not increase ADCP of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced ADCP of CD19'CD38hlgh / +B cells when compared to daratumumab. The ADCP assay described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells.

[0084] In certain embodiments, “does not substantially reduce the amount of CD19' CD38hlgh / +B cells” refers to an antibody that, when administered, does not increase ADCC of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced ADCC of CD19'CD38hlgh / +B cells when compared to daratumumab. The ADCC assay described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells.

[0085] In certain embodiments, “does not substantially reduce the amount of CD19' CD38hlgh / +B cells” refers to an antibody that, when administered, does not increase CDC of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced CDC of CD19'CD38hlgh / +B cells when compared to daratumumab. The CDC assay described in the Examples can be used also to show that a multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells.

[0086] In certain embodiments, “does not substantially reduce the amount of CD19' CD38hlgh / +B cells” refers to an antibody that, when administered, does not increase direct apoptosis of CD19'CD38hlgh / +B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced direct apoptosis of CD19'CD38hlgh / +B cells when compared to daratumumab. The measurement of the direct apoptosis described in theExamples can be used also to show that a multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghB cells.

[0087] In certain embodiments, “does not substantially reduce the amount of naive B cells (CD19+CD20+IgM+IgD+CD27 )” refers to an antibody that, when administered, does not increase the depletion of CD19+CD20+IgM+IgD+CD27 naive B cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced depletion of CD19+CD20+IgM+IgD+CD27 naive B cells when compared to Tafasitamab, Blinatumomab, Obinutuzumab, or Glofitamab. The observed depletion of naive B cells may be attributed to ADCC, ADCP, CDC, direct apoptosis, or a combination thereof in the presence of the multispecific antibody or multispecific antibody fragment thereof.

[0088] Accordingly, in some embodiments, provided herein are methods of treating an autoimmune disorder or an inflammatory disorder in an individual, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby treating the autoimmune disorder. In certain embodiments, the autoimmune disorder is characterized by the presence of antibodies in the individual that bind double stranded deoxyribonucleic acid (dsDNA).

[0089] In certain embodiments, inflammatory disorder is characterized by the presence of antibodies in the individual that bind double stranded deoxyribonucleic acid (dsDNA). In certain instances, the presence of antibodies that bind dsDNA indicates that an autoimmune and inflammatory disorder is a B cell-associated autoimmune and inflammatory disorder. In certain embodiments treating the autoimmune disorder or the inflammatory disorder comprises reducing the amount of the antibodies that bind dsDNA in the individual. The presence or number (e.g., amount) of antibodies that bind dsDNA can be measured those known in the art (e.g., an immunoassay performed on a blood sample).

[0090] In certain embodiments, inflammatory disorder is characterized by the presence of antibodies in the individual that bind anti-nuclear antibodies (ANAs), anti-double stranded deoxyribonucleic acid (dsDNA), anti-Ro / La, anti-Sm, anti-phospholipid, anti-ribonucleoprotein (RNP), anti-glyceraldehyde-3 -phosphate dehydrogenase (GAPDH), anti -hi stones, antisynthetase (autoantibodies to aminoacyl -tRNA synthetases), anti-centromere, anti-Scl-70 (antitopoisomerase I), anti-RNA polymerase III, anti -aminoacyl -tRNA synthetase (including anti-Jo-1), anti-Mi-2 antibodies, anti-SRP (signal recognition particle), anti -mitochondrial (AMAs), anti-smooth muscle (ASMAs), anti -neutrophil cytoplasmic, anti-thyroid autoantibodies, antitransglutaminase, or a combination thereof. In some embodiments, the autoimmune disorder is characterized by the presence of antibodies in the individual comprising anti-nuclear antibodies(ANAs), anti-double stranded deoxyribonucleic acid (dsDNA), anti-Ro / La, anti-Sm, antiphospholipid, anti-ribonucleoprotein (RNP), anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), anti -hi stones, anti -synthetase (autoantibodies to aminoacyl -tRNA synthetases), anticentromere, anti-Scl-70 (anti-topoisomerase I), anti-RNA polymerase III, anti-aminoacyl-tRNA synthetase (including anti-Jo-1), anti-Mi-2 antibodies, anti-SRP (signal recognition particle), anti -mitochondrial (AMAs), anti-smooth muscle (ASMAs), anti -neutrophil cytoplasmic, antithyroid autoantibodies, anti-transglutaminase, or a combination thereof.

[0091] In certain embodiments, the autoimmune or inflammatory disorder is characterized by the presence of autoantibodies in the individual comprising anti-desmoglein-1 (Dsgl) antibodies, anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSK) antibodies, anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, anti-BP180 antibodies, anti-BP230 antibodies, anti-signal recognition particle (SRP) antibodies, anti -3 -hydroxy-3 -methylglutaryl-CoA reductase (HMGCR) antibodies, or a combination thereof.

[0092] In certain embodiments, the autoimmune or inflammatory disease is endocrine, hematological, neurological, nephritic, ophthalmological, hepatic, vascular, dermatological, and combinations thereof.

[0093] In certain embodiments, the autoimmune disorder or the inflammatory disorder is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), anti -neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), or Type 1 diabetes (T1D). In certain embodiments, the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti -phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis, and combinations thereof.

[0094] In some embodiments, the autoimmune disorder comprises pemphigus. In some embodiments, the pemphigus is pemphigus vulgaris. In some embodiments, the pemphigus is pemphigus foliaceus. In some embodiments, the autoimmune disorder comprises myasthenia gravis. In some embodiments, the autoimmune disorder comprises myositis. In someembodiments, the myositis is immune-mediated necrotizing myopathy. In some embodiments, the autoimmune disorder comprises pemphigus, myasthenia gravis, or myositis. In some embodiments, the autoimmune disorder comprises pemphigus. In some embodiments, the pemphigus is pemphigus vulgaris. In some embodiments, the pemphigus is pemphigus foliaceus. In some embodiments, the autoimmune disorder comprises myasthenia gravis. In some embodiments, the autoimmune disorder comprises myositis. In some embodiments, the myositis is immune-mediated necrotizing myopathy. In some embodiments, the myositis is dermatomyositis. In some embodiments, the myositis is anti -synthetase syndrome. In some embodiments, the autoimmune or inflammatory disorder comprises Lambert-Eaton syndrome, Goodpasture’s syndrome, Sjogren's syndrome, eosinophilic granulomatosis with polyangiitis (EGPA), ulcerative colitis, giant cell arteritis, Behget's disease, Takayasu's arteritis, autoimmune poly endocrine syndrome, acute disseminated encephalomyelitis, anti-NMDA receptor encephalitis, chronic inflammatory demyelinating polyneuropathy, autoimmune pancreatitis, autoimmune oophoritis, autoimmune orchitis, or stiff person syndrome, MOG antibody-associated disease (MOGAD), autoimmune autonomic ganglionopathy, autoimmune nodopathies, minimal change disease, focal segmental glomerulosclerosis, anti-LRP2 (antibrush border) nephropathy, cryoglobulinemic vasculitis (type II / III), IgA vasculitis (Henoch-Schbnlein Purpura), autoantibody C3 glomerulopathy, immune thrombotic thrombocytopenic purpura (iTTP; anti-ADAMTS13), cold agglutinin disease (CAD), Evans syndrome, autoimmune pure red cell aplasia, chronic autoimmune neutropenia, hidradenitis suppurativa, dermatitismucous membrane pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, paraneoplastic pemphigus, pemphigoid gestationis, non-infectious uveitis, or thyroid eye disease, and combinations thereof.

[0095] In some embodiments, also provided herein are methods of treating lupus in an individual, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby treating lupus in the individual. In certain embodiments, treating the lupus comprises reducing an amount of antibodies that bind dsDNA in the individual. In certain embodiments, treating the lupus comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38. In certain embodiments, the B cells are CD19+CD38lowor CD19+CD38hlgh. In certain embodiments, treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, CD19lowCD38highB cells, or any combination thereof in the individual. In certain embodiments the multispecific antibody or multispecific antibody fragment does not substantially reduce theamount of CD19'CD38hlgh. In certain embodiments, the multispecific antibody or multispecific antibody fragment does not reduce the amount of CD19'CD38hlghto a level that would require a supportive treatment such as IVIG.

[0096] Further provided are, in some embodiments, methods of reducing the number of antibodies in an individual that bind dsDNA, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD19 and CD38, thereby reducing the number of antibodies in the individual that bind dsDNA.

[0097] As described herein and used in the methods provided herein, the multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38: (i)increases antibodydependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; and (ii)(a) does not increase ADCP of CD19'CD38hlghB cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (ii)(b) results in reduced ADCP of CD19'CD38hlghB cells when compared to daratumumab; and / or (iii) increases antibody-dependent cell cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or direct apoptosis of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; and does not increase ADCC, CDC, or direct apoptosis of CD19'CD38hlghB cells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or results in reduced ADCC, CDC, or direct apoptosis of CD19-CD38high cells when compared to daratumumab.

[0098] The antibodies can be administered to a subject in need thereof by any route suitable for the administration of antibody-containing pharmaceutical compositions, such as, for example, subcutaneous, intraperitoneal, intravenous, intramuscular, intratumoral, or intracerebral, etc. In certain embodiments, the antibodies are administered intravenously. In certain embodiments, the antibodies are administered subcutaneously. In certain embodiments, the antibodies are administered intratumoral.

[0099] The multispecific antibodies can be administered in any therapeutically effective amount. In certain embodiments, the therapeutically acceptable amount is between about 0.1 mg / kg and about 50 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 40 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 20 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 10 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 5 mg / kg and about 30 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 5 mg / kgand about 20 mg / kg. Therapeutically effective amounts include amounts sufficient to ameliorate one or more symptoms associated with the disease or affliction to be treated.Exemplary Embodiments

[0100] Embodiment 1 : A method of treating an autoimmune disorder or an inflammatory disorder in an individual in need thereof, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby treating the autoimmune disorder or an inflammatory disorder.

[0101] Embodiment 2: The method of embodiment 1, wherein the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-nuclear antibodys (ANAs), anti -double stranded deoxyribonucleic acid (dsDNA) antibodies, anti-Ro / La antibodies, anti-Sm antibodies, anti-phospholipid antibodies, anti-ribonucleoprotein (RNP) antibodies, anti-glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) antibodies, anti-histones antibodies, anti -synthetase (autoantibodies to aminoacyl -tRNA synthetases) antibodies, anticentromere antibodies, anti-Scl-70 (anti-topoisomerase I) antibodies, anti-RNA polymerase III antibodies, anti-aminoacyl-tRNA synthetase (including anti-Jo-1) antibodies, anti-Mi-2 antibodies, anti-signal recognition particle (SRP), anti -mitochondrial (AMAs) antibodies, antismooth muscle (ASMAs) antibodies, anti -neutrophil cytoplasmic antibodies, anti-thyroid antibodies antibodies, anti-transglutaminase antibodies, or a combination thereof.

[0102] Embodiment 3: The method of embodiment 1, wherein the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-desmoglein-1 (Dsgl) antibodies, anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSK) antibodies, anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, anti-BP180 antibodies, anti-BP230 antibodies, anti-signal recognition particle (SRP) antibodies, anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, or a combination thereof.

[0103] Embodiment 4: The method of any one of embodiments 1-3, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of B cells in the individual that express CD19 and CD38.

[0104] Embodiment 5: The method of embodiment 6, wherein the B cells are CD19+CD381OW / - or CD19+CD38high.

[0105] Embodiment 6: The method of any one of embodiments 1-4, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) thenumber of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells in the individual.

[0106] Embodiment 7: The method of any one of embodiments 1-6, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of memory B cells (CD19+CD20+IgD CD27+) or plasmablasts (CD19+CD20 CD27highCD38high).

[0107] Embodiment 8: The method of any one of embodiments 1-6, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of long-lived plasma cells (CD19 CD38hlghB cells).

[0108] Embodiment 9: The method of any one of embodiments 1-6, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of Naive B cells. (CD 19+ CD20+ IgM+IgD+CD27 ).

[0109] Embodiment 10: The method of any one of embodiments 1-9, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce IgG levels in the individual.

[0110] Embodiment 11 : The method of any one of embodiments 1-10, wherein the treating does not induce hypogammaglobulinemia in the individual.

[0111] Embodiment 12: The method of any one of embodiments 1-11, wherein the autoimmune disorder or the inflammatory disorder comprises systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), and Type 1 diabetes (T1D).

[0112] Embodiment 13: The method of any one of embodiments 1-11, wherein the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti -phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis.

[0113] Embodiment 14: The method of any one of embodiments 1-11, wherein the autoimmune disorder comprises pemphigus, myasthenia gravis, or myositis.

[0114] Embodiment 15: The method of embodiment 14, wherein the autoimmune disorder comprises pemphigus.

[0115] Embodiment 16: The method of embodiment 15, wherein the pemphigus is pemphigus vulgaris.

[0116] Embodiment 17: The method of embodiment 15, wherein the pemphigus is pemphigus foliaceus.

[0117] Embodiment 18: The method of embodiment 14, wherein the autoimmune disorder comprises myasthenia gravis.

[0118] Embodiment 19: The method of embodiment 18, wherein the autoimmune disorder comprises myositis.

[0119] Embodiment 20: The method of embodiment 19, wherein the myositis is immune-mediated necrotizing myopathy.

[0120] Embodiment 21: The method of embodiment 19, wherein the myositis is immune-mediated necrotizing myopathy.

[0121] Embodiment 22: The method of embodiment 19, the myositis is dermatomyositis.

[0122] Embodiment 23: The method of embodiment 19, wherein the myositis is antisynthetase syndrome.

[0123] Embodiment 24: The method of embodiment 1, wherein the autoimmune or inflammatory disorder comprises Lambert-Eaton syndrome, Goodpasture’s syndrome, Sjogren's syndrome, eosinophilic granulomatosis with polyangiitis (EGPA), ulcerative colitis, giant cell arteritis, behget' s disease, Takayasu's arteritis, autoimmune polyendocrine syndrome, acute disseminated encephalomyelitis, anti-NMDA receptor encephalitis, chronic inflammatory demyelinating polyneuropathy, autoimmune pancreatitis, autoimmune oophoritis, autoimmune orchitis, or stiff person syndrome, MOG antibody-associated disease (MOGAD), autoimmune autonomic ganglionopathy, autoimmune nodopathies, minimal change disease, focal segmental glomerulosclerosis, anti-LRP2 (anti-brush border) nephropathy, cryoglobulinemic vasculitis (type II / III), IgA vasculitis (Henoch-Schbnlein Purpura), autoantibody C3 glomerulopathy, immune thrombotic thrombocytopenic purpura (iTTP; anti-ADAMTS13), cold agglutinin disease (CAD), Evans syndrome, autoimmune pure red cell aplasia, chronic autoimmune neutropenia, hidradenitis suppurativa, dermatitismucous membrane pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, paraneoplastic pemphigus, pemphigoid gestationis, non-infectious uveitis, or thyroid eye disease.

[0124] Embodiment 25: A method of reducing (e.g., depleting) the number of B cells in the individual that express CD 19 and CD38, the method comprising: administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby reducing the number of B cells in the individual that express CD 19 and CD38, wherein the B cells that express CD 19 and CD38 comprise CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD381OWB cells and CD19+CD38high / +B cells.

[0125] Embodiment 26: The method of embodiment 25, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19'CD38hlghcells.

[0126] Embodiment 27: The method of embodiment 25 or 26, wherein administering the multispecific antibody or multispecific antibody fragment reduces (e.g., depletes) the number of memory B cells (CD19+ CD20+ IgD CD27+) or plasmablasts (CD19+ CD20- CD27hiCD38hi).

[0127] Embodiment 28: The method of any one of embodiments 25-27, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of long-lived plasma cells (CD19 CD38hlghB cells).

[0128] Embodiment 29: The method of any one of embodiments 25-28, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of Naive B cells. (CD19+CD20+IgM+IgD+CD27 ).

[0129] Embodiment 30: The method of any one of embodiments 25-29, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce IgG levels in the individual.

[0130] Embodiment 31: The method of any one of embodiments 25-30, wherein administering the multispecific antibody or multispecific antibody fragment does not result in hypogammaglobulinemia.

[0131] Embodiment 32: The method of any one of embodiments 25-31, wherein the individual has a disorder characterized by immunoglobulin autoimmunity.

[0132] Embodiment 33: The method of any one of embodiments 1-32, wherein the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38: (i) increases antibody-dependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells, compared to a human IgGl control or null control; (ii) (a) does not increase ADCP of CD 19" CD38hlghcells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced ADCP of CD19'CD38hlghcells when compared to daratumumab; (iii) increases antibody-dependent cell cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or direct apoptosis of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; and / or (iv) (a) does not increase ADCC, CDC, or direct apoptosis of CD19'CD38hlghcells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or (b) results in reduced ADCC, CDC or direct apoptosis of CD19'CD38hlghcells when compared to daratumumab.

[0133] Embodiment 34: The method of any one of embodiments 1-33, wherein multispecific antibody or multispecific antibody fragment is a bispecific antibody or bispecific antibody fragment that binds CD 19 and CD38.

[0134] Embodiment 35: The method of any one of embodiments 1-34, wherein the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 comprises: an anti-CD38 heavy chain variable domain and an anti-CD38 light chain variable domain; and an anti-CD19 heavy chain variable domain and an anti-CD19 light chain variable domain.

[0135] Embodiment 36: The method of embodiment 35, wherein: the anti-CD38 heavy chain variable domain comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9, the anti-CD38 light chain variable domain comprises: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25, the anti-CD19 heavy chain variable comprises: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and the anti-CD19 light chain variable domain comprises: a light chain complementaritydetermining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

[0136] Embodiment 37: The method of any one of embodiments 1-36, wherein the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 is a common light chain bispecific antibody.

[0137] Embodiment 38: The method of embodiment 37, wherein the common light chain bispecific antibody comprises: an anti-CD38 heavy chain variable domain comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9, an anti-CD19 heavy chain variable comprising: a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and a common light chain variable domain comprising: a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, or a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

[0138] Embodiment 39: The method of embodiment 38, wherein the anti-CD38 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 1, the anti-CD19 heavy chain variable domain comprises anamino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 2, and common light chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 3.

[0139] Embodiment 40: The method of embodiment 38, wherein the common light chain bispecific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 4, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 5, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 6.

[0140] Embodiment 41: The method of any one of embodiments 37-39, wherein: the anti-CD38 heavy chain variable domain and the anti-CD19 heavy chain variable domain each comprise a negatively-charged amino acid at heavy chain variable domain position 1 per Kabat numbering; the anti-CD38 heavy chain constant domain and the anti-CD19 heavy chain constant domain each lack a C-terminal lysine residue (K447 per EU numbering); and the common light chain bispecific antibody comprises an experimental isoelectric point (pl) of less than 9.

[0141] Embodiment 42: The method of embodiment 41, wherein the common light chain bispecific antibody exhibits a Hydrophobicity (HIC) retention time of less than about 10 minutes.

[0142] Embodiment 43: The method of any one of embodiments 38-42, wherein the terminal lysine residue is K447 per EU numbering.

[0143] Embodiment 44: The method of any one of embodiments 34-43, wherein the anti-CD19 heavy chain variable domain comprises a serine at position 84 and / or a leucine at position 108 according to Kabat numbering.

[0144] Embodiment 45: The method of any one of embodiments 38-44, wherein the common light chain variable region comprises a histidine at position 32 according to Kabat numbering.

[0145] Embodiment 46: The method of any one of embodiments 41-45, wherein the negatively-charged amino acid is glutamic acid.

[0146] Embodiment 47: The method of any one of embodiments 41-46, wherein the pl is between 8.7 and 9.

[0147] Embodiment 48: The method of any one of embodiments 1-47, wherein the multispecific antibody or multispecific antibody fragment comprises an afucosylated Fc region.

[0148] Embodiment 49: The method of any one of embodiments 1-48, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprisingone or more modifications relative to wild-type IgG that decreases antibody dependent cell cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), or antibody dependent cell phagocytosis (ADCP).

[0149] Embodiment 50: The method of embodiment 49, wherein one or more modifications relative to wild-type IgG comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S; P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof.

[0150] Embodiment 51: The method of embodiment 49 or 50, wherein one or more modifications relative to wild-type IgG comprise L234A, L235E, G237A, A330S, P331S (AEASS).

[0151] Embodiment 52: The method of any one of embodiments 1-48, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increase affinity to FcRn.

[0152] Embodiment 53: The method of any one of embodiments 1-48, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wild-type IgG that increases the plasma half-life of the multispecific antibody or multispecific antibody fragment.

[0153] Embodiment 54: The method of embodiment 53, wherein the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

[0154] Embodiment 55: A common light chain multi specific antibody that binds CD 19 and CD38, wherein the common light chain multispecific antibody comprises: (i) an anti-CD38 heavy chain amino acid sequence comprising SEQ ID NO: 26, (ii) an anti-CD19 heavy chain amino acid sequence comprising SEQ ID NO: 27, (iii) a first common light chain amino acid sequence comprising SEQ ID NO 28, and (iv) a second common light chain amino acid sequence comprising SEQ ID NO 28, wherein the anti-CD38 heavy chain amino acid sequence, the anti-CD19 heavy chain amino acid sequence, or both comprises an Fc region comprising one or more modifications relative to wild-type IgG that increases the plasma half-life of the multispecific antibody or multispecific antibody fragment.

[0155] Embodiment 56: The common light chain multispecific antibody that binds CD19 and CD38 of embodiment 55, wherein the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2.

[0156] Embodiment 57: The common light chain multispecific antibody that binds CD 19 and CD38 of embodiment 55, wherein the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2a.

[0157] Embodiment 58: The common light chain multispecific antibody that binds CD19 and CD38 of embodiment 55, wherein the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

[0158] Embodiment 59: The common light chain multispecific antibody that binds CD19 and CD38 of embodiment 55, comprising one or more modifications relative to wild-type IgG wherein the one or more modifications comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S; P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof.

[0159] Embodiment 60: The common light chain multispecific antibody that binds CD19 and CD38 of embodiment 55, comprising one or more modifications relative to wild-type IgG, wherein the one or more modifications comprise L234A, L235E, G237A, A330S, P331S (AEASS).Definitions

[0160] The term “CD19” or “Cluster of Differentiation 19” (also known as B4, T-cell surface antigen Leu-12, and CVID3) refers to a B-cell lineage surface biomarker or transmembrane protein that in humans is encoded by the gene CD19. CD19 can function as coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes, which decreases the threshold for activation of downstream signaling pathways and for triggering B cell responses to antigens. Structurally, a CD19 amino acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence, e.g., of GenBank accession no. NM_001178098.2 -^NP OO I I 71569.1 or NM_001770.6 — NP_001761.3 over a sequence length of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 amino acids or over the full length of the polypeptide. Structurally, a CD 19 nucleic acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the nucleic acid sequence, e.g., of GenBank accession no. NG 007275.1 or NCBI Gene ID 930, over a sequence length of at least 300, 500, 750, 1000, 1250, 1500 nucleic acids or over the full length of the polynucleotide. The sequence alignments can be performed using any alignment algorithm known in the art, e.g., BLAST, ALIGN, set to default settings.

[0161] The term “CD38” or “Cluster of Differentiation 38” (also known as ADPRC1) refers to a B-cell surface biomarker or transmembrane protein that in humans is encoded by the gene CD38. CD38 can function in B-cell signaling that leads to cellular activation and proliferation. Structurally, a CD38 amino acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence, e.g., of GenBank accession no. NM_00l 775.4 NP_00l 766.2 over a sequence length of at least 50, 100, 150, 200, 250, amino acids or over the full length of the polypeptide. There is a second isoform of CD38 with a premature stop codon that may be expressed at low levels in some cells. Structurally, a CD19 nucleic acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the nucleic acid sequence, e.g., of GenBank accession no. NC_000004.12 or NCBI Gene ID 952, over a sequence length of at least 300, 500, 750 nucleic acids or over the full length of the polynucleotide. The sequence alignments can be performed using any alignment algorithm known in the art, e.g., BLAST, ALIGN, set to default settings.

[0162] The term “CD20” or “Cluster of Differentiation 20” (also known as B-lymphocyte surface antigen Bl) refers to a B-cell lineage surface biomarker or transmembrane protein that in humans is encoded by the gene CD20. Structurally, a CD20 amino acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence, e.g., of Uniprot entry Pl 1836 over a sequence length of at least 50, 100, 150, 200, 250, amino acids or over the full length of the polypeptide.

[0163] A “target” as referred to herein refers to the portion of a molecule that participates with a binding moiety of a molecule, peptide, polypeptide, antibody, or antibody fragment. A target can comprise an amino acid sequence and / or a carbohydrate, lipid or other chemical entity. An “antigen” is a target comprising a portion that is able to be bound by an adaptive immune molecule such as an antibody or antibody fragment, B-cell receptor, or T-cell receptor.

[0164] “ ADCC” or “antibody dependent cell-mediated cytotoxicity” as used herein, refers to the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC can be correlated with binding to FcyRIIIa wherein increased binding to FcyRIIIa leads to an increase in ADCC activity. “ADCP” or antibody dependent cell-mediated phagocytosis, as used herein, can refer to the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0165] A bispecific antibody generally refers to and includes antibody formats that possesses the ability to specifically bind to at least two structurally distinct targets. The specific binding can be the result of two distinct binding moieties that are structurally distinct at the molecular level,including but not limited to distinct non-identical amino acid sequences; or a single binding moiety that is able to specifically bind to two structurally distinct targets with high affinity (e.g., with a KD less than about lxlOA-6). An antibody, or antibody fragment referred to as “multispecific” refers to a molecule that possesses the ability to specifically bind to at least two or more structurally distinct targets. A “bispecific antibody” including grammatical equivalents refers to a bispecific molecule that binds to two distinct targets and preserves at least one fragment of an antibody able to specifically bind a target, for example, a variable region, heavy or light chain, or one or more complementarity determining regions from an antibody molecule. A “multispecific antibody” including grammatical equivalents refers to a multispecific molecule that preserves at least one fragment of an antibody able to specifically bind with a target, for example, a variable region, heavy or light chain, or complementarity determining region from an antibody molecule.

[0166] Asymmetric bispecific antibodies generally comprise a heavy chain / light chain (HC / LC) pair from an antibody specific for target A and an HC / LC pair from an antibody specific for target B, creating a hetero-bifiinctional antibody. Hetero-bifunctional antibodies such as these face the problem of unproductive formation of the molecule when it is being produced. HC / LC-A:HC / LC-B is desired, but is usually thermodynamically or statistically unfavorable from all the possible combinations possible. Multiple schemes have been introduced to circumvent this problem. In some instances, the HC / LC pair from an antibody with specificity for A and the HC / LC pair from an antibody with specificity for B further comprise mutations to the FC region to increase the probability of formation of an antibody with HC / LC- A:HC / LC-B. This can be achieved by engineering structural features such as “knobs” into the FC region for HC-A, and “holes” into HC-B, or vice versa, that promote formation of heterodimers between HC-A and HC-B. Another scheme to promote HC-A:HC-B heterodimers is to engineer amino acid residues in the FC portion of HC-A and HC-B to comprise charge pairs that favor electrostatic interactions between HC-B and HC-A. Another scheme to address the problem of chain association is to replace the variable regions of one of the HC / LC pairs with a single-chain binding molecules (e.g., VHH or an scFv). Such that one-half of the molecule comprises a classical HC / LC pair and the other comprises a HC constant region fused or otherwise connected to the single-chain binding molecule. Further modifications can be made to promote proper HC / LC paring and include engineering mutations to the HC and LC for either A or B to favor formation of the proper HC / LC pair; CrossMab technology, which entails swapping the corresponding constant regions of the HC / LC pair. Symmetric bi specific antibodies circumvent the chain association problem by not relying on formation of a hetero-bifunctional molecule. Such examples include: the dual-variable domain molecule, which comprises stacked variableregions of differing specificity; the IgG-scFv molecule, which comprises an scFv of a differing specificity fused to the c-terminus of heavy chain of a classical antibody molecule; the (scFV)4-FC, which comprises two scFvs connected by an Fc region of an Ig (the Fes dimerize creating a bispecific, tetravalent molecule); the DART-Fc and the two-in-one, amongst others.

[0167] The terms “polypeptide” and “protein” are used interchangeably and refers to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, can include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides can contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0168] The terms “complementarity determining region,” and “CDR,” which are synonymous with “hypervariable region” or “HVR,” are known in the art to refer to noncontiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-Ll, CDR-L2, CDR-L3). “Framework regions” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho”numbering scheme); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modelling antibodies on the WEB,” Protein Eng. 2000 Dec;13(12):819-24 (“AbM” numbering scheme. In certain embodiments, the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[0169] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively (See e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0170] Specific binding or binding of antibody molecules described herein refers to binding mediated by one or more CDR portions of the antibody. Not all CDRs may be required for specific binding. Specific binding can be demonstrated for example by an ELISA against a specific recited target or antigen that shows significant increase in binding compared to an isotype control antibody.

[0171] The term “constant region” can refer to a light chain or heavy chain constant region. Light chain constant regions have two main isotypes kappa and lambda. Heavy chain constant regions may comprise any one of 5 isotypes: IgA, IgD, IgG, IgE, or IgM. The IgG istypes is further comprises of IgGl, IgG2, IgG3, IgG4 subclasses. Heavy chain constant regions comprise a CHI, hinge, CH2, and / or a CH3 domain. Residues of light and heavy chain constant regions can be numbered according to the EU numbering scheme (Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969).) or the Kabat numbering scheme (Kabat, E.A. et al., Sequences of proteins of immunological interest. 5th Edition - US Department of Health and Human Services, NIH publication n° 91-3242, pp 662,680,689 (1991)). Constant regions may comprise an Fc region as described herein.

[0172] A “linker” herein is also referred to as “linker sequence” “spacer” “tethering sequence” or grammatical equivalents thereof. A “linked ’ as referred herein connects two distinct molecules that by themselves possess target binding, catalytic activity, or are naturally expressed and assembled as separate polypeptides. For example, two distinct binding moieties or a heavy-chain / light-chain pair. A number of strategies may be used to covalently link moleculestogether. These include but are not limited to polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents. In one aspect of this embodiment, the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. The linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr. The linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In one embodiment, the linker is from about 1 to 50 amino acids in length or about 1 to 30 amino acids in length. In one embodiment, linkers of 1 to 20 amino acids in length may be used. Useful linkers include glycine-serine polymers, including for example (GS)n, (GSGGS)n, (GGGGS)n, and (GGGS)n, where n is an integer of at least one, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers. Exemplary, linkers for linking antibody fragments or single chain variable fragments can include AAEPKSS, AAEPKSSDKTHTCPPCP (SEQ ID NO: 19), GGGG (SEQ ID NO: 20), or GGGGDKTHTCPPCP (SEQ ID NO: 21). Alternatively, a variety of non-proteinaceous polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers.

[0173] “Fragment-based” bispecific antibodies or bispecific antibodies comprising a “single chain variable fragment” or “scFv” of this disclosure can refer to a single chain antibody, or fragment thereof, that comprises two binding moieties and a linker connecting the two binding moieties. The linker may be a polypeptide linker or other linker of suitable flexibility so as not to inhibit binding of either targeting moiety. Fragment based bispecific antibody formats include tandem VHH antibodies, tandem scFvs, scFv-Fabs, F(ab)2, dual-affinity retargeting antibodies (DARTs). Such fragment-based antibodies can be further manipulated to comprise additional binding moieties with specificity for a given target e.g., A2:BI, AI:B2 or A2:B2, or with fragments of an Fc region to improve pharmacokinetics or promote ADCC, ADCP, or CDC.

[0174] A “binding moiety” refers to a portion of a molecule, peptide, polypeptide, antibody, or antibody fragment that mediates specific binding to a recited target or antigen or epitope. By way of example, the binding moiety of an antibody may comprise a heavy-chain / light-chain variable region pair or one or more complementarity determining regions (CDRs).

[0175] A “target” as referred to herein refers to the portion of a molecule that participates with a binding moiety of a molecule, peptide, polypeptide, antibody, or antibody fragment. A target can comprise an amino acid sequence and / or a carbohydrate, lipid or other chemicalentity. An “antigen” is a target comprising a portion that is able to be bound by an adaptive immune molecule such as an antibody or antibody fragment, B-cell receptor, or T-cell receptor.

[0176] In some embodiments, the bispecific antibodies provided herein have a dissociation constant (KD) of about 10 pM, 1 pM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, or 0.001 nM or less e.g., 10sM or less, e.g., from 10sM to 1013M, e.g., from 109M to 1013M) for the antibody target. The antibody target can be a CD19 target, a CD38 target, or a target comprising both CD19 and CD38. KD can be measured by any suitable assay. In certain embodiments, KD can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000 or a BIACORE®-3000 or Octet).

[0177] A “humanized” antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody optionally can include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of a non-human antibody refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0178] Among the provided antibodies are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.

[0179] “ ADCC” or “antibody dependent cell-mediated cytotoxicity” as used herein, refers to the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC can be correlated with binding to FcyRIIIa wherein increased binding to FcyRIIIa leads to an increase in ADCC activity. “ADCP” or antibody dependent cell-mediated phagocytosis, as used herein, can refer to the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0180] The terms “polypeptide” and “protein” are used interchangeably and refers to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, can include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides can contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0181] As described herein, the term “percent (%) sequence identity,” and terms related thereto, in the context of amino acid sequences or nucleic acid sequences, is the percentage of amino acid residues or nucleic acid residues in a candidate sequence that are identical with the amino acid residues or nucleic acid residues, respectively, in a selected sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity or percent nucleic acid identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as Clustal Omega, BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software, with BLAST being the alignment algorithm of preference. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared, although for simplicity it maybe preferred to use default parameters.

[0182] As used herein, the term “individual” is synonymous with patient and / or subject and includes and / or refers to a human and may be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein. However, examples are not limited to humansand include, chimpanzees, marmosets, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. The term individual includes vertebrates. The individual is typically a human and may be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein.

[0183] As used herein, treating or treatment of includes and / or refers to ameliorating the disease or disorder or symptoms thereof (e.g., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In certain embodiments, treating or treatment also includes and / or refers to alleviating or ameliorating at least one physical and / or biological parameters including those which may not be discernible by the patient. In certain embodiments, treating or treatment includes and / or refers to modulating a disease, disorder, or biological process either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical and / or biological parameter), or both. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying the onset or development or progression of the disease or disorder. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying or inhibiting the deterioration of (i) a healthy physiological state or (ii) a baseline physiological state (e.g., the progression of a disease or disorder). Treatment includes the administration of a molecule of this disclosure with the intent to beneficially effect a physiological disease state.

[0184] As used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of’ and / or “consisting of,” unless context clearly connotes otherwise. Similarly, as used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of’ and / or “consists of,” unless context clearly connotes otherwise.

[0185] As used herein, the term “about,” in the context of a given value or range, includes and / or refers to a value or range that is within 10% of the given value or range.

[0186] As used herein, the term “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein.EXAMPLES

[0187] The following illustrative examples are representative of embodiments of compositions and methods described herein and are not meant to be limiting in any way.Example 1. Anti-mouse CD19 / CD38 multispecific Ab (MBS-1938-1) is effective in reducing anti-dsDNA antibodies in prophylactic lupus model

[0188] The efficacy of MBS-1938-1 was assessed in MRL / MpJ-Faslpr / J lupus mouse model. Briefly, 8-week-old mice (n=10 / group) were administered either PBS, isotype control (10 mg / kg), MBS-1938-1 (10 mg / kg), or cyclophosphamide (25 mg / kg, positive control) biweekly for 12 weeks. Body weight was monitored twice weekly, proteinuria was assessed weekly, and anti-dsDNA antibody levels were measured 2-4 weeks, pending blood volume, until the end of the study at 12 weeks post-treatment. Mice were also observed for visual signs of enlarged lymph nodes (lymphadenopathy). As a hallmark of systemic lupus erythematosus (SLE), anti-nuclear antibody (ANA) levels were measured at week 16.

[0189] The treatment was well tolerated across all the groups. By week 12, all groups exhibited slightly elevated levels of proteinuria (data not shown) and anti-dsDNA, with the cyclophosphamide-treated group displaying the lowest levels (FIG. 1A and FIG. 2A). As the disease progressed, the PBS and isotype control -treated groups showed a marked increase in anti-dsDNA antibody levels by week 14 (FIG. IB and FIG. 2B). In contrast, mice treated with MBS 1938-1 showed only a minimal increase in antibody levels, which remained comparable to the cyclophosphamide-treated group (FIGs. 1A and IB). By week 15, three out 4 mice that succumbed to lymphadenopathy were from the PBS or isotype treated group (data not shown). Between week 14 to week 18, although both the MBS 1938-1 and isotype treated groups showed a trend of increase in the dsDNA antibody levels compared to cyclophosphamide-treated group (FIG. 2A), the MBS 1938-1 treated group consistently exhibited significantly lower levels of anti-dsDNA antibody across all the time points relative to the isotope control group. By week 16, mice in the isotype control exhibited a pronounced increase in ANA levels, which became even more pronounced by week 20 (FIG.2B). In contrast, mice treated with MBS 1938-1 showed a delay and significantly lower increase in ANA levels at week 20 compared to the isotype control group. By week 20, all groups demonstrated elevated ANA levels, with the cyclophosphamide-treated group exhibiting the lowest levels. Collectively, these findings indicate that anti-CD19 / CD38 antibodies can delay the progression of lupus.Example 2. Anti-mouse CD19 / CD38 multispecific Ab (MBS-1938-1) is effective in blocking diabetes progression in prophylactic Type 1 diabetes model

[0190] Although islet antigen-reactive T cells are widely considered the primary pathogenic effectors of pancreatic [3-cell destruction in Type 1 Diabetes Mellitus (T1DM), a growing body of evidence highlights the significant role of islet-reactive B cells in disease pathogenesis. TheseB cells play critical roles in presenting antigen to T cells and in the production of cytokines and autoantibodies in humans and mice. The efficacy of MBS was further assessed in NOD / ShiLtJ mice. Briefly, 6-week-old mice (n=10 / group) were treated biweekly with either PBS, isotype control (10 mg / kg), MBS- 1938-1 (10 mg / kg), or anti-CD40L (13.8 mg / kg, positive control), which was administered every three weeks. Treatment continued until at least 50% of mice in control groups reach diabetes onset. Body weight was monitored twice weekly, and fasting blood glucose levels were measured weekly. Mice were also observed for signs of autoimmunity, including hunched posture, scruffy coat, and reduced activity.

[0191] The treatment was well tolerated. As shown in FIG.3A and 3B, starting at week 7, mice in the PBS-treated group began to exhibit the signs of diabetes onset (defined as blood glucose > 250 mg / dL), and ultimately succumbed to disease progression. In contrast, mice treated with MBS exhibited a delay in disease onset and maintained normal blood glucose levels up to week 12. Similarly, mice treated with anti-CD40L exhibited a significant delay in diabetes onset. By week 17— a timepoint at which 50% of the mice in the PBS-treated group had died, 90% of the mice in the MBS- 1938-1 -treated group and 80% of the mice in the anti-CD40L-treated group remained alive. Taking together, these results indicate that anti-CD19 / CD38 are effective in blocking diabetes progression. Thus, a CD19 / CD38 multispecific shows promise in a traditionally T cell-based model of autoimmune disease. Without being bound by theory this may be due to the ability of the CD19 / CD38 binding antibody to kill CD38lowcells that act as antigen presenting cells and promote pathogenic T cell survival and activation.Example 3. Anti-human CD19 / CD38 multispecific antibodies B55-001 and BSM6F (afucosylated) effectively eliminates CD19+CD38+ B cells and CD19+CD38lowB cells while preserving CD19 CD38hlghlong-lived plasma cells

[0192] CD19 is expressed from progenitor B cells to plasma cells, and its expression gradually decreases during differentiation. CD 19 expression spans the entire differentiation stage of B cells and, therefore, serve as a specific marker on the B cell surface. CD38 is expressed in the early B-cell development when stimulated by cytokines, endotoxins, and interferons. The expression levels of CD38 continue to change as B cells differentiate, eventually peaking in plasma cells. Anti-CD38 primarily targets CD38 surface proteins on plasma cells. While anti-CD38 effectively eliminates CD19+CD38+ plasmablasts, short-lived plasma cells, and long-lived plasma cells (populations #1), which are key mediators of autoimmune pathogenesis, it fails to eliminate CD19+CD381ow memory B cells and preplasmablasts (population #2), which can rapidly differentiate into pathologic plasmablasts (FIG.4). Moreover, anti-CD38 also eliminates CD19-CD38hi long-lived plasma cells (population #3), which produce the protective antibodies generated by vaccines and infections (FIG. 4).Therefore, an antibody that can selectively eliminate CD19+CD38+ B cells and CD19+CD381ow B cells while preserving CD19-CD38hi long-lived plasma cells is highly desirable.

[0193] Assays were designed and conducted to reveal the difference between anti-CD38 monoclonal antibodies and B55-001 in terms of their binding and cytotoxic effects on various B cell populations. B55-001 showed increased binding to populations #1 and #2 and reduced binding to population #3 compared to anti-CD38 therapies (data not shown), supporting the notion that B55-001 has potential to suppress autoimmunity.

[0194] To explore whether the administration of B55-001 can induce potent killing of CD19+CD38+ B cells (populations #1), an antibody-dependent cellular phagocytosis (ADCP) assay was performed to assess the extent of macrophage-mediated phagocytosis of CD19+CD38hi Ramos human cancer cells triggered by the presence of antibodies. Briefly, target cells (Ramos human B lymphocyte cell line) were labeled with pH-sensitive dye (pHrodo Green) and incubated with B55-001, BSM6F (afucosylated variant of B55-001), daratumumab, mezagitamab, felzartamab, or control hlgGl isotype at concentrations of 0, 0.001, 0.01, 0.1, or 1 ug / ml for 15 min, followed by co-culturing with in vitro differentiated human macrophage effector cells (E:T ratio 1 :2) for 4 hours. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells by flow cytometry. The experiment was performed using macrophages from two healthy donors, with cells seeded in triplicates for each assay.

[0195] Flow cytometry data revealed dose-dependent phagocytosis of target cells triggered by the administered antibodies across all the groups, except the hlgGl isotype group (FIG. 5).Macrophages mediated potent phagocytosis in the presence of B55-001, BSM6F, or anti-CD38 antibodies, including daratumumab, mezagitamab, and felzartamab (FIG. 5). B55-001 and BSM6F showed lower potency in triggering phagocytosis at a concentration of 0.001 ug / ml compared to anti-CD38 antibodies at the same concentration (FIG. 5). However, at concentrations higher than 0.001 ug / ml, B55-001 and BSM6F exhibited a similar extent to trigger phagocytosis compared with anti-CD38 antibodies (FIG. 5). These data indicate that both B55-001 and BSM6F are effective in killing CD19+CD38hi B cells, which are the key mediators of autoimmune pathogenesis.

[0196] To assess whether the administration of B55-001 can induce potent killing of CD19+CD381ow B cells (population #2), a similar ADCP assay was performed to evaluate theextent of macrophage-mediated phagocytosis of CD19+CD381ow isolated B cells triggered by the added antibodies. Briefly, target cells (isolated B cells) were labeled with pH-sensitive dye (pHrodo Green) and incubated with B55-001, BSM6F, daratumumab, mezagitamab, felzartamab, or control hlgGl isotype at concentrations of 0, 0.05, 0.5, or 5 ug / ml for 15 min, followed by co-culturing with in vitro differentiated human macrophage effector cells (E:T ratio 1 :2) for 4 hours. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells by flow cytometry. The experiment was performed using macrophages from two healthy donors, with cells seeded in triplicates for each assay.

[0197] The administration of B55-01 or BSM6F in the co-culture exhibited enhanced potency in triggering phagocytosis of target cells in a dose-dependent manner, while the administration of anti-CD38 antibodies, including daratumumab, mezagitamab, and felzartamab failed to do so (FIG. 6). These data indicate that both B55-001 and BSM6F are capable of effectively eliminating CD19+CD381owB cells, which can differentiate into the B cell mediators of Ig autoimmunity. Taken together, B55-001 and BSM6F shows clear difference from anti-CD38 monoclonal antibodies for autoimmunity.

[0198] To investigate whether the administration of B55-001 can preserve long-lived CD19-CD38hi plasma cells (population # 3), which are the source of humoral immunity, a similar ADCP assay was performed to measure the extent of macrophage-mediated phagocytosis of CD19-CD38hi NCL-H929 human cancer cells triggered by the antibodies. Briefly, target cells (NCI-H929 human cancer cell line) were labeled with pH-sensitive dye (pHrodo Green) and incubated with B55-001, BSM6F, daratumumab, mezagitamab, felzartamab, or control hlgGl isotype at concentrations of 0, 0.001, 0.01 ug / ml for 15 min, followed by co-culturing with in vitro differentiated human macrophage effector cells (E:T ratio 1:2) for 4 hours. ADCP activity was measured as the percentage of CTV+and pHrodo Green111double positive cells by flow cytometry. The experiment was performed with macrophages from two healthy donors, with cells seeded in triplicate.

[0199] The presence of anti-CD38 antibodies, including daratumumab, mezagitamab and felzartamab, in the co-culture exhibited enhanced potency in triggering phagocytosis of target cells in a dose dependent manner, though felzartamad to a less extent (FIG. 7A). Nevertheless, macrophages in the presence of B55-001 or BSM6F did not show any phagocytosis, as comparable percentages of CTV+and pHrodo Green111double positive cells were observed in B55-001, BSM6F, and hlgG isotype groups (FIG. 7A). These data indicate that both B55-001 and BSM6F induce negligible effects on CD19-CD38hi cells and are therefore capable of preserving them.

[0200] Additionally, an ADCC assay was conducted to evaluate whether B55-001 can preserve long-lived B cells. Briefly, CD19-CD38hi target cells (NCI-H929)) were treated with mezagitamab, daratumumab, felzartamab, B55-001, or hlgGl isotype in triplicate followed by coculturing with effector cells (reporter cell line engineered to express human FcyRIIIa VI 58 for ADCC) for 4-6 hours. Bio-Gio™ Luciferase substrate was added to wells and luminescence measured on plate reader. Following engagement with Fc region of antibody bound target cells, NFAT-mediated luciferase activity was measured as the relative light units (RLU). As shown in FIG. 7B, effector cells treated with mezagitamab, daratumumab, or felzartamab exhibited dosedependent cytotoxicity against tumor cells. In contrast, effector cells did not induce significant tumor cell killing when treated with B55-001, showing minimal cytotoxic activity at concentrations exceeding 1 ug / ml. These data further indicate that B55-001 does not mediate the killing of CD19-CD38hi cells, unlike anti-CD38 therapies.

[0201] Taken together, these data suggest that B55-001 has a broader coverage than CD 19 biologies which often fail to eliminate pathogenic B cells with low CD 19 expression. Furthermore, in contrast to CD38 mAbs which often inadequately eliminate CD19+CD381ow B cells while inadvertently eliminating beneficial CD19-CD38hi plasma cells, B55-001 demonstrates selectivity, eliminating pre-blasmablasts that drive autoimmunity and sparing the desired long-lived plasma cells (FIG. 4). These advantages highlight that B55-001 can serve as a more precise and effective therapeutic for targeting pathogenic B cells.Example 4. Afucosylated version of B55-001 (BSM6F) exhibits greater cytotoxicity against CD19+CD38+and CD19+CD38lowcells

[0202] Afucosylated antibodies exhibit higher therapeutic efficacies than their fucosylated counterparts through antibody -dependent cellular cytotoxicity (ADCC) mechanism. To achieve better efficacy, B55-001 was afucosylated and further validated by an ADCC assay. Target cells, either isolated B cells from one donor or human cancer cell lines, were seeded in triplicates and treated with B55-001, BSM6F (afucosylated variant of B55-001), hlgGl isotype, or anti-CD20 at the indicated concentrations, followed by co-culturing with effector cells for 6 hours. The effector cells were a reporter cell line engineered to express human FcyRIIIa VI 58. Bio-Gio™ Luciferase subtrate was added to wells and luminescence measured on plate reader. Following engagement with Fc region of antibody bound target cells, NFAT-mediated luciferase activity was measured as the relative light units (RLU).

[0203] The engineered effector cells exhibited dose-dependent cytotoxicity against all tested target cells in the presence of B55-001, BSM6F, or anti-CD20 (FIGs. 8A-8C). Of note, BSM6Finduced a much greater cytotoxic effect on target cells compared to its counterpart B55-001(FIGs. 8A-8C). These data indicate that afucosylated B55-001 shows increased ADCC activity targeting populations #1 and #2 compared to B55-001.Example 5. Co-targeting CD38 and CD19 achieves deeper depletion and efficacy compared to targeting CD19 alone

[0204] To compare the killing efficacy of B55-001 and anti-CD19 antibody in targeting CD191owCD38+ cells, SU-DHL-4 cells which express extremely low levels of CD19 (CD19 ABC ~ 2,200 available receptors on average) were implanted subcutaneously into the flank of CB17 / scid mice. When tumor volumes reached 125-175 mm3, mice were randomized (N=10 mice / group) and dosed intravenously twice weekly for 4 weeks with 10 mg / kg of each antibody. Tumors and body weights were measured 3 times per week. As shown in FIG. 9A, tumors in the hlgGl control group progressed rapidly. Treatment with the ani-CD19 antibody Tafasitamab moderately inhibited tumor growth. In contrast, treatment with B55-001 or B55-001 Fc-dead variant resulted in significant suppression of tumor progression throughout the dosing period (FIG. 9A). These findings indicate that B55-001 exerts potent cytotoxic effects on B cells with low CD 19 expression, which are only partially targeted by anti -CD 19 antibodies. Moreover, the observation that both wild-type and Fc-effector function deficient (Fc-dead) variants of B55-001 effectively suppressed tumor progression in an immunodeficient mouse model suggests that B55-001 mediates direct apoptosis-included cell killing, independent of immune effector functions.

[0205] To further validate the differential killing efficacy between the bispecific anti-CD19 / CD38 antibody and anti-CD19 in targeting various B cell populations, an anti-mouse anti-CD19 / CD38 antibody (MBS1938-1) and other anti-mouse antibodies were tested in a murine model. Briefly, 0.5 mg KLH was implanted subcutaneously to female C57BL / 6 mice on day 0 and day 14 to induce antibody production. Starting on day -4, mice were randomized (N=10 mice / group) and dosed intravenously twice weekly until day 13 with 10 mg / kg of each antibody. On day 14 (prior to the booster), blood was collected from all mice via retro-orbital sinus. On day 21, all mice were euthanized and blood collected via cardiac puncture. As shown in FIG. 9B, by day 21, anti -KLH titers were readily detected in the isotype control treated group. A reduction in titers was observed in the anti -CD 19 treated group. In contrast, very low anti -KLH titers were detected in mice treated with anti-CD19 / CD38, anti-CD40L, or anti-CD20 antibody. Further analysis of the B cell population revealed that both the bispecific anti-CD19 / CD38 and anti-CD20 antibody effectively depleted B220+ B cells (FIG. 9C). In comparison, anti-CD19antibody treatment resulted in only modest B cell depletion, while anti-CD40L preserved B220+ B cells but effectively suppressed anti-KLH antibody production through a distinct mechanism (FIG. 9C). These results demonstrate that the bispecific anti-CD19 / CD38 antibody achieves a deeper depletion of antibody-secreting B-cells and reduction in IgG anti-KLH titers compared to anti-CD19 antibody.Example 6. B55-001 shows enhanced direct apoptosis

[0206] Antibodies targeting B cells can mediate depletion through mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). As shown in FIGs. 20A and 20B, CDC activity of B 55-001 was evaluated using Daudi and SUDHL-4 tumor cells incubated for 2 hours with B55-001, its afucosylated variant (BSM6Faf), or the hlgG isotype control. Both B55-001 and the afucosylated variant induced robust, dose-dependent cytotoxicity in Daudi and SUDHL-4 tumor cells, in the presence of human complement. These results demonstrated that B55-001 mediated target cell killing, at least in part, through CDC. Additionally, B55-001’s ADCC activity was assessed using Daudi and SUDHL-4 tumor cells as target cells and. Cocultured target cells and effector cells were incubated with B55-001, B55-001 Fc-dead variant which lacking Fc effector function, or hlgGl isotype control for 6 hours and cytotoxicity was measured using a reporter assay. B55-001 induced dose-dependent cytotoxicity, while the Fc-dead variant and isotype control showed no detectable cytotoxicity against the tumor cells (FIGs.20C and 20D) These results indicate that the target cell killing mediated by B55-001 is at least partly attributable to ADCC. Furthermore, B55-OOTs ADCP activity was evaluated using Daudi and Raji cells as target cells. Tumor cells and macrophages were labeled with Phrodo Green and cell trace violet respectively and cocultured in the presence of B55-001, B55-001 Fc-dead variant, anti-CD20, or hlgGl isotype control. Both B55-001 and anti-CD20 antibodies mediated robust, dose-dependent phagocytosis of tumor cells, while the B55-001 Fc-dead variant and IgGl control failed to induce phagocytosis (FIGs. 20E and 20F). The data further demonstrated that ADCP is one of the mechanisms contributing to B55-001-mediated target cell killing.

[0207] In addition to these Fc effector functions, emerging evidence suggests that certain antibodies may also induce direct apoptosis of B cells, exhibiting a more efficacious mechanism of action which is independent of immune effector cells. Based on the findings in Example 5, it is hypothesized that B55-001 can induce B cell apoptosis by stabilizing CD19 / CD38 / CD81 complex, thereby triggering cell death independently of Fc-mediated effector functions (FIG.10). To validate this, various B cell tumor cell lines were treated with B55-001 or Tafasitamab(anti-CD19), and cell lysis was assessed. Briefly, cells were seeded in triplicate and incubated for 48 hours with the indicated antibodies at a concentration of 0.2 nM, washed, stained with Annexin V, and subsequently stained with viability dye before analysis by flow cytometry. Specific lysis was calculated by dividing the count of live target cells by the average count in untreated wells. As shown in FIG. 11A, B55-001 consistently resulted in higher levels of cell lysis across multiple tumor cell lines, whereas Tafasitamab induced only baseline levels of lysis. These findings indicate that B55-001 is capable of mediating direct apoptosis in B cells through an Fc-independent mechanism.

[0208] To compare the direct apoptotic effects of B55-001 and daratumumab (anti-CD38), a similar assay was performed in which various B cell tumor cell lines were treated with either B55-001 or daratumumab, and cell lysis was assessed. Cells were seeded in triplicate and incubated for 48 hours with the indicated antibodies at a concentration of 0.2 nM, washed, stained with Annexin V, and subsequently stained with viability dye before analysis by flow cytometry. Specific lysis was calculated by dividing the count of live target cells by the average count in untreated wells. As shown in FIG. 11B, B55-001 induced stronger cell lysis compared to the daratumumab, although the latter also triggered measurable levels of lysis in Daudi, EB1, and SU-DHL-4 cells. Notably, B55-001 consistently outperformed daratumumab across all the tested cell lines. These results furter support that B55-001 mediates potent direct apoptosis in B cells.

[0209] To determine the antibody concentration required to induce apoptosis (EC50), WSU-DLCL2, Raji, and Daudi cells were treated with B55-001, Tafasitamab, daratumumab, or hlgGl isotype control at a top concentration of 33 nM followed by a five-fold dilution series, and the percentage of viable cells were counted. Cells were seeded in triplicate and incubated for 48 hours with the tested antibodies at indicated concentrations, washed, and stained with viability dye before analysis by flow cytometry. Percent viability was calculated by dividing the count of live target cells by the average count in untreated wells. As shown in FIGs. 12A-12C, B55-001 induced dose-dependent cell lysis across all three cell lines. Notably, cells treated with B55-001 exhibited a lower percentage of viable cells compared to those treated with either daratumumab or Tafasitamab. Additionally, Tafasitamab failed to induce significant lysis in WSU-DLCL2 and Daudi cells, with only moderate activity observed in Raji cells, while daratumumab induced minimal lysis in WSU-DLCL2 cels and moderate levels in Raji and Daudi cells. These results indicate that B55-001 mediates more potent apoptosis than anti-CD19 or anti-CD38 antibody.

[0210] Furthermore, to confirm whether B55-001 can rapidly mediate direct apoptosis, the activity of B55-001 and anti-CD19 and anti-CD38 mAbs was evaluated across various human Bcell lymphoma cell lines. Briefly, tumor cells were plated in triplicate and treated with the monospecific anti-CD38 antibodies, anti-CD19 antibodies, the bispecific anti-CD19 / CD38 antibody B55-001, or the Fc-dead variants of B55-001 for 30 minutes. Following incubation, the cells were labeled with propidium iodide (PI), and the number of viable cells (PIneg) were enumerated by flow cytometry. As shown in FIG. 12D, B55-001 induced rapid apoptosis across all tumor cell lines tested. In contrast, anti-CD38 mAbs (isatuximab and daratumumab) induced moderate direct apoptosis in Daudi, EB1, and Raji cells but not in all tumor cell lines tested, while anti-CD19 mAbs (Tafasitamab and inebilizumab) exerted minimal or modest effects. These data show that B55-001 induces rapid and potent killing of CD19+CD38+B cell lymphoma cells and does not require cross-linking via FcgR to mediate direct apoptosis.Example 7. B55-001 selectively preserves NK cells and non-target CD38+ immune cells while depleting CD19+CD38+ B cells

[0211] Previous studies have reported that treatment of daratumumab in multiple Myeloma (MM) patitents results in a reduction of circulating natural killer (NK) cells, as NK cells also express CD38. This off-target depletion likely impairs the efficacy of ADCC in patients receiving CD38 -targeting therapies. To assess whether B55-001 induces similar NK cell depletion, CD38+ target cells were treated with indicated antibodies and co-cultured with effector or phagocytic cells, followed by measurement of ADCC or ADCP using reporter assays. Briefly, CD38+target cells (human myeloma lines) were treated with test articles in triplicate followed by co-culturing with effector cells (reporter cell line engineered to express human FcyRIIIa VI 58 for ADCC or engineered THP-1 cells that express a luciferase reporter driven by FcyR-dependent response elements for ADCP) for 4-6 hours. Bio-Gio™ luciferase substrate was added to wells and luminescence measured on plate reader. As shown in FIGs. 13A-13B, mezagitamab, daratumumab, or felzartamab mediated dose-dependent cytotoxicity and phagocytosis against CD38+ target cells. In contrast, B55-001 did not induce ADCC in NCI-14929 cells except at high antibody concentrations, and only a minimal phagocytic effect was observed in MOLP-8 cells (FIGs. 13A-13B). These results demonstrated that B55-001 does not effectively target CD38+ / CD19- cells, providing strong evidence that it is unlikely to deplete CD38+NK cells.

[0212] To further evaluate the off-target effects of B55-001 on CD38+ but CD19- cells, human peripheral blood mononuclear cells (PBMCs) were used as target cells. Cryopreserved donor PBMCs were thawed and treated with indicated antibodies (highest concentration shown, 150 or 100 pg / mL for healthy donor and cancer blood, respectively) for 24 hours. Followingovernight incubation with the indicated antibodies, the viability of immune cell subsets was evaluated. B55-001 treated PBMCs maintained high viability in the subsets, including CD3+CD38+ T cells, CD56+CD38+NK cells, CD1 lb / 1 Ic+Cd38+ monocytes / DCs (FIG. 14A).In contrast, treatment with anti-CD52 antibody (alemtuzumab) resulted in significant cell death, consistent with the broad expression of CD52 on PBMCs (FIG, 14A). These results indicate that B55-001 selectively spares CD38+CD19- immune cells and does not cause off-target cytotoxicity.

[0213] An additional assay was conducted to evaluate B55-001’s activity against PBMC derived CD19+CD38hi B cells. Healthy donor derived B cells were isolated and differentiated to CD19+CD38hi B-cells by coculturing with feeder cells and cytokines. Next, CD19+CD38hi B-cells were fluorescently labeled with VF405 and then added to PBMC cultures at a 1 :4 ratio (CD19+CD38 B-cells:PBMC) and treated with indicated antibodies at 33 nM concentration for 24 hours. After overnight incubation with B55-001, the number of viable cells which were fluorescently labeled with VF405 was significantly reduced. These results suggest that B55-001 selectively targets and kills CD 19 and CD38 double positive cells while sparing CD38 single positive cells.Example 8. B55-001 mediates effective depletion of pathogenic plasmablasts while preserving naive B cells

[0214] Naive B cells are important component of a healthy immune system and play a key role in mounting protective humoral immune responses against pathogens. Although depletion of pathogenic B cells can help alleviate autoimmune symptoms, indiscriminate elimination of all B cell subsets can be detrimental, as it may compromise the body’s ability to produce humoral responses to pathogens and vaccines. In the previous example, B55-001 was shown to preserve long-lived plasma cells (CD19-CD38hi), in this example, the effect of B55-001 on the naive B cell population was evaluated. Briefly, to assess whether B55-001 preserve naive B cells, cryopreserved PBMCs from heathy donors were plated and treated with B55-001, monospecific anti-CD19 antibodies, or monospecific anti-CD20 antibodies for 48 hours. Following incubation, viable naive B cells characterized as CD19+CD20+BAFFR+ cells were enumerated by flow cytometry. As shown in FIGs. 21A and 21B, treatment with either monospecific anti-CD19 antibodies (Tafasitamab, or Blinatumomab), or monospecific anti-CD20 antibodis (Obinutuzumab or Glofitamab) resulted in markedly stronger depletion of naive B cells compared to treatment with B55-001. The level of naive B cell depletion mediated by B55-001 was comparable to that observed with the isotype control. These results demonstrate that thebispecific anti-CD19 / CD38 antibody B55-001 does not target naive B cell population. However, it effectively preserves this population.

[0215] While B55-001 preserves naive B cells, additional assays were performed to confirm that it can effectively deplete pathogenic CD19+CD38+ plasmablasts under similar experimental conditions. Briefly, human B cells were differentiated and expanded in ImmunoCult™ B cell medium containing B cell expansion supplement for 9-11 days and used as target cells.Cryopreserved PBMCs were depleted of CD3+ T cells and added to the plasmablasts as effector cells at a 4:1 E:T ratio and cultured overnight with the monospecific anti-CD38 antibody, anti-CD19 antibody, anti-CD20 antibody, or the bispecific antiCD19 / CD38 antibody B55-001.Following incubation, viable plasmablasts were enumerated by flow cytometry. As shown in FIGs. 22 A and 22B, B55-001 effectively depleted the plasmablasts to an extent comparable to the monospecific anti-CD38 antibody Felzartamab and monospecific anti-CD20 antibody Obinutuzumab, whereas the monospecific anti-CD19 antibody Inebilizumab induced a lesser degree of depletion. These results demonstrate that B55-001 effectively depleted plasmablasts at levels comparable to those observed with the monospecific antibodies.

[0216] Furthermore, B55-001 was evaluated for its ability to kill CD19+CD38+plasmablasts / plasma cells via direct apoptosis. Briefly, human B cells wereexpanded / differentiated in ImmunoCult™ B cell medium containing B cell expansion supplement for 10 days. Cells were plated and treated with the monospecific anti-CD38 antibody, anti-CD19 antibody, anti-CD20 antibody, the bispecific antiCD19 / CD38 antibody B55-001, or the Fc-effector function deficient (Fc-dead) variants of B55-001 for 1.5 hours. Following incubation, the cells were labeled with propidium iodide (PI), and the number of viable plasmablasts (PIneg) were enumerated by flow cytometry. As shown in FIGs. 23A and 23B, B55-001 and the Fc-dead variants of B55-001 rapidly induced depletion of plasmablasts, whereas the monospecific antibodies failed to do so. Taken together, these data show that B55-001 can potently kill cells that are representative of pathogenic B cells and can do so more effectively than anti-CD19, anti-CD20, or anti-CD38 mAbs.

[0217] The previous assays demonstrate that the bispecific anti-CD19 / CD38 antibody B55-001 effectively preserve naive B cells while potently killing plasmablasts in vitro. In this study, further experiment are designed to evaluate whether administration of B55-001 preserves naive B cells in a vaccine challenge setting. In heathy adults, plasmablasts are rare under baseline conditions and a vaccine challenge (e.g., Day 0) typically creates a predictable plasmablast burst around day 6 to 8. Briefly, heathy adults are vaccinated against hepatitis A on day 0, and B55-001, anti-CD19, anti-CD20, anti-CD38 mAbs or isotype control antibody is administrated onday 7. Peripheral blood B cells are analyzed on days 7, 14, 21, and 28. Specifically, naive B cells, memory B cells, plasmablasts, and CD19- long-lived plasma cells are enumerated by flow cytometry, and vaccine-specific IgG titers are monitored on indicated days. The detailed experimental design is shown in Table 3.Table 3. Experimental design for evaluation of B55-001 on B cell subsets following hepatitis A vaccine challenge in healthy adultsClinicalObjective Read-out CommentHypothesisVaccine challenge to show Naive B- No change in CD 19+ CD20+ preserved serologic cells frequency IgM+ IgD+ CD27 response / immune defense (Hep AMeasure B-cellMemory B- Decrease in CD 19+ CD20+subset frequency in —cells frequency IgD CD27+peripheral bloodDecrease in CD 19+ CD20Plasmablasts Vaccine challenge frequency CD27hlCD38hlCD 19- No change in Existing VaccineMeasure Ig levelsLLPCs IgG levels IgG TitersExample 9. Pharmacokinetics and safety evaluation of B55-001

[0218] The physicochemical profile of B55-001 antibody, including binding affinity, purity, stability, and isoelectric point was characterized and is summarized in Table 4, suggesting a clear path through development and manufacturing.Table 4. Physicochemical profile of B55-001Parameter B55-001Binding KDCD19 8-13 nMBinding KD CD38 2-3 nMPurity (TO, pH 5, pH 6) 93-96%Hydrophobicity (HIC) retention time 9.9 (low)Isoelectric Focusing (cIEF) isoelectric point 8.9pyroGlutamate Not detectedAsn deamidation / Met oxidation VH & VL < 0.5% site-specific72.8°CThermal stability (Tm) 75.6°C83.2°CPolyspecificity PassstandardGlycosylation in FcG0F / G1F / G2F ratios

[0219] In this example, B55-001’s pharmacokinetics and safety profile were evaluated. 3 mg / kg B55-001 antibody or IgGl was administered intravenously to female CB-17 / SCID mice and serum concentrations were measured over a 21 -day period. The observed and model-predicted serum concentration are shown in FIGs. 15A-15B, demonstrating consistent pharmacokinetic behavior over the study duration. The pharmacokinetic profile of B55-001 was comparable to that of an IgGl control antibody, indicating similar serum stability.

[0220] To further assess the safety profile of B55-001, potential risks such as hemagglutination and hemolysis in human blood were subsequently evaluated. Briefly, whole blood from each donor was washed three times with excess IX PBS by centrifugation for 5 minutes at 1200 rpm at room temperature. The cell pellet was resuspended in IX PBS at a 1:50 final dilution to obtain the “whole blood substrate”. B55-001, anti-CD47 (positive control), or human IgG isotype control were incubated with whole blood substrate for 1 hour at 37 °C, 5% CO2. After incubation, plates were photographed and examined by two independent reviewers for evidence of hemagglutination. Following 1 hour incubation with the indicated antibodies, dose-dependent hemagglutination was observed in whole blood substrate with the anti-CD47 antibody. In contrast, whole blood substrates treated with B55-001 or the human IgGlisotype control showed no detectable hemagglutination (FIG. 16A). These results demonstrated thatB55-001 does not induce hemagglutination in human blood. Next, hemolysis assays were conducted to investigate any potential for red blood cell (RBC) lysis caused by B55-001 treatment. Human whole substrates were incubated with various concentrations of B55-001, IgGl isotype control, or positive control solution and hemolysis was assessed by measuring the absorbance of the supernatant from each well at 540 nm. The Hemolytic Index for each replicate per treatment was then calculated. As shown in FIG. 16B, no hemolysis was observed at any concentration tested after whole substrates were incubated with B55-001. These data demonstrated that B55-001 does not induce hemolysis in human blood.

[0221] Following the hemagglutination and hemolysis assays, the direct binding of B55-001 antibody to human platelets and RBCs was evaluated to further assess its safety profile. Whole blood cells were incubated with fluorescently labeled B55-001, anti-CD41 (positive control), or human IgGl isotype antibodies. Fluorescence-positive platelets and RBCs were readily detected when incubated with fluorescently labeled anti-CD41 (FIGs. 17A-17B). In contrast, no fluorescence-positive platelets or RBCs were detected in whole blood samples treated with fluorescently labeled B55-001 or the IgGl isotype control, indicating a lack of non-specific binding (FIGs. 17A, 17B, and 17D). In a parallel binding assay assessing immune cell subsets, B55-001 showed minimal binding to T cells, and monocytes, with some variations observed in NK cell binding across different blood samples (FIG. 17C and 17E). Notably, nearly all B cells were fluorescence-positive for B55-001 binding, consistent with its expected specificity for the B cell subset (FIG. 17C and 17E). To evaluate whether B 55-001 induces cytokine release in human PBMCs, inflammatory cytokine secretion was evaluated following incubation of human PBMCs with B55-001 or other control antibodies. Human PBMCs were incubated with the indicated antibodies in a soluble format or a wet-coated format for 24 hours at 37°C, 5% CO2. Supernatant was harvested and stored at -80°C. Inflammatory cytokines, such as IL-2, IL-6, IL-10, TNF-a, and IFN-y were measured from the supernatant by MesoScale Discovery (MSD). As shown in FIGs. 18A and 18B, TNF-a was readily detected in the supernatant of PBMCs incubated with anti-CD3 in a dose-dependent manner. In contrast, only minimal levels of TNF-a, if any, were detected in the supernatants of PBMCs incubated with various concentrations of B55-001, or human IgGl control. These results demonstrated that B55-001 does not induce cytokine release in human PBMCs.

[0222] To evaluate the efficacious dose range of B55-001, DoHH2 tumor cells were inoculated in immunodeficient mice. Tumor-bearing mice were then treated with B55-001 at escalating doses over a 14-day period. As shown in FIG. 19A, B55-001 exhibited suppression of tumor growth in a dose-dependent manner, with doses as low as 0.3 mg / kg effectively slowingtumor progression. The efficacy of B55-001 was further assessed in a Ramos tumor model. Consistently, B55-001 showed anti-tumor efficacy at doses as low as 0.3 mg / kg (FIG. 19B). These results suggest that B55 is active at doses ranging from 0.3 mg / kg to 1 mg / kg.

[0223] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0224] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.SEQUENCESSEQ ID Sequence Origin NO:1 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFS Anti-CD38 he WVRQAPGQGLEWMGRVIPQLGIANSAQKFQGRV (variable region) TITADKSTSTAYMELSSLRSEDTAVYYCARDDIAA LGPFDYWGQGTLVTVSS2 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTIN Anti-CD19 he WVRQAPGQGLEWMGGIIPIFGIPNYAQKFQGRVTI (variable region) TADESTNTAYMELSSLRSEDTAVYYCARASGGSA D YS YGMD VWGQGTL VT VS S3 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAW Anti-CD38 / Anti-CD19YQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDF 1c common TLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK (variable region) 4 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFS Anti-CD38 bi specific WVRQAPGQGLEWMGRVIPQLGIANSAQKFQGRV arm Knob TITADKSTSTAYMELSSLRSEDTAVYYCARDDIAA LGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FP AVLQ S SGL YSL S S VVTVP S S SLGTQT YICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPP SRDELTKNQ VSLWCLVKGF YP SDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG5 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTIN Anti -CD 19 bi specific WVRQAPGQGLEWMGGIIPIFGIPNYAQKFQGRVTI arm Hole TADESTNTAYMELSSLRSEDTAVYYCARASGGSA DYSYGMD VWGQGTL VTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PG6 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAW Anti-CD38 / anti-CD 19YQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDF light chain TLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECAnti- SYAFS CD38 VH CDR1 PQLGIA Anti-CD38 VH CDR2Anti- DIAALGPFD CD38 VH CDR3 SYTIN Anti- CD19 VH CDR1 Anti- PIFG CD19 VH CDR2 Anti- SGGSADYSYGMD CD19 VH CDR3 Anti- SQGISSW CD38 VL CDR1 Anti- AAS CD38 VL CDR2 Anti- YNSYPR CD38 VL CDR3 PFLGIA Anti-CD38 VH CDR2 PHLGIA Anti-CD38 VH CDR2 PFLGTA Anti-CD38 VH CDR2 AAEPKS SDKTHTCPPCP Linker GGGG Linker GGGGDKTHTCPPCP Linker DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAW Anti-CD19_VL YQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQYKRYPYTFGQGTKLEIKAnti- QGISSWLA CD19 VL CDR1 Anti- AAS CD19 VL CDR2 Anti- QQYKRYPYT CD19 VL CDR3 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFS Anti-CD38 bi specific WVRQAPGQGLEWMGRVIPQLGIANSAQKFQGRV arm Knob (YTE) TITADKSTSTAYMELSSLRSEDTAVYYCARDDIAA LGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FP AVLQ S SGL YSL S S VVTVP S S SLGTQT YICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIA VEWESNGQPENNYKTTPP VLD SDGSFFL YSKLT VD KSRWQQGNVF SC S VMHEALHNHYTQKSLSLSPG EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTIN Anti -CD 19 bi specific WVRQAPGQGLEWMGGIIPIFGIPNYAQKFQGRVTI arm Hole (YTE) TADESTNTAYMELSSLRSEDTAVYYCARASGGSA DYSYGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNV NHI<PSNTI<VDI<I<VEPI<SCDI<THTCPPCPAPELLGG PSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PG DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAW Anti-CD38 light chain YQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC

Claims

CLAIMS1. A method of treating an autoimmune disorder or an inflammatory disorder in an individual in need thereof, the method comprising:administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby treating the autoimmune disorder or an inflammatory disorder.

2. The method of claim 1, wherein the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-nuclear antibodies (ANAs), anti-double stranded deoxyribonucleic acid (dsDNA) antibodies, anti-Ro / La antibodies, anti-Sm antibodies, anti-phospholipid antibodies, anti-ribonucleoprotein (RNP) antibodies, anti-glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) antibodies, antihistones antibodies, anti-synthetase (autoantibodies to aminoacyl-tRNA synthetases) antibodies, anti-centromere antibodies, anti-Scl-70 (anti-topoisomerase I) antibodies, anti-RNA polymerase III antibodies, anti-aminoacyl-tRNA synthetase (including anti-Jo- 1) antibodies, anti -Mi-2 antibodies, anti-signal recognition particle (SRP), anti- mitochondrial (AMAs) antibodies, anti-smooth muscle (ASMAs) antibodies, antineutrophil cytoplasmic antibodies, anti-thyroid antibodies antibodies, antitransglutaminase antibodies, or a combination thereof.

3. The method of claim 1, wherein the autoimmune disorder is characterized by the presence of autoantibodies in the individual comprising anti-desmoglein-1 (Dsgl) antibodies, anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSK) antibodies, anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, anti-BP180 antibodies, anti-BP230 antibodies, anti-signal recognition particle (SRP) antibodies, anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, or a combination thereof.

4. The method of claim 1, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of B cells in the individual that express CD 19 and CD38.

5. The method of claim 4, wherein the B cells are CD19+CD38lowor CD19+CD38hlgh.

6. The method of claim 4, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of CD19+CD38lowB cells, CD19+CD38hlgh / +B cells, CD19lowCD38hlghB cells, or any combination thereof in the individual.

7. The method of claim 1, wherein treating the autoimmune disorder or the inflammatory disorder comprises reducing (e.g., depleting) the number of memory B cells (CD19+CD20+ IgD CD27+) or plasmablasts (CD19+ CD20- CD27highCD38high).

8. The method of claim 1, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of long-lived plasma cells (CD19‘ CD38highB cells).

9. The method of claim 1, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce the amount of naive B cells (CD19+CD20+IgM+IgD+CD27 -).

10. The method of claim 1, wherein treating the autoimmune disorder or the inflammatory disorder does not substantially reduce IgG levels in the individual.

11. The method of claim 1, wherein the treating does not induce hypogammaglobulinemia in the individual.

12. The method of claim 1, wherein the autoimmune disorder or the inflammatory disorder comprises systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Graves’s disease (GD), anti -neutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV), primary Sjogren's syndrome (pSS), myositis, systemic sclerosis (SSc), generalized myasthenia gravis (gMG), or Type 1 diabetes (T1D).

13. The method of claim 1, wherein the autoimmune disorder or the inflammatory disorder comprises vasculitis, pemphigus vulgaris, primary biliary cholangitis, celiac disease, autoimmune hepatitis, scleroderma, anti-phospholipid syndrome, Hashimoto Thyroiditis, psoriasis, pernicious anemia, Addison’s disease, inflammatory bowel disease, Crohn’s disease, vitiligo, CREST syndrome, Guillain-Barre syndrome, alopecia areata, IgA nephropathy, lupus nephritis, primary membranous nephropathy, antibody meditated graft rejection, chronic inflammatory demyelinating polyradiculoneuropathy, autoimmune encephalitis, neuromyelitis optica, immune thrombocytopenia, bullous pemphigoid, autoimmune hemolytic anemia, atopic dermatitis, allergic asthma, chronic urticaria, food allergy, IgG4 related disease, or eosinophilic esophagitis, and combinations thereof.

14. The method of claim 1, wherein the autoimmune disorder comprises pemphigus, myasthenia gravis, or myositis.

15. The method of claim 14, wherein the autoimmune disorder comprises pemphigus.

16. The method of claim 15 wherein the pemphigus is pemphigus vulgaris.

17. The method of claim 15 wherein the pemphigus is pemphigus foliaceus.

18. The method of claim 14, wherein the autoimmune disorder comprises myasthenia gravis.

19. The method of claim 18, wherein the autoimmune disorder comprises myositis.

20. The method of claim 19, wherein the myositis is immune-mediated necrotizing myopathy.

21. The method of claim 19, wherein the myositis is immune-mediated necrotizing myopathy.

22. The method of claim 19, wherein the myositis is dermatomyositis.

23. The method of claim 19, wherein the myositis is anti -synthetase syndrome.

24. The method of claim 1, wherein the autoimmune or inflammatory disorder comprises Lambert-Eaton syndrome, Goodpasture’s syndrome, Sjogren's syndrome, eosinophilic granulomatosis with polyangiitis (EGPA), ulcerative colitis, giant cell arteritis, behget' s disease, Takayasu's arteritis, autoimmune polyendocrine syndrome, acute disseminated encephalomyelitis, anti-NMDA receptor encephalitis, chronic inflammatory demyelinating polyneuropathy, autoimmune pancreatitis, autoimmune oophoritis, autoimmune orchitis, stiff person syndrome, MOG antibody-associated disease (MOGAD), autoimmune autonomic ganglionopathy, autoimmune nodopathies, minimal change disease, focal segmental glomerulosclerosis, anti-LRP2 (anti-brush border) nephropathy, cryoglobulinemic vasculitis (type II / III), IgA vasculitis (Henoch-Schbnlein Purpura), autoantibody C3 glomerulopathy, immune thrombotic thrombocytopenic purpura (iTTP; anti-ADAMTS13), cold agglutinin disease (CAD), Evans syndrome, autoimmune pure red cell aplasia, chronic autoimmune neutropenia, hidradenitis suppurativa, dermatitismucous membrane pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, paraneoplastic pemphigus, pemphigoid gestationis, non- infectious uveitis, or thyroid eye disease, and combinations thereof..

25. A method of reducing (e.g., depleting) the number of B cells in an individual that express CD 19 and CD38, the method comprising:administering to the individual a multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, thereby reducing the number of B cells in the individual that express CD 19 and CD38,wherein the B cells that express CD19 and CD38 comprise CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells.

26. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of CD19' CD38highB cells.

27. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment reduces (e.g., depletes) the number of memory B cells (CD 19+ CD20+ IgD CD27+) or plasmablasts (CD19+ CD20- CD27hiCD38hi).

28. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of long-lived plasma cells (CD19 CD38hlghB cells).

29. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce the amount of Naive B cells. (CD 19+ CD20+ IgM+IgD+CD27 ).

30. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment does not substantially reduce IgG levels in the individual.

31. The method of claim 25, wherein administering the multispecific antibody or multispecific antibody fragment does not result in hypogammaglobulinemia.

32. The method of claim 25, wherein the individual has a disorder characterized by immunoglobulin autoimmunity.

33. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38, in an in vitro assay:(i) increases antibody-dependent cellular phagocytosis (ADCP) of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38hlgh / +B cells, compared to a human IgGl control or null control; (ii) does not increase ADCP of CD19'CD38hlghcells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or results in reduced ADCP of CD19'CD38hlghcells when compared to daratumumab;(iii) increases antibody-dependent cell cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or direct apoptosis of CD19+CD38lowB cells, CD19+CD38high / +B cells, or both CD19+CD38lowB cells and CD19+CD38high / +B cells, compared to a human IgGl control or null control; and / or(iv) does not increase ADCC, CDC, or direct apoptosis of CD19'CD38hlghcells more than 2-fold or 1.5-fold when compared to a human IgGl control or null control, or results in reduced ADCC, CDC, or direct apoptosis of CD19'CD38hlghcells when compared to daratumumab.

34. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment is a bispecific antibody or bispecific antibody fragment that binds CD 19 and CD38.

35. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment that binds CD 19 and CD38 comprises:an anti-CD38 heavy chain variable domain and an anti-CD38 light chain variable domain; andan anti-CD19 heavy chain variable domain and an anti-CD19 light chain variable domain.

36. The method of claim 35, wherein:the anti-CD38 heavy chain variable domain comprises:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9,the anti-CD38 light chain variable domain comprises:a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, ora light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25,the anti-CD19 heavy chain variable comprises:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; andthe anti-CD19 light chain variable domain comprises:a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, ora light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

37. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment that binds CD19 and CD38 is a common light chain bispecific antibody.

38. The method of claim 37, wherein the common light chain bispecific antibody comprises:an anti-CD38 heavy chain variable domain comprising:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 7, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 8, 16. 17, or 18, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 9,an anti-CD19 heavy chain variable comprising:a heavy chain complementarity determining domain 1 (CDRH1) comprising an amino acid sequence set forth in SEQ ID NO: 10, a heavy chain complementarity determining domain 2 (CDRH2) comprising an amino acid sequence set forth in SEQ ID NO: 11, a heavy chain complementarity determining domain 3 (CDRH3) comprising an amino acid sequence set forth in SEQ ID NO: 12; and a common light chain variable domain comprising:a light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 13 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 15, ora light chain complementarity determining domain 1 (CDRL1) comprising an amino acid sequence set forth in SEQ ID NO: 23 a light chain complementarity determining domain 2 (CDRL2) comprising an amino acid sequence of AAS, a light chain complementarity determining domain 3 (CDRL3) comprising an amino acid sequence set forth in SEQ ID NO: 25.

39. The method of claim 38, wherein the anti-CD38 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 1, the anti-CD19 heavy chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 2, and common light chain variable domain comprises an amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:

3.

40. The method of claim 38, wherein the common light chain bispecific antibody comprises an anti-CD38 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 4 or 26, an anti-CD19 heavy chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 5 or 27, and a common light chain amino acid sequence having at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% to SEQ ID NO: 6.

41. The method of claim 38, wherein:the anti-CD38 heavy chain variable domain and the anti-CD19 heavy chain variable domain each comprise a negatively-charged amino acid at heavy chain variable domain position 1 per Kabat numbering;the anti-CD38 heavy chain constant domain and the anti-CD19 heavy chain constant domain each lack a C-terminal lysine residue (K447 per EU numbering); andthe common light chain bispecific antibody comprises an experimental isoelectric point (pl) of less than 9.

42. The method of claim 41, wherein the common light chain bispecific antibody exhibits a Hydrophobicity (HIC) retention time of less than about 10 minutes.

43. The method of claim 41, wherein the terminal lysine residue of K447 per EU numbering is absent.

44. The method of claim 34, wherein the anti -CD 19 heavy chain variable domain comprises a serine at position 84 and / or a leucine at position 108 according to Kabat numbering.

45. The method of claim 38, wherein the common light chain variable region comprises a histidine at position 32 according to Kabat numbering.

46. The method of claim 41, wherein the negatively-charged amino acid is glutamic acid.

47. The method of claim 41, wherein the pl is between 8.7 and 9.

48. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment comprises an afucosylated Fc region.

49. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wildtype IgG that decreases antibody dependent cell cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), or antibody dependent cell phagocytosis (ADCP).

50. The method of claim 49, wherein one or more modifications relative to wild-type IgG comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S; P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof.

51. The method of claim 49, wherein one or more modifications relative to wild-type IgG comprise L234A, L235E, G237A, A330S, P331S (AEASS).

52. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wildtype IgG that increase affinity to FcRn.

53. The method of claim 1, wherein the multispecific antibody or multispecific antibody fragment comprises an Fc region comprising one or more modifications relative to wildtype IgG that increases the plasma half-life of the multispecific antibody or multispecific antibody fragment.

54. The method of claim 52, wherein the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

55. A common light chain multispecific antibody that binds CD19 and CD38, wherein the common light chain multispecific antibody comprises:(i) an anti-CD38 heavy chain amino acid sequence comprising SEQ ID NO: 26, (ii) an anti-CD19 heavy chain amino acid sequence comprising SEQ ID NO: 27, (iii) a first common light chain amino acid sequence comprising SEQ ID NO 28, and (iv) a second common light chain amino acid sequence comprising SEQ ID NO 28, wherein the anti-CD38 heavy chain amino acid sequence, the anti-CD19 heavy chain amino acid sequence, or both comprises an Fc region comprising one or moremodifications relative to wild-type IgG that increases the plasma half-life of the multispecific antibody or multispecific antibody fragment.

56. The common light chain multispecific antibody that binds CD19 and CD38 of claim 55, wherein the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2.

57. The common light chain multispecific antibody that binds CD19 and CD38 of claim 55, wherein the one or more modifications relative to wild-type IgG comprise one or more modifications listed in Table 2a.

58. The common light chain multispecific antibody that binds CD19 and CD38 of claim 55, wherein the one or more modifications relative to wild-type IgG comprise M252Y / S254T / T256E (YTE) per EU numbering.

59. The common light chain multispecific antibody that binds CD19 and CD38 of claim 55, comprising one or more modifications relative to wild-type IgG wherein the one or more modifications comprise any one or more of L234A; L235A; L235E; G236R; G237A; P238S; H268A; K322A; P329A; P329G; A330S; P331S; N298A; L234, L235 (LALA); L234A, L235E (LALE); L234, L235, G237A (LALAGA); L234, L235, P329A (LALAPA); L234, L235, P329A (LALAPG); L234A, L235E, G237A, A330S, P331S (AEASS) or any combination thereof.

60. The common light chain multispecific antibody that binds CD19 and CD38 of claim 55, comprising one or more modifications relative to wild-type IgG, wherein the one or more modifications comprise L234A, L235E, G237A, A330S, P331S (AEASS).

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