Anti-b lymphocyte stimulator antibodies

Abstract

Antibodies that specifically bind to BLyS are described, as well as methods of making and using such antibodies.

Description

Attorney Docket No.: 2017284-0018 ANTI-B LYMPHOCYTE STIMULATOR ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Prov. Appln. No.63 / 631,900 filed April 9, 2024, the entire contents of which are hereby incorporated by reference in their entirety. BACKGROUND

[0002] Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes. SLE is a heterogeneous disease, and the pattern of organ involvement and response to treatment can differ among patients. There remains a need for effective therapies against autoimmune diseases, such as SLE. SUMMARY OF INVENTION

[0003] In one aspect, the disclosure features an antibody that binds B lymphocyte stimulator (BLyS), or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence selected from any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and / or (b) a light chain variable domain (VL) comprising an amino acid sequence selected from any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, an antibody that binds B lymphocyte stimulator (BLyS), or an antigen-binding fragment thereof, comprises: (a) a heavy chain variable domain (VH) comprising an amino acid sequence selected from any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence selected from any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60.

[0004] In another aspect, the disclosure features an antibody that binds BLyS, or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, Page 1 of 82 12621951v1Attorney Docket No.: 2017284-0018 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and / or (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58. In some embodiments, an antibody that binds BLyS, or an antigen-binding fragment thereof, comprises: (a) a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58.

[0005] In another aspect, the disclosure features an antibody that binds BLyS, or an antigen-binding portion thereof, comprising: a heavy chain variable domain (VH) comprising one, two, or three complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1, CDR-H2, and CDR-H3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100, 101, and 102; SEQ ID NOs: 112, 113, and 114; SEQ ID NOs: 118, 119, and 120; SEQ ID NOs: 124, 125, and 126; SEQ ID NOs: 130, 131, and 132; SEQ ID NOs: 136, 137, and 138; SEQ ID NOs: 142, 143, and 144; SEQ ID NOs: 148, 149, and 150; SEQ ID NOs: 154, 155, and 156; SEQ ID NOs: 160, 161, and 162; SEQ ID NOs: 166, 167, and 168; SEQ ID NOs: 172, 173, and 174; SEQ ID NOs: 178, 179, and 180; SEQ ID NOs: 184, 185, and 186; SEQ ID NOs: 190, 191, and 192; SEQ ID NOs: 196, 197, and 198; SEQ ID NOs: 202, 203, and 204; SEQ ID NOs: 208, 209, and 210; SEQ ID NOs: 214, 215, and 216; SEQ ID NOs: 220, 221, and 222; SEQ ID NOs: 226, 227, and 228; SEQ ID NOs: 232, 233, and 234; SEQ ID NOs: 238, 239, and 240; SEQ ID NOs: 244, 245, and 246; SEQ ID NOs: 250, 251, and 252; SEQ ID NOs: 256, 257, and 258; SEQ ID NOs: 262, 263, and 264; SEQ ID NOs: 268, 269, and 270; or SEQ ID NOs: 274, 275, and 276. In some embodiments, an antibody that binds BLyS, or an antigen- Page 2 of 82 12621951v1Attorney Docket No.: 2017284-0018 binding portion thereof, comprises: a heavy chain variable domain (VH) comprising the CDR set CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1, CDR-H2, and CDR-H3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100, 101, and 102; SEQ ID NOs: 112, 113, and 114; SEQ ID NOs: 118, 119, and 120; SEQ ID NOs: 124, 125, and 126; SEQ ID NOs: 130, 131, and 132; SEQ ID NOs: 136, 137, and 138; SEQ ID NOs: 142, 143, and 144; SEQ ID NOs: 148, 149, and 150; SEQ ID NOs: 154, 155, and 156; SEQ ID NOs: 160, 161, and 162; SEQ ID NOs: 166, 167, and 168; SEQ ID NOs: 172, 173, and 174; SEQ ID NOs: 178, 179, and 180; SEQ ID NOs: 184, 185, and 186; SEQ ID NOs: 190, 191, and 192; SEQ ID NOs: 196, 197, and 198; SEQ ID NOs: 202, 203, and 204; SEQ ID NOs: 208, 209, and 210; SEQ ID NOs: 214, 215, and 216; SEQ ID NOs: 220, 221, and 222; SEQ ID NOs: 226, 227, and 228; SEQ ID NOs: 232, 233, and 234; SEQ ID NOs: 238, 239, and 240; SEQ ID NOs: 244, 245, and 246; SEQ ID NOs: 250, 251, and 252; SEQ ID NOs: 256, 257, and 258; SEQ ID NOs: 262, 263, and 264; SEQ ID NOs: 268, 269, and 270; or SEQ ID NOs: 274, 275, and 276.

[0006] In another aspect, the disclosure features an antibody that binds BLyS, or an antigen-binding portion thereof, comprising a light chain variable domain (VL) comprising one, two, or three complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 103, 104, and 105; SEQ ID NOs: 115, 116, and 117; SEQ ID NOs: 121, 122, and 123; SEQ ID NOs: 127, 128, and 129; SEQ ID NOs: 133, 134, and 135; SEQ ID NOs: 139, 140, and 141; SEQ ID NOs: 145, 146, and 147; SEQ ID NOs: 151, 152, and 153; SEQ ID NOs: 157, 158, and 159; SEQ ID NOs: 163, 164, and 165; SEQ ID NOs: 169, 170, and 171; SEQ ID NOs: 175, 176, and 177; SEQ ID NOs: 181, 182, and 183; SEQ ID NOs: 187, 188, and 189; SEQ ID NOs: 193, 194, and 195; SEQ ID NOs: 199, 200, and 201; SEQ ID NOs: 205, 206, and 207; SEQ ID NOs: 211, 212, and 213; SEQ ID NOs: 217, 218, and 219; SEQ ID NOs: 223, 224, and 225; SEQ ID NOs: 229, 230, and 231; SEQ ID NOs: 235, 236, and 237; SEQ ID NOs: 241, 242, and 243; SEQ ID NOs: 247, 248, and 249; SEQ ID NOs: 253, 254, and 255; SEQ ID NOs: 259, 260, and 261; SEQ ID NOs: 265, 266, and 267; SEQ ID NOs: 271, 272, and 273; or SEQ ID NOs: 277, 278, and 279. In some embodiments, an antibody that binds BLyS, or an antigen-binding portion thereof, comprises a light chain variable domain (VL) comprising the CDR set CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid Page 3 of 82 12621951v1Attorney Docket No.: 2017284-0018 sequences, respectively, of: SEQ ID NOs: 103, 104, and 105; SEQ ID NOs: 115, 116, and 117; SEQ ID NOs: 121, 122, and 123; SEQ ID NOs: 127, 128, and 129; SEQ ID NOs: 133, 134, and 135; SEQ ID NOs: 139, 140, and 141; SEQ ID NOs: 145, 146, and 147; SEQ ID NOs: 151, 152, and 153; SEQ ID NOs: 157, 158, and 159; SEQ ID NOs: 163, 164, and 165; SEQ ID NOs: 169, 170, and 171; SEQ ID NOs: 175, 176, and 177; SEQ ID NOs: 181, 182, and 183; SEQ ID NOs: 187, 188, and 189; SEQ ID NOs: 193, 194, and 195; SEQ ID NOs: 199, 200, and 201; SEQ ID NOs: 205, 206, and 207; SEQ ID NOs: 211, 212, and 213; SEQ ID NOs: 217, 218, and 219; SEQ ID NOs: 223, 224, and 225; SEQ ID NOs: 229, 230, and 231; SEQ ID NOs: 235, 236, and 237; SEQ ID NOs: 241, 242, and 243; SEQ ID NOs: 247, 248, and 249; SEQ ID NOs: 253, 254, and 255; SEQ ID NOs: 259, 260, and 261; SEQ ID NOs: 265, 266, and 267; SEQ ID NOs: 271, 272, and 273; or SEQ ID NOs: 277, 278, and 279.

[0007] In another aspect, the disclosure features an antibody that binds BLyS, or an antigen-binding portion thereof, comprising (a) a heavy chain variable domain (VH) comprising three complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and (b) a light chain variable domain (VL) comprising three complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100-105; SEQ ID NOs: 112-117; SEQ ID NOs: 118-123; SEQ ID NOs: 124-129; SEQ ID NOs: 130-135; SEQ ID NOs: 136-141; SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 154-159; SEQ ID NOs: 160-165; SEQ ID NOs: 166-171; SEQ ID NOs: 172-177; SEQ ID NOs: 178-183; SEQ ID NOs: 184-189; SEQ ID NOs: 190-195; SEQ ID NOs: 196-201; SEQ ID NOs: 202-207; SEQ ID NOs: 208-213; SEQ ID NOs: 214-219; SEQ ID NOs: 220-225; SEQ ID NOs: 226-231; SEQ ID NOs: 232-237; SEQ ID NOs: 238-243; SEQ ID NOs: 244-249; SEQ ID NOs: 250-255; SEQ ID NOs: 256-261; SEQ ID NOs: 262-267; SEQ ID NOs: 268-273; or SEQ ID NOs: 274-279.

[0008] In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 136-141; SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 160-165; or SEQ ID NOs: 202-207.

[0009] In another aspect, the disclosure features an antibody that competes for binding to BLyS with any one of the antibodies described herein. Page 4 of 82 12621951v1Attorney Docket No.: 2017284-0018

[0010] In some embodiments, the antibody has an in vitro binding (KD) to BLyS of about 0.001 nM to about 1 nM.

[0011] In some embodiments, the antibody is a human antibody.

[0012] In some embodiments, the antibody is a humanized antibody.

[0013] In some embodiments, the antibody is a monoclonal antibody.

[0014] In another aspect, the disclosure features a nucleic acid sequence encoding the antibody or antigen-binding fragment thereof of any one of the antibody or antigen-binding fragments described herein.

[0015] In another aspect, the disclosure features a vector comprising the nucleic acid sequence as described herein.

[0016] In another aspect, the disclosure features a host cell comprising the nucleic acid sequence as described herein or the vector as described herein.

[0017] In another aspect, the disclosure features, a method of treating an autoimmune disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody, or antigen-binding fragment thereof, of any one of the antibodies or antigen- binding fragments described herein.

[0018] In some embodiments, the autoimmune disorder is systemic lupus erythematosus, lupus nephritis, Sjogren’s syndrome, IgA nephropathy, pemphigus vulgaris, neuromyelitis optica spectrum disorders, multiple myeloma, rheumatoid arthritis, or multiple sclerosis. DEFINITIONS

[0019] A or An: The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0020] Affinity: As used herein, the term “affinity” refers to the characteristics of a binding interaction between an antigen binding moiety (e.g., an antibody described herein) and an antigen target (e.g., BLyS) and that indicates the strength of the binding interaction. In some Page 5 of 82 12621951v1Attorney Docket No.: 2017284-0018 embodiments, the measure of affinity is expressed as a dissociation constant (KD). In some embodiments, an antigen binding moiety has a high affinity for an antigen target (e.g., a KD of less than about 10-7M, less than about 10-8M, or less than about 10-9M).

[0021] Amino acid: As used herein, term “amino acid,” in its broadest sense, refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N–C(H)(R)–COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an l-amino acid. “Standard amino acid” refers to any of the twenty standard l-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. As used herein, “synthetic amino acid” encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including carboxy- and / or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can change the peptide’s circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond. Amino acids may comprise one or more posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term “amino acid” is used interchangeably with “amino acid residue,” and may refer to a free amino acid and / or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide.

[0022] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprised of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each heavy chain Page 6 of 82 12621951v1Attorney Docket No.: 2017284-0018 is comprised of at least four domains (each about 110 amino acids long)– an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y’s stem). A short region, known as the “switch”, connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain comprises two domains – an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers are composed of two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to one another and the tetramer is formed. Naturally-produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as “complement determining regions” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally-occurring antibodies binds to elements of the complement system, and also to receptors on effector cells, including for example effector cells that mediate cytotoxicity. As is known in the art, affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure include glycosylated Fc domains, including Fc domains with modified or engineered such glycosylation. For purposes of the present disclosure, in certain embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen), or Page 7 of 82 12621951v1Attorney Docket No.: 2017284-0018 produced by recombinant engineering, chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are fully human, or are humanized, primatized, chimeric, etc, as is known in the art. Moreover, the term “antibody” as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antibody utilized in accordance with the present disclosure is in a format selected from, but not limited to, intact IgG, IgE and IgM, bi- or multi- specific antibodies (e.g., Zybodies®, etc), single chain Fvs, polypeptide-Fc fusions, Fabs, cameloid antibodies, masked antibodies (e.g., Probodies®), Small Modular ImmunoPharmaceuticals (“SMIPsTM”), single chain or Tandem diabodies (TandAb®), VHHs, Anticalins®, Nanobodies®, minibodies, BiTE®s, ankyrin repeat proteins or DARPINs®, Avimers®, a DART, a TCR-like antibody, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, a TrimerX®, MicroProteins, Fynomers®, Centyrins®, and a KALBITOR®. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., poly-ethylene glycol, etc.)).

[0023] Antibody Fragment: As used herein, an “antibody fragment” includes a portion of an intact antibody, such as, for example, the antigen-binding or variable region of an antibody. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments; triabodies; tetrabodies; linear antibodies; single-chain antibody molecules; and multi-specific antibodies formed from antibody fragments. For example, antibody fragments include isolated fragments, “Fv” fragments (consisting of the variable regions of the heavy and light chains), recombinant single chain polypeptide molecules in which light and heavy chain variable regions are connected by a peptide linker (“scFv proteins”), recombinant single domain antibodies consisting of a variable domain of an antibody heavy chain (e.g., VHH), and minimal recognition units consisting of the amino acid residues that mimic a hypervariable region (e.g., a hypervariable Page 8 of 82 12621951v1Attorney Docket No.: 2017284-0018 region of a heavy chain variable domain (VH), a hypervariable region of a light chain variable domain (VL), one or more CDR domains within the VH, and / or one or more CDR domains within the VL). In many embodiments, an antibody fragment contains sufficient sequence of the parent antibody of which it is a fragment that it binds to the same antigen as does the parent antibody; in some embodiments, a fragment binds to the antigen with a comparable affinity to that of the parent antibody and / or competes with the parent antibody for binding to the antigen. Examples of antigen binding fragments of an antibody include, but are not limited to, Fab fragment, Fab’ fragment, F(ab’)2 fragment, scFv fragment, Fv fragment, dsFv diabody, dAb fragment, Fd’ fragment, Fd fragment, heavy chain variable region, and an isolated complementarity determining region (CDR) region. An antigen binding fragment of an antibody may be produced by any means. For example, an antigen binding fragment of an antibody may be enzymatically or chemically produced by fragmentation of an intact antibody and / or it may be recombinantly produced from a gene encoding the partial antibody sequence. Alternatively or additionally, antigen binding fragment of an antibody may be wholly or partially synthetically produced. An antigen binding fragment of an antibody may optionally comprise a single chain antibody fragment. Alternatively or additionally, an antigen binding fragment of an antibody may comprise multiple chains which are linked together, for example, by disulfide linkages. An antigen binding fragment of an antibody may optionally comprise a multimolecular complex. A functional antibody fragment typically comprises at least about 50 amino acids and more typically comprises at least about 200 amino acids.

[0024] Antigen target: As used herein, an “antigen target” is any molecule specifically bound by an antibody described herein. In some embodiments, an antigen target is BLyS.

[0025] Approximately or about: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Page 9 of 82 12621951v1Attorney Docket No.: 2017284-0018

[0026] Binding: It will be understood that the term “binding”, as used herein, typically refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties; indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts – including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0027] Complementarity Determining Region or CDR: The term “CDR”, as used herein, means a complementarity determining region within an immunoglobulin variable region sequence. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the heavy and light chain variable regions. The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems, including Kabat, Chothia, IMGT, AbM, and Contact. The system described by Kabat (Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K. S. & Foeller, C. (1991). Sequences of Proteins of Immunological Interest, 5th edit. National Institutes of Health, Bethesda, MD) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk (1987) J. Mol. Biol.196:901-917; Chothia et al. (1989) Nature 342:877-883) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995) FASEB J.9:133-139 and MacCallum (1996) J. Mol. Biol.262(5):732-45. Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of Page 10 of 82 12621951v1Attorney Docket No.: 2017284-0018 prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. Software programs (e.g., abYsis) are available and known to those of skill in the art for analysis of antibody sequence and determination of CDRs. Unless otherwise noted, CDRs of the present disclosure are described according to Abhinandan et al., Molecular Immunology 45:3832-3839 (2008).

[0028] Constant region: As used herein, the term “constant region” refers to a polypeptide that corresponds to, or is derived from, one or more constant region immunoglobulin domains of an antibody. A constant region can include any or all of the following immunoglobulin domains: a CH1 domain, a hinge region, a CH2 domain, a CH3 domain (derived from an IgA, IgD, IgG, IgE, or IgM), and a CH4 domain (derived from an IgE or IgM).

[0029] Fc region: As used herein, the term “Fc region” refers to a dimer of two “Fc polypeptides”, each “Fc polypeptide” comprising the constant region of an antibody excluding the first constant region immunoglobulin domain. In some embodiments, an “Fc region” includes two Fc polypeptides linked by one or more disulfide bonds, chemical linkers, or peptide linkers. “Fc polypeptide” refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and may also include part or all of the flexible hinge N-terminal to these domains. For IgG, “Fc polypeptide” comprises immunoglobulin domains Cgamma2 (Cγ2) and Cgamma3 (Cγ3) and the lower part of the hinge between Cgamma1 (Cγ1) and Cγ2. Although the boundaries of the Fc polypeptide may vary, the human IgG heavy chain Fc polypeptide is usually defined to comprise residues starting at T223 or C226 or P230, to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Services, Springfield, VA). For IgA, Fc polypeptide comprises immunoglobulin domains Calpha2 (Cα2) and Calpha3 (Cα3) and the lower part of the hinge between Calpha1 (Cα1) and Cα2. An Fc region can be synthetic, recombinant, or generated from natural sources such as IVIG.

[0030] Identity: As used herein, the term “identity” refers to the overall relatedness between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptides. In some embodiments, nucleic acids or polypeptides are considered to be “substantially identical” to one another if their sequences are at least 25%, 30%, 35%, 40%, Page 11 of 82 12621951v1Attorney Docket No.: 2017284-0018 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or substantially 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller, 1989, which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0031] Immunoglobulin variable domain: The term “immunoglobulin variable domain” or “variable domain”, as used herein, means an immunoglobulin domain that is or includes four “framework regions” (referred to in the art and herein as “framework region 1” or “FR1”; as “framework region 2” or “FR2”; as “framework region 3” or “FR3”; and as “framework region 4” or “FR4”, respectively); which framework regions are interrupted by three “complementarity determining regions” or “CDRs” (referred to in the art and herein as “complementarity determining region 1” or “CDR1”; as “complementarity determining region 2” or “CDR2”; and as “complementarity determining region 3” or “CDR3”, respectively). In some embodiments, Page 12 of 82 12621951v1Attorney Docket No.: 2017284-0018 the general structure or sequence of an immunoglobulin variable domain can be indicated as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0032] Ka: As used herein, “Ka” refers to an association rate of a particular antigen binding moiety and an antigen target to form an antigen binding moiety / antigen target complex.

[0033] Kd: As used herein, “Kd” refers to a dissociation rate of a particular antigen binding moiety / antigen target complex.

[0034] KD: As used herein, “KD” refers to a dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). KD values can be determined using methods well established in the art, e.g., by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.

[0035] Polypeptide: As used herein, a “polypeptide”, generally speaking, is a string of at least two amino acids attached to one another by a peptide bond. In some embodiments, a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides sometimes include “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain, optionally.

[0036] Protein: As used herein, the term “protein”, refers to a polypeptide (i.e., a string of at least two amino acids linked to one another by peptide bonds). Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete polypeptide chain as produced by a cell (with or without a signal sequence), or can be a portion thereof. Those of ordinary skill will appreciate that a protein can sometimes include more than one polypeptide chain, for example linked by one or more disulfide bonds or associated by other means. Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc. In some embodiments, proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. Page 13 of 82 12621951v1Attorney Docket No.: 2017284-0018

[0037] Reference: As used herein, “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0038] Selective binding: As used herein, “selective binding”, “selectively binds” “specific binding”, or “specifically binds” refers, with respect to an antigen binding moiety and an antigen target, preferential association of an antigen binding moiety to an antigen target and not to an entity that is not the antigen target. A certain degree of non-specific binding may occur between an antigen binding moiety and a non-target. In some embodiments, an antigen binding moiety selectively binds an antigen target if binding between the antigen binding moiety and the antigen target is greater than 2-fold, greater than 5-fold, greater than 10-fold, or greater than 100- fold as compared with binding of the antigen binding moiety and a non-target. In some embodiments, an antigen binding moiety selectively binds an antigen target if the binding affinity is less than about 10-5M, less than about 10-6M, less than about 10-7M, less than about 10-8M, or less than about 10-9M.

[0039] Subject: By “subject” is meant a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some Page 14 of 82 12621951v1Attorney Docket No.: 2017284-0018 embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0040] Suffering from: A subject who is “suffering from” a disease, disorder, or condition (e.g., an autoimmune disorder) has been diagnosed with and / or exhibits one or more symptoms of the disease, disorder, or condition.

[0041] Symptoms are reduced: According to the present invention, “symptoms are reduced” when one or more symptoms of a particular disease, disorder or condition is reduced in magnitude (e.g., intensity, severity, etc.) or frequency. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom. It is not intended that the present invention be limited only to cases where the symptoms are eliminated. The present invention specifically contemplates treatment such that one or more symptoms is / are reduced (and the condition of the subject is thereby “improved”), albeit not completely eliminated.

[0042] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” refers to an amount of an antibody or composition described herein that confers a therapeutic effect on a treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of an antibody or composition effective to treat, ameliorate, or prevent a particular disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and / or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount can be administered in a dosing regimen that may comprise multiple unit doses. For any particular antibody or composition, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific pharmaceutical agent employed; the specific composition employed; the age, body weight, general health, sex and diet Page 15 of 82 12621951v1Attorney Docket No.: 2017284-0018 of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic molecule employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0043] Treatment: As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of an antibody or composition described herein that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and / or condition. DETAILED DESCRIPTION OF INVENTION

[0044] The present disclosure is based, in part, on the discovery of antibodies that selectively bind to BLyS. The disclosure also relates to nucleic acids encoding such antibodies, or antigen-binding fragments thereof, cells comprising such nucleic acids, and methods of use. Anti-BLyS Antibodies

[0045] B Lymphocyte Stimulator (BLyS) is a known protein that in humans is encoded by the TNFSF13B gene. BLyS is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family, and is a ligand for receptors TNFRSF13B / TACI, TNFRSF17 / BCMA, and TNFRSF13C / BAFF-R. BLyS is expressed in B cell lineage cells, and acts as a potent B cell activator. It has also been shown to play an important role in proliferation and differentiation. BLyS is also known as B-cell activating factor (BAFF) and TNF- and APOL-related leukocyte Page 16 of 82 12621951v1Attorney Docket No.: 2017284-0018 expressed ligand (TALL-1) and the Dendritic cell-derived TNF-like molecule (CD257 antigen; cluster of differentiation 257).

[0046] Provided herein are antibodies that specifically bind to BLyS. In some embodiments, the BLyS is human BLyS. In some embodiments, an antibody provided herein comprises a light chain. In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain.

[0047] In some embodiments, an antibody provided herein comprises a heavy chain. In some embodiments, the heavy chain is an IgA. In some embodiments, the heavy chain is an IgA1. In some embodiments, the heavy chain is an IgA2. In some embodiments, the heavy chain is an IgD. In some embodiments, the heavy chain is an IgE. In some embodiments, the heavy chain is an IgG. In some embodiments, the heavy chain is an IgG1. In some embodiments, the heavy chain is an IgG2. In some embodiments, the heavy chain is an IgG3. In some embodiments, the heavy chain is an IgG4. In some embodiments, the heavy chain is an IgM.

[0048] In some embodiments, an antibody provided herein binds human BLyS with a KD of less than or equal to about 1 x10-7M, 1 x10-8M, 1 x10-9M, 1 x10-10M, 1 x10-11M, or 1 x10-12, e.g., as measured by biolayer interferometry.

[0049] In some embodiments, an antibody provided herein comprises an antibody fragment. In some embodiments, an antibody provided herein consists of an antibody fragment. In some embodiments, an antibody provided herein consists essentially of an antibody fragment. In some embodiments, an antibody fragment is an Fv fragment. In some embodiments, an antibody fragment is a Fab fragment. In some embodiments, an antibody fragment is a F(ab’)2fragment. In some embodiments, an antibody fragment is a Fab’ fragment. In some embodiments, an antibody fragment is an scFv (sFv) fragment. In some embodiments, an antibody fragment is an scFv-Fc fragment. In some embodiments, an antibody fragment is a single domain antibody.

[0050] In some embodiments, an antibody fragment provided herein is derived from an illustrative antibody provided herein. In some embodiments, an antibody fragment provided Page 17 of 82 12621951v1Attorney Docket No.: 2017284-0018 herein is not derived from an illustrative antibody provided herein and may, for example, be isolated de novo according to methods provided herein for obtaining antibody fragments.

[0051] In some embodiments, an antibody or antibody fragment provided herein binds to and antagonizes BLyS activity, as measured by one or more assays or biological effects described herein. In some embodiments, an antibody or antibody fragment provided herein prevents BLyS from interacting with one or more of its receptors, as described herein.

[0052] In some embodiments, an antibody or antibody fragment provided herein competes for binding to BLyS with one or more antibodies exemplified herein. In some embodiments, an antibody or antibody fragment provided herein binds the same epitope of BLyS as one or more antibodies exemplified herein. In some embodiments, an antibody or antibody fragment provided herein binds an overlapping epitope of BLyS as one or more antibodies exemplified herein. In some embodiments, an antibody or antibody fragment provided herein binds a distinct epitope of BLyS from one or more antibodies exemplified herein.

[0053] In some embodiments, antibodies provided herein are monoclonal antibodies. In some embodiments, antibodies provided herein are polyclonal antibodies.

[0054] In some embodiments, antibodies provided herein comprise a chimeric antibody. In some embodiments, antibodies provided herein consist of a chimeric antibody. In some embodiments, antibodies provided herein consist essentially of a chimeric antibody. In some embodiments, antibodies provided herein comprise a humanized antibody. In some embodiments, antibodies provided herein consist of a humanized antibody. In some embodiments, antibodies provided herein consist essentially of a humanized antibody. In some embodiments, antibodies provided herein comprise a human antibody. In some embodiments, antibodies provided herein consist of a human antibody. In some embodiments, antibodies provided herein consist essentially of a human antibody.

[0055] In some embodiments, antibodies provided herein comprise an alternative scaffold. In some embodiments, antibodies provided herein consist of an alternative scaffold. In some embodiments, antibodies provided herein consist essentially of an alternative scaffold. Any suitable alternative scaffold may be used. In some embodiments, an alternative scaffold is Page 18 of 82 12621951v1Attorney Docket No.: 2017284-0018 an AdnectinTM, an iMab, an Anticalin®, an EETI-II / AGRP, a Kunitz domain, a thioredoxin peptide aptamer, an Affibody®, a DARPin, an Affilin, a Tetranectin, a Fynomer, or an Avimer.

[0056] In certain aspects, an antibody provided herein inhibits binding of BLyS to BAFF-R. In certain aspects, an antibody provided herein inhibits binding of human BLyS to human BAFF-R. In some embodiments, an antibody provided herein reduces binding of human BLyS to human BAFF-R to a level that is about 5%, 10%, 20%, 40%, or 50% less than level of binding of human BLyS to BAFF-R observed with a reference antibody (e.g., an antibody that does not bind BLyS or a known anti-BLyS antibody, e.g., belimumab).

[0057] In certain aspects, an antibody provided herein inhibits binding of BLyS to TACI. In certain aspects, an antibody provided herein inhibits binding of human BLyS to human TACI. In some embodiments, an antibody provided herein reduces binding of human BLyS to human TACI to a level that is about 5%, 10%, 20%, 40%, or 50% less than level of binding of human BLyS to TACI observed with a reference antibody (e.g., an antibody that does not bind BLyS or a known anti-BLyS antibody, e.g., belimumab).

[0058] In certain aspects, an antibody provided herein inhibits binding of BLyS to BCMA. In certain aspects, an antibody provided herein inhibits binding of human BLyS to human BCMA. In some embodiments, an antibody provided herein reduces binding of human BLyS to human BCMA to a level that is about 5%, 10%, 20%, 40%, or 50% less than level of binding of human BLyS to BCMA observed with a reference antibody (e.g., an antibody that does not bind BLyS or a known anti-BLyS antibody, e.g., belimumab).

[0059] In certain aspects, an antibody provided herein binds to rhesus monkey BLyS. In certain aspects, an antibody provided herein binds to cynomolgus monkey BLyS^

[0060] It is known that when an antibody is expressed in cells, an antibody can be modified after translation. Examples of posttranslational modifications include cleavage of a lysine at the C-terminus of the heavy chain by a carboxypeptidase; modification of glutamine or glutamic acid at the N-terminus of the heavy chain and the light chain to pyroglutamic acid by pyroglutamylation; glycosylation; oxidation; deamidation; and glycation, and it is known that such posttranslational modifications occur in various antibodies (See Journal of Pharmaceutical Sciences, 2008, Vol.97, p.2426-2447, incorporated by reference in its entirety). In some Page 19 of 82 12621951v1Attorney Docket No.: 2017284-0018 embodiments, an antibody or antibody fragment provided herein has undergone posttranslational modification. Examples of an antibody or antibody fragment thereof that have undergone posttranslational modification include an antibody or antibody fragment thereof that have undergone pyroglutamylation at the N-terminus of the heavy chain variable region and / or deletion of lysine at the C-terminus of the heavy chain. It is known in the art that such posttranslational modification due to pyroglutamylation at the N-terminus and deletion of lysine at the C-terminus does not have any influence on the activity of the antibody or fragment thereof (Analytical Biochemistry, 2006, Vol.348, p.24-39). Exemplary Sequences of Anti-BLyS Antibodies

[0061] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 100-105. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:100; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:101; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:102; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:103; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:104; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:105.

[0062] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:1 and a VL comprising the amino acid sequence of SEQ ID NO:2.

[0063] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 112-117. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:112; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:113; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:114; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:115; a CDR-L2 Page 20 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:116; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0064] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:5 and a VL comprising the amino acid sequence of SEQ ID NO:6.

[0065] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 118-123. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:118; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:119; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:120; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:121; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:122; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:123.

[0066] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:7 and a VL comprising the amino acid sequence of SEQ ID NO:8.

[0067] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 124-129. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:124; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:125; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:126; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:127; a CDR-L2 Page 21 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:128; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:129.

[0068] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:9 and a VL comprising the amino acid sequence of SEQ ID NO:10.

[0069] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 130-135. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:130; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:131; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:132; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:133; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:134; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:135.

[0070] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:12. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:11 and a VL comprising the amino acid sequence of SEQ ID NO:12.

[0071] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 136-141. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:136; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:137; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:138; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:139; a CDR-L2 Page 22 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:140; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:141.

[0072] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:13. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:14. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:13 and a VL comprising the amino acid sequence of SEQ ID NO:14.

[0073] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 142-147. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:142; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:143; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:144; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:145; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:146; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:147.

[0074] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:15. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:16. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:15 and a VL comprising the amino acid sequence of SEQ ID NO:16.

[0075] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 148-153. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:148; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:149; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:150; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:151; a CDR-L2 Page 23 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:152; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:153.

[0076] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:17. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:17 and a VL comprising the amino acid sequence of SEQ ID NO:18.

[0077] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 154-159. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:154; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:155; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:156; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:157; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:158; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:159.

[0078] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:19. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:19 and a VL comprising the amino acid sequence of SEQ ID NO:20.

[0079] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 160-165. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:160; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:161; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:162; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:163; a CDR-L2 Page 24 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:164; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:165.

[0080] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:21. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:22. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:21 and a VL comprising the amino acid sequence of SEQ ID NO:22.

[0081] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 166-171. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:166; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:167; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:168; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:169; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:170; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:171.

[0082] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:23. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:24. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:23 and a VL comprising the amino acid sequence of SEQ ID NO:24.

[0083] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 172-177. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:172; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:173; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:174; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:175; a CDR-L2 Page 25 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:176 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:177.

[0084] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:25. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:26. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL comprising the amino acid sequence of SEQ ID NO:26.

[0085] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 178-183. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:178; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:179; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:180; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:181; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:182; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:183.

[0086] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:27. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:28. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:27 and a VL comprising the amino acid sequence of SEQ ID NO:28.

[0087] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 184-189. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:184; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:185; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:186; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:187; a CDR-L2 Page 26 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:188; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:189.

[0088] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:29. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:30. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:29 and a VL comprising the amino acid sequence of SEQ ID NO:30.

[0089] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 190-195. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:190; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:191; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:192; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:193; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:194; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:195.

[0090] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:32.

[0091] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 196-201. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:196; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:197; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:198; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:199; a CDR-L2 Page 27 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:200; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:201.

[0092] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:33. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:33 and a VL comprising the amino acid sequence of SEQ ID NO:34.

[0093] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 202-207. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:202; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:203; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:204; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:205; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:206; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:207.

[0094] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:35 and a VL comprising the amino acid sequence of SEQ ID NO:36.

[0095] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 208-213. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:208; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:209; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:210; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:211; a CDR-L2 Page 28 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:212; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:213.

[0096] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:37. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:38. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:37 and a VL comprising the amino acid sequence of SEQ ID NO:38.

[0097] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 214-219. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:214; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:215; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:216; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:217; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:218; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:219.

[0098] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:39. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:40. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:39 and a VL comprising the amino acid sequence of SEQ ID NO:40.

[0099] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 220-225. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:220; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:221; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:222; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:223; a CDR-L2 Page 29 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:224; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:225.

[0100] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:41. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:41 and a VL comprising the amino acid sequence of SEQ ID NO:42.

[0101] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 226-231. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:226; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:227; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:228; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:229; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:230; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:231.

[0102] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:43. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:44. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:43 and a VL comprising the amino acid sequence of SEQ ID NO:44.

[0103] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 232-237. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:232; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:233; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:234; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:235; a CDR-L2 Page 30 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:236; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:237.

[0104] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:45. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:46. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:46.

[0105] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 238-243. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:238; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:239; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:240; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:241; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:242; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:243.

[0106] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:47. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:48. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:47 and a VL comprising the amino acid sequence of SEQ ID NO:48.

[0107] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 244-249. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:244; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:245; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:246; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:247; a CDR-L2 Page 31 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:248; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:249.

[0108] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:49. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:50. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:49 and a VL comprising the amino acid sequence of SEQ ID NO:50.

[0109] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 250-255. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:250; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:251; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:252; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:253; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:254; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:255.

[0110] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:51. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:52. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:51 and a VL comprising the amino acid sequence of SEQ ID NO:52.

[0111] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 256-261. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:256; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:257; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:258; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:259; a CDR-L2 Page 32 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:260; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:261.

[0112] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:53. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:54. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:53 and a VL comprising the amino acid sequence of SEQ ID NO:54.

[0113] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 262-267. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:262; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:263; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:264; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:265; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:266; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:267.

[0114] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:55. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:56. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:55 and a VL comprising the amino acid sequence of SEQ ID NO:56.

[0115] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 268-273. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:268; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:269; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:270; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:271; a CDR-L2 Page 33 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprising the amino acid sequence of SEQ ID NO:272; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:273.

[0116] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:57. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:58. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:57 and a VL comprising the amino acid sequence of SEQ ID NO:58.

[0117] In some embodiments, an antibody or antibody fragment provided herein comprises one or more CDRs comprising the amino acid sequence of SEQ ID NOs: 274-279. In some embodiments, an antibody or antibody fragment provided herein comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:274; a CDR-H2 comprising the amino acid sequence of SEQ ID NO:275; a CDR-H3 comprising the amino acid sequence of SEQ ID NO:276; a CDR-L1 comprising the amino acid sequence of SEQ ID NO:277; a CDR-L2 comprising the amino acid sequence of SEQ ID NO:278; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:279.

[0118] In some embodiments, an antibody or antibody fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:59. In some embodiments, an antibody or antibody fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:60. In some embodiments, an antibody or antibody fragment provided herein comprises: a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:60.

[0119] In some embodiments, an antibody or antibody fragment provided herein comprises an amino acid sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to one or more of SEQ ID NOs: 1, 2, 5-60, 100-105, and 112-279. In some embodiments, an antibody or antibody fragment provided herein comprises an amino acid sequence of one or more of SEQ ID NOs: 1, 2, 5-60, 100-105, and 112-279, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid Page 34 of 82 12621951v1Attorney Docket No.: 2017284-0018 substitutions. In some embodiments, antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. Monospecific and Multispecific Anti-BLyS Antibodies

[0120] In some embodiments, antibodies or antibody fragments provided herein are monospecific antibodies.

[0121] In some embodiments, the antibodies or antibody fragments provided herein are multispecific antibodies.

[0122] In some embodiments, a multispecific antibody provided herein binds more than one antigen. In some embodiments, a multispecific antibody binds 2 antigens. In some embodiments, a multispecific antibody binds 3 antigens. In some embodiments, a multispecific antibody binds 4 antigens.

[0123] In some embodiments, a multispecific antibody provided herein binds more than one epitope on a BLyS antigen. In some embodiments, a multispecific antibody binds 2 epitopes on a BLyS antigen.

[0124] In some embodiments, a multispecific antibody provided herein is a bispecific antibody that binds a BLyS antigen and a non-BLyS antigen. In some embodiments, a bispecific antibody binds a BLyS antigen and an APRIL antigen. For example, in some embodiments, a bispecific antibody includes an anti-BLyS antibody or antibody fragment provided herein and an anti-APRIL antibody or antibody fragment. Anti-APRIL antibodies are known in the art and include, e.g., BION1301.

[0125] In some embodiments, a multispecific antibody comprises an immunoglobulin comprising at least two different heavy chain variable regions each paired with a common light chain variable region (a “common light chain antibody”). The common light chain variable Page 35 of 82 12621951v1Attorney Docket No.: 2017284-0018 region can form a distinct antigen-binding domain with each of the two different heavy chain variable regions. See Merchant et al., Nature Biotechnol., 1998, 16:677-681.

[0126] In some embodiments, a multispecific antibody comprises an immunoglobulin comprising an antibody or fragment thereof attached to one or more of the N- or C-termini of the heavy or light chains of such immunoglobulin. See Coloma and Morrison, Nature Biotechnol., 1997, 15:159-163. In some embodiments, an antibody comprises a tetravalent bispecific antibody.

[0127] In some embodiments, a multispecific antibody comprises a hybrid immunoglobulin comprising at least two different heavy chain variable regions and at least two different light chain variable regions. See Milstein and Cuello, Nature, 1983, 305:537-540; and Staerz and Bevan, Proc. Natl. Acad. Sci. USA, 1986, 83:1453-1457.

[0128] In some embodiments, a multispecific antibody comprises immunoglobulin chains with one or more electrostatic modifications to promote assembly of Fc hetero-multimers. See WO 2009 / 089004.

[0129] In some embodiments, a multispecific antibody comprises a bispecific single chain molecule. See Traunecker et al., EMBO J., 1991, 10:3655-3659; and Gruber et al., J. Immunol., 1994, 152:5368-5374; each of which is incorporated by reference in its entirety.

[0130] In some embodiments, a multispecific antibody comprises a heavy chain variable domain and a light chain variable domain connected by a polypeptide linker, where the length of the linker is selected to promote assembly of multispecific antibody with the desired multispecificity. For example, monospecific scFvs can form when a heavy chain variable domain and light chain variable domain are connected by a polypeptide linker of more than 12 amino acid residues. See U.S. Pat. Nos.4,946,778 and 5,132,405. In some embodiments, reducing polypeptide linker length to fewer than 12 amino acid residues can prevent pairing of heavy and light chain variable domains on the same polypeptide chain, and can allow pairing of heavy and light chain variable domains from one chain with the complementary domains on another chain. The resulting antibody has multispecificity, with specificity of each binding site contributed by more than one polypeptide chain. Polypeptide chains comprising heavy and light chain variable domains that are joined by linkers between 3 and 12 amino acid residues can form Page 36 of 82 12621951v1Attorney Docket No.: 2017284-0018 dimers (diabodies). With linkers between 0 and 2 amino acid residues, trimers (triabodies) and tetramers (tetrabodies) can be formed. However, the exact type of oligomerization can depend on the amino acid residue composition and the order of the variable domain in each polypeptide chain (e.g., VH-linker-VL vs. VL-linker-VH), in addition to the linker length. A skilled person can select the appropriate linker length based on the desired multispecificity. Glycovariants

[0131] An antibody or antibody fragment provided herein can be altered to increase, decrease and / or eliminate the extent to which it is glycosylated. Glycosylation of antibodies is typically either “N-linked” or “O-linked.” In some embodiments, glycosylation of an antibody is reduced by enzymatic deglycosylation, expression in a bacterial host, or modification of an amino acid residue utilized for glycosylation. In some embodiments, an antibody can include one or more amino acid substitutions to alter glycosylation.

[0132] “N-linked” glycosylation refers to attachment of a carbohydrate moiety to a side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X- threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Presence of either of these tripeptide sequences in an antibody creates a potential glycosylation site.

[0133] “O-linked” glycosylation refers to attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0134] Addition or deletion of N-linked glycosylation sites to or from an antibody provided herein can be accomplished by altering the amino acid sequence such that one or more of the above-described tripeptide sequences is created or removed. Addition or deletion of O- linked glycosylation sites can be accomplished by addition, deletion, or substitution of one or more serine or threonine residues in or to (as the case may be) the sequence of an antibody.

[0135] In some embodiments, an antibody provided herein comprises a glycosylation motif that is different from a naturally occurring antibody. Any suitable naturally occurring glycosylation motif can be modified in the antibody provided herein. Structural and Page 37 of 82 12621951v1Attorney Docket No.: 2017284-0018 glycosylation properties of immunoglobulins are known in the art and summarized, for example, in Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52.

[0136] In some embodiments, an antibody provided herein comprises an IgG1 Fc region that is glycoengineered to include a modified oligosaccharide attached to asparagine 297 (Asn 297). Naturally occurring IgG1 antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn 297 of the CH2 domain of the Fc region. See Wright et al., TIBTECH, 1997, 15:26-32. The oligosaccharide attached to Asn 297 may include various carbohydrates such as mannose, N- acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.

[0137] In some embodiments, an antibody provided herein comprises an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740. In some embodiments, such antibodies do not comprise any fucose at position Asn 297. Amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546. Examples of cell lines capable of producing defucosylated antibody include Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No.2003 / 0157108; WO 2004 / 056312), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107).

[0138] In some embodiments, an antibody provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such glycovariants may have improved CDC function. Examples of such glycovariants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.

[0139] In some embodiments, an antibody provided herein comprises a bisected oligosaccharide, such as a biantennary oligosaccharide attached to the Fc region of the antibody that is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or Page 38 of 82 12621951v1Attorney Docket No.: 2017284-0018 improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878; U.S. Pat. No.6,602,684; and U.S. Pat. Pub. No.2005 / 0123546.

[0140] Other illustrative glycovariants that may be incorporated into an antibody provided herein are described, for example, in U.S. Pat. Pub. Nos.2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos.2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. Biol., 2004, 336:1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622.

[0141] In some embodiments, an antibody provided herein is an aglycosylated antibody. An aglycosylated antibody can be produced using any method known in the art or described herein. In some aspects, an aglycosylated antibody is produced by modifying an antibody to remove all glycosylation sites. In some embodiments, glycosylation sites are removed only from the Fc region of an antibody. In some embodiments, an aglycosylated antibody is produced by expressing an antibody in an organism that is not capable of glycosylation, such as E. coli, or by expressing an antibody in a cell-free reaction mixture. Fc Region and Variants

[0142] In certain embodiments, an antibody provided herein comprises an Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions, insertions, and / or deletions relative to a naturally occurring Fc region. In some embodiments, an antibody with such substitutions, insertions, and / or deletions exhibits altered stability, glycosylation, and / or other characteristics. In some embodiments, an antibody with such substitutions, insertions, and / or deletions is an aglycosylated antibody.

[0143] A “variant Fc region” or “engineered Fc region” is an Fc region comprising an amino acid sequence that differs relative to a native-sequence Fc region by virtue of at least one amino acid modification, such as one or more amino acid substitutions. In some embodiments, a variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or to the Fc region of a parent polypeptide, e.g., from about one to about ten amino acid substitutions, e.g., from about one to about five amino acid substitutions, in a native-sequence Fc Page 39 of 82 12621951v1Attorney Docket No.: 2017284-0018 region or in the Fc region of the parent polypeptide. In some embodiments, a variant Fc region has at least about 80% homology with a native-sequence Fc region and / or with an Fc region of a parent polypeptide, e.g., at least about 90% or 95% homology therewith.

[0144] In some embodiments, a variant Fc region includes three amino acid substitutions in the CH2 region at EU index positions 234, 235, and 237 (e.g., L234A, L235A, and G237A) to reduce Fc^R binding (see Duncan et al., (1988) Nature 332:563 and Hezareh et al., (2001) J Virol 75, 12161-12168 ).

[0145] In some embodiments, a variant Fc region includes two amino acid substitutions at EU index positions 330 and 331, which can reduce complement fixation (see Tao et al., J. Exp. Med.178:661 (1993) and Canfield and Morrison, J. Exp. Med.173:1483 (1991)). In some embodiments, a variant Fc region includes substitution into human IgG1 of IgG2 residues at positions 233-236 and IgG4 residues at positions 327, 330 and 331, which can reduce ADCC and CDC (see, for example, Armour KL. et al., 1999 Eur J Immunol.29(8):2613-24; and Shields RL. et al., 2001. J Biol Chem.276(9):6591-604; U.S. Pat. No.9,150,641).

[0146] In some embodiments, a variant Fc region includes amino acid substitution N297A or N297G, which results in loss of a glycosylation site on the protein. Additionally or alternatively, increasing, decreasing, removing, or other modifications of sugar chains may be achieved by methods common in the art, such as a chemical method, an enzymatic method or by expressing an antibody in a genetically engineered production cell line. Such cell lines can include microorganisms, e.g. Pichia Pastoris, and mammalians cell line, e.g. CHO cells, that naturally express glycosylating enzymes. Further, microorganisms or cells can be engineered to express glycosylating enzymes, or can be rendered unable to express glycosylation enzymes (See e.g., Hamilton, et al., Science, 313:1441 (2006); Kanda, et al, J. Biotechnology, 130:300 (2007); Kitagawa, et al., J. Biol. Chem., 269 (27): 17872 (1994); Ujita-Lee et al., J. Biol. Chem., 264 (23): 13848 (1989); Imai-Nishiya, et al, BMC Biotechnology 7:84 (2007); and WO 07 / 055916). As one example of a cell engineered to have altered sialylation activity, the alpha-2,6- sialyltransferase 1 gene has been engineered into Chinese Hamster Ovary cells and into sf9 cells. Antibodies expressed by these engineered cells are thus sialylated by the exogenous gene product. A further method for obtaining Fc molecules having a modified amount of sugar residues compared to a plurality of native molecules includes separating said plurality of Page 40 of 82 12621951v1Attorney Docket No.: 2017284-0018 molecules into glycosylated and non-glycosylated fractions, for example, using lectin affinity chromatography (See e.g., WO 07 / 117505).

[0147] In some embodiments, a variant Fc region includes L234A / L235A to reduce Fc^R binding (see, for example, Armour et al. (1999) Eur J Immunol.29(8):2613-24). In some embodiments, a variant Fc region is a human IgG1 Fc region comprising one or more substitutions at positions selected from S228 (e.g., S228A), L234 (e.g., L234A), L235 (e.g., L235A), D265 (e.g., D265A), and N297 (e.g., N297A). In some embodiments, a variant Fc region is a human IgG1 Fc region where amino acids at position 233 to 236 (ELLG) are replaced with PVA.

[0148] In some embodiments, a variant Fc region is a human IgG4 Fc region comprising one or more of the hinge-stabilizing substitutions S228P and L235E. In some embodiments, a variant Fc region is a human IgG4 Fc region comprising the hinge-stabilizing substitution S228P. See Aalberse et al., Immunology, 2002, 105:9-19. In some embodiments, the IgG4 Fc region comprises one or more of the following substitutions: E233P, F234V, and L235A. See Armour et al., Mol. Immunol., 2003, 40:585-593. In some embodiments, the IgG4 Fc region comprises a deletion at position G236.

[0149] In some embodiments, a variant Fc region is a human IgG2 Fc region comprising one or more of substitutions A330S and P331S.

[0150] In some embodiments, a variant Fc region includes an amino acid substitution at one or more positions selected from 238, 265, 269, 270, 297, 327 and 329. See U.S. Pat. No. 6,737,056. Such variant Fc regions include Fc regions with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, e.g., substitution of residues 265 and 297 with alanine. See U.S. Pat. No.7,332,581. In some embodiments, a variant Fc region includes an alanine at amino acid position 265. In some embodiments, a variant Fc region includes an alanine at amino acid position 297.

[0151] In some embodiments, a variant Fc region includes one or more amino acid substitutions that improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, a variant Fc region includes one or more amino Page 41 of 82 12621951v1Attorney Docket No.: 2017284-0018 acid substitutions at positions 239, 332, and 330, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006,103:4005-4010.

[0152] In some embodiments, a variant Fc region includes one or more substitutions to increase half-life. Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn) are described, for example, in Hinton et al., J. Immunol., 2006, 176:346-356; and U.S. Pat. Pub. No.2005 / 0014934; each of which is incorporated by reference in its entirety. Such variant Fc regions include those with substitutions at one or more of Fc region residues: 238, 250, 256, 265, 272, 286, 303, 305, 307, 311, 312, 314, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428, and 434 of an IgG. In some embodiments, a variant Fc region includes one or more of the amino acid substitutions M252Y, S254T, and T256E.

[0153] In some embodiments, a variant Fc region is one described in U.S. Pat. Nos. 7,371,8265,648,260, and 5,624,821; Duncan and Winter, Nature, 1988, 322:738-740; and WO 94 / 29351. Constant Regions

[0154] In some embodiments, an antibody provided herein comprises one or more constant regions. Various constant regions suitable for inclusion in antibodies are known in the art. In some embodiments, an antibody provided herein comprises one or more of the exemplary constant regions depicted in Table 1 and Table 2: Table 1: Heavy Chain Constant Region Sequences AMM IgG1 constant AMM IgG2a constant human IgG1 constant S V A S PPage 42 of 82 12621951v1Attorney Docket No.: 2017284-0018 AMM IgG1 constant AMM IgG2a constant human IgG1 constant K G T G K P GTable 2: Light Chain Constant Region Sequences Human Kappa constant sequence Human Lambda C2 constant sequence I T D

[0155] In some embodiments, an antibody provided herein comprises a constant region having an amino acid sequence that at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NOs: 301-305. In some embodiments, an antibody provided herein Page 43 of 82 12621951v1Attorney Docket No.: 2017284-0018 comprises a heavy chain constant region having an amino acid sequence that at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NOs: 301-303, and a light chain constant region having an amino acid sequence that at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 304 or 305. Nucleotides, Vectors, and Host Cells

[0156] The present disclosure also provides isolated nucleic acids encoding anti-BLyS antibodies, vectors comprising the nucleic acids, and host cells comprising the vectors and nucleic acids, as well as recombinant techniques for production of antibodies.

[0157] In some embodiments, the present disclosure includes a nucleic acid sequence that encodes an amino acid sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to any one of the amino acid sequences of SEQ ID NOs: 1, 2, 5-60, 100-105, and 112- 279. In some embodiments, the present disclosure includes a nucleic acid sequence that encodes an amino acid sequence of any one of SEQ ID NOs: 1, 2, 5-60, 100-105, and 112-279, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0158] For recombinant production of an antibody, one or more nucleic acids encoding an antibody may be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or expression. In some embodiments, a nucleic acid may be produced by homologous recombination, for example as described in U.S. Patent No.5,204,244.

[0159] Many suitable expression vectors are known in the art. Vector components can generally include one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, for example as described in U.S. Patent No.5,534,615.

[0160] Suitable host cells include, without limitation, any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells. Suitable prokaryotes include, e.g., eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Page 44 of 82 12621951v1Attorney Docket No.: 2017284-0018 Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. In some embodiments, an E. coli cloning host is E. coli 294. Additional strains include, e.g., E. coli B, E. coli X1776, and E. coli W3110.

[0161] Eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for anti-BLyS antibody-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Other genera, species, and strains are available and useful, such as but not limited to Schizosaccharomyces pombe, Kluyveromyces (K. lactis, K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. drosophilarum, K. thermotolerans, and K. marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis), and filamentous fungi such as, for example Penicillium, Tolypocladium, and Aspergillus (A. nidulans and A. niger).

[0162] Exemplary mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse sertoli cells; African green monkey kidney cells (VERO-76), and the like.

[0163] Host cells used to produce an anti-BLyS antibody can be cultured in a variety of media as is known in the art. Commercially available media such as, for example, Ham’s F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco’s Modified Eagle’s Medium (DMEM) are suitable for culturing host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and U.S. Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, and 5,122,469; or WO 90 / 03430 and WO 87 / 00195 can be used.

[0164] Any of these media may be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Appropriate culture conditions, such as temperature, pH, and the like, can be Page 45 of 82 12621951v1Attorney Docket No.: 2017284-0018 selected based on the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.

[0165] When using recombinant techniques, antibodies can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. For example, Carter et al. (Bio / Technology, 1992, 10:163-167, incorporated by reference in its entirety) describes a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris can be removed by centrifugation.

[0166] In some embodiments, an antibody is produced in a cell-free system. In some embodiments, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225. In some embodiments, a cell-free system utilizes a cell- free extract from a eukaryotic cell or from a prokaryotic cell. In some embodiments, a prokaryotic cell is E. coli.

[0167] Where the antibody is secreted into the medium, supernatants from such expression systems can generally first be concentrated, e.g., using a commercially available protein concentration filter, for example, an Amicon®or Millipore®Pellcon®ultrafiltration unit. A protease inhibitor such as PMSF can be included in any of the foregoing steps to inhibit proteolysis, and antibiotics can be included to prevent the growth of adventitious contaminants.

[0168] An antibody prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and / or affinity chromatography. Protein A can be used as an affinity ligand depending on the species and isotype of Fc domain that is present in the antibody, as is known in the art. For example, protein A can be used to purify antibodies that comprise human γ1, γ2, or γ4 heavy chains (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13). Protein G can be used to purify all mouse isotypes and for human γ3 (Guss et al., EMBO J., 1986, 5:1567-1575). Page 46 of 82 12621951v1Attorney Docket No.: 2017284-0018

[0169] In some embodiments, an affinity ligand is associated with a matrix, such as agarose, for purification. However, other matrices are available and can be used. In some embodiments, mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene can be used. In some embodiments, BakerBond ABX®resin can be used for purification of antibodies that comprise a CH3 domain.

[0170] Additional techniques for protein purification, such as fractionation on an ion- exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin Sepharose®, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available, and can be applied by one of skill in the art.

[0171] Following preliminary purification step(s), a mixture of a produced antibody and contaminants can be subjected to low pH hydrophobic interaction chromatography using, e.g., an elution buffer at a pH between about 2.5 to about 4.5, e.g., performed at low salt concentrations (e.g., from about 0 to about 0.25 M salt). Methods of Making Antibodies

[0172] In some embodiments, monoclonal antibodies of the present disclosure can be obtained, for example, using the hybridoma method described by Kohler et al., Nature, 1975, 256:495-497 and / or by recombinant DNA methods (see e.g., U.S. Patent No.4,816,567). Hybridoma cells can serve as a useful source of DNA encoding antibodies with desired properties. Monoclonal antibodies can also be obtained, for example, using phage or yeast-based libraries. See e.g., U.S. Patent Nos.8,258,082 and 8,691,730.

[0173] DNA encoding monoclonal antibodies can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Once isolated, DNA can be placed into expression vectors, which can then be transfected into host cells to produce the monoclonal antibodies, as described herein.

[0174] Chimeric antibodies described herein can be produced using methods known in the art, as described in, e.g., U.S. Pat. No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 1984, 81:6851-6855. In some embodiments, a chimeric antibody is made by using Page 47 of 82 12621951v1Attorney Docket No.: 2017284-0018 recombinant techniques to combine a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) with a human constant region.

[0175] Humanized antibodies described herein can be produced by replacing most, or all, of the structural portions of a non-human monoclonal antibody with corresponding human antibody sequences, using methods known in the art. In some embodiments, a humanized antibody includes human sequences except for antigen-specific variable domains, or CDRs, which can include non-human sequences. Methods to obtain humanized antibodies include those described in, for example, Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. U.S.A., 1998, 95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073- 36078; Queen et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Patent Nos. 5,585,089, 5,693,761, 5,693,762, and 6,180,370.

[0176] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g., humanized mice). See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggemann et al., Year in Immuno., 1993, 7:33; and U.S. Patent Nos.5,591,669, 5,589,369 and 5,545,807. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al., J. Mol. Biol., 1991, 227:381-388; Marks et al., J. Mol. Biol., 1991, 222:581- 597; and U.S. Pat. Nos.5,565,332 and 5,573,905). Human antibodies can also be generated by in vitro activated B cells (see e.g., U.S. Patent. Nos.5,567,610 and 5,229,275) and / or derived from yeast-based libraries (see e.g., U.S. Patent No.8,691,730).

[0177] Antibody fragments provided herein can be made by any suitable method, such as methods described herein and / or those known in the art. Suitable methods include, e.g., recombinant techniques and proteolytic digestion of whole antibodies (see, e.g., Hudson et al., Nat. Med., 2003, 9:129-134). Methods of making scFv antibodies are described, for example, in Plückthun, in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp.269-315 (1994); WO 93 / 16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458. Page 48 of 82 12621951v1Attorney Docket No.: 2017284-0018 Antibody Assays

[0178] A variety of assays known in the art may be used to identify and characterize an anti-BLyS antibody provided herein. For example, specific BLyS-binding activity of an antibody provided herein can be evaluated by any suitable method, including, e.g., using SPR, BLI, RIA and MSD-SET. Additionally, BLyS-binding activity can be evaluated by ELISA assays or Western blot assays.

[0179] Assays for measuring competition between two antibodies are known in the art and described, e.g., in Harlow and Lane, Antibodies: A Laboratory Manual ch.14, 1988, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

[0180] Assays for mapping epitopes to which an antibody provided herein bind are described, e.g., in Morris “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66, 1996, Humana Press, Totowa, N.J. In some embodiments, an epitope is determined by peptide competition. In some embodiments, an epitope is determined by mass spectrometry. In some embodiments, an epitope is determined by crystallography.

[0181] Effector function following treatment with an antibody provided herein can be evaluated using a variety of in vitro and in vivo assays known in the art, including those described in Ravetch and Kinet, Annu. Rev. Immunol., 1991, 9:457-492; U.S. Pat. Nos. 5,500,362, 5,821,337; Hellstrom et al., Proc. Nat’l Acad. Sci. USA, 1986, 83:7059-7063; Hellstrom et al., Proc. Nat’l Acad. Sci. USA, 1985, 82:1499-1502; Bruggemann et al., J. Exp. Med., 1987, 166:1351-1361; Clynes et al., Proc. Nat’l Acad. Sci. USA, 1998, 95:652-656; WO 2006 / 029879; WO 2005 / 100402; Gazzano-Santoro et al., J. Immunol. Methods, 1996, 202:163- 171; Cragg et al., Blood, 2003, 101:1045-1052; Cragg et al. Blood, 2004, 103:2738-2743; and Petkova et al., Int’l. Immunol., 2006, 18:1759-1769.

[0182] In some embodiments, a therapeutic activity of an antibody provided herein is assessed (e.g., an activity of an antibody in decreasing severity or symptom of a disease or condition, or in delaying appearance of a symptom of a disease or condition). In some embodiments, a pharmacologic activity of an antibody is assessed (e.g., bioavailability, pharmacokinetics, pharmacodynamics). For methods of analyzing bioavailability, pharmacokinetics, and pharmacodynamics of antibodies, see, e.g., Weiner et al., J. Pharm. Page 49 of 82 12621951v1Attorney Docket No.: 2017284-0018 Biomed. Anal.15(5):571-9, 1997; Srinivas et al., J. Pharm. Sci.85(1):1-4, 1996; and Srinivas et al., Pharm. Res.14(7):911-6, 1997. Formulations and Administration

[0183] An antibody provided herein can be formulated in any appropriate pharmaceutical composition and administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, the intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.

[0184] An antibody provided herein can be incorporated into a pharmaceutical composition. Pharmaceutical compositions comprising an antibody can be formulated by methods known to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences pp. 1447-1676 (Alfonso R. Gennaro, ed., 19th ed.1995)). Pharmaceutical compositions can be administered parenterally in the form of an injectable formulation comprising a sterile solution or suspension in water or another pharmaceutically acceptable liquid. For example, a pharmaceutical composition can be formulated by suitably combining a polypeptide with pharmaceutically acceptable vehicles or media, such as sterile water and physiological saline, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, flavoring excipient, diluent, vehicle, preservative, binder, followed by mixing in a unit dose form required for generally accepted pharmaceutical practices. The amount of active ingredient included in pharmaceutical preparations is such that a suitable dose within the designated range is provided.

[0185] A sterile composition for injection can be formulated in accordance with conventional pharmaceutical practices using distilled water for injection as a vehicle. For example, physiological saline or an isotonic solution containing glucose and other supplements such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride may be used as an aqueous solution for injection, optionally in combination with a suitable solubilizing agent, for example, alcohol such as ethanol and polyalcohol such as propylene glycol or polyethylene glycol, and a nonionic surfactant such as polysorbate 80™, HCO-50 and the like.

[0186] Nonlimiting examples of oily liquid include sesame oil and soybean oil, and it may be combined with benzyl benzoate or benzyl alcohol as a solubilizing agent. Other items Page 50 of 82 12621951v1Attorney Docket No.: 2017284-0018 that may be included are a buffer such as a phosphate buffer, or sodium acetate buffer, a soothing agent such as procaine hydrochloride, a stabilizer such as benzyl alcohol or phenol, and an antioxidant. A formulated injection can be packaged in a suitable ampule.

[0187] Route of administration can be parenteral, for example, administration by injection, transnasal administration, transpulmonary administration, or transcutaneous administration. Administration can be systemic or local by intravenous injection, intramuscular injection, intraperitoneal injection, or subcutaneous injection.

[0188] A suitable means of administration can be selected based on the age and condition of the patient. A single dose of the pharmaceutical composition containing an antibody can be selected from a range of 0.001 to 1000 mg / kg of body weight. On the other hand, a dose can be selected in the range of 0.001 to 100000 mg / body weight, but the present disclosure is not limited to such ranges. The dose and method of administration can vary depending on the weight, age, condition, and the like of the patient, and can be suitably selected as needed by those skilled in the art. Disorders and Conditions

[0189] In some embodiments, an antibody or antibody fragment provided herein (or a composition comprising an antibody or antibody fragment provided herein) is administered to a subject suffering from or at risk of an autoimmune disorder. In some embodiments, administration of an antibody or antibody fragment provided herein (or a composition comprising an antibody or antibody fragment provided herein) to a subject reduces or inhibits binding of BLyS to one or more of BAFF-R, TACI, and / or BCMA, e.g., as compared to a prior measurement from the same subject or a reference value. In some embodiments, an antibody or antibody fragment provided herein (or a composition comprising an antibody or antibody fragment provided herein) is administered to a subject to treat or prevent an autoimmune disorder.

[0190] The term “autoimmune disorder”, as used herein, refers to any disorder that results from an autoimmune response. In some embodiments, a subject suffering from an autoimmune disorder exhibits an inappropriate and / or excessive response to a self-antigen. An antibody or antibody fragment provided herein) can be administered to a subject suffering from Page 51 of 82 12621951v1Attorney Docket No.: 2017284-0018 or at risk of any autoimmune disorder, and the present disclosure is not limited to any particular autoimmune disorder. Examples of autoimmune disorders include, but are not limited to, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison’s disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo disease, Balo concentric sclerosis, Bechet’s syndrome, Bickerstaff's brainstem encephalitis, Blau syndrome, bullous pemphigoid, cancer, Castleman disease, celiac disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, cranial arteritis, CREST syndrome, Crohn’s disease, Cushing’s syndrome, cutaneous leukocytoclastic angiitis, Degos disease, Dercum’s disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, diffuse cutaneous systemic sclerosis, Dressler’s syndrome, discoid lupus erythematosus, eczema, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa acquisita, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, firodysplasia ossificans progressiva, fibrosing aveolitis, Focal segmental glomerulosclerosis, gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis (Wegener’s granulomatosis), Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s encephalitis, Hashimoto’s thyroiditis, hemolytic anaemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic inflammatory demyelinating disease, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, inflammatory demyelinating polyneuropathy, interstitial cystitis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), lupoid hepatitis, lupus nephritis, Majeed syndrome, Membranous nephropathy, Meniere’s disease, microscopic Page 52 of 82 12621951v1Attorney Docket No.: 2017284-0018 polyangiitis, Miller Fisher syndrome, Minimal change disease, mixed connective tissue disease, morphea, Mucha-Habermann disease, multiple myeloma, multiple sclerosis, myasthenia gravis, myositis, a neuromyelitis optica spectrum disorder, neuromyotonia, ocular cicatricial pemphigoid, opsoclonus myoclonus syndrome, Ord’s thyroiditis, palindromic rheumatism, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry- Romberg syndrome, Parsonage-Turner syndrome, pars planitis, pemphigus, pemphigus vulgaris, permicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen’s encephalitis, Raynaud’s phenomenon, relapsing polychondritis, Reiter’s syndrome, restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatoid fever, sarcoidosis, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, Sjogren’s syndrome, spondylarthropathy, stiff person syndrome, Still’s disease, subacute bacterial endocarditis, Susac syndrome, Sweet syndrome, Sydenham chorea, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu’s arteritis, temporal arteritis, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondylarthropathy, vasculitis, and vitiligo. Kits

[0191] The present disclosure also provides kits comprising an antibody provided herein. The kits may be used for the treatment, prevention, and / or diagnosis of a disease or disorder, as described herein. In some embodiments, a kit comprises (i) a container containing an antibody and (ii) a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and IV solution bags. The label or package insert indicates that the composition is used for treating the selected condition.

[0192] Alternatively, or additionally, a kit may further comprise an additional container comprising a pharmaceutically acceptable excipient. In some embodiments, the excipient is a buffer. The kit can further include other materials desirable from a commercial and user standpoint, including filters, needles, and syringes. Page 53 of 82 12621951v1Attorney Docket No.: 2017284-0018 EXEMPLARY EMBODIMENTS

[0193] Embodiment 1. An antibody that binds B lymphocyte stimulator (BLyS), or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence selected from any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence selected from any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60.

[0194] Embodiment 2. An antibody that binds BLyS, or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58.

[0195] Embodiment 3. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising a heavy chain variable domain (VH) comprising three complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1, CDR-H2, and CDR-H3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100, 101, and 102; SEQ ID NOs: 112, 113, and 114; SEQ ID NOs: 118, 119, and 120; SEQ ID NOs: 124, 125, and 126; Page 54 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 130, 131, and 132; SEQ ID NOs: 136, 137, and 138; SEQ ID NOs: 142, 143, and 144; SEQ ID NOs: 148, 149, and 150; SEQ ID NOs: 154, 155, and 156; SEQ ID NOs: 160, 161, and 162; SEQ ID NOs: 166, 167, and 168; SEQ ID NOs: 172, 173, and 174; SEQ ID NOs: 178, 179, and 180; SEQ ID NOs: 184, 185, and 186; SEQ ID NOs: 190, 191, and 192; SEQ ID NOs: 196, 197, and 198; SEQ ID NOs: 202, 203, and 204; SEQ ID NOs: 208, 209, and 210; SEQ ID NOs: 214, 215, and 216; SEQ ID NOs: 220, 221, and 222; SEQ ID NOs: 226, 227, and 228; SEQ ID NOs: 232, 233, and 234; SEQ ID NOs: 238, 239, and 240; SEQ ID NOs: 244, 245, and 246; SEQ ID NOs: 250, 251, and 252; SEQ ID NOs: 256, 257, and 258; SEQ ID NOs: 262, 263, and 264; SEQ ID NOs: 268, 269, and 270; or Page 55 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 274, 275, and 276.

[0196] Embodiment 4. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising a light chain variable domain (VL) comprising three complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR- L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 103, 104, and 105; SEQ ID NOs: 115, 116, and 117; SEQ ID NOs: 121, 122, and 123; SEQ ID NOs: 127, 128, and 129; SEQ ID NOs: 133, 134, and 135; SEQ ID NOs: 139, 140, and 141; SEQ ID NOs: 145, 146, and 147; SEQ ID NOs: 151, 152, and 153; SEQ ID NOs: 157, 158, and 159; SEQ ID NOs: 163, 164, and 165; SEQ ID NOs: 169, 170, and 171; SEQ ID NOs: 175, 176, and 177; SEQ ID NOs: 181, 182, and 183; SEQ ID NOs: 187, 188, and 189; SEQ ID NOs: 193, 194, and 195; SEQ ID NOs: 199, 200, and 201; SEQ ID NOs: 205, 206, and 207; SEQ ID NOs: 211, 212, and 213; SEQ ID NOs: 217, 218, and 219; Page 56 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 223, 224, and 225; SEQ ID NOs: 229, 230, and 231; SEQ ID NOs: 235, 236, and 237; SEQ ID NOs: 241, 242, and 243; SEQ ID NOs: 247, 248, and 249; SEQ ID NOs: 253, 254, and 255; SEQ ID NOs: 259, 260, and 261; SEQ ID NOs: 265, 266, and 267; SEQ ID NOs: 271, 272, and 273; or SEQ ID NOs: 277, 278, and 279.

[0197] Embodiment 5. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising (a) a heavy chain variable domain (VH) comprising three complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and (b) a light chain variable domain (VL) comprising three complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100-105; SEQ ID NOs: 112-117; SEQ ID NOs: 118-123; SEQ ID NOs: 124-129; SEQ ID NOs: 130-135; SEQ ID NOs: 136-141; SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 154-159; Page 57 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 160-165; SEQ ID NOs: 166-171; SEQ ID NOs: 172-177; SEQ ID NOs: 178-183; SEQ ID NOs: 184-189; SEQ ID NOs: 190-195; SEQ ID NOs: 196-201; SEQ ID NOs: 202-207; SEQ ID NOs: 208-213; SEQ ID NOs: 214-219; SEQ ID NOs: 220-225; SEQ ID NOs: 226-231; SEQ ID NOs: 232-237; SEQ ID NOs: 238-243; SEQ ID NOs: 244-249; SEQ ID NOs: 250-255; SEQ ID NOs: 256-261; SEQ ID NOs: 262-267; SEQ ID NOs: 268-273; or SEQ ID NOs: 274-279.

[0198] Embodiment 6. The antibody of Embodiment 5, or antigen-binding portion thereof, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 136-141; Page 58 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 160-165; or SEQ ID NOs: 202-207.

[0199] Embodiment 7. An antibody that competes for binding to BLyS with the antibody of any one of Embodiments 1-6.

[0200] Embodiment 8. The antibody of any one of Embodiments 1-7, wherein the antibody has an in vitro binding (KD) to BLyS of about 0.001 nM to about 1 nM, e.g., about 0.05 nM to about 1 nM, e.g., about 0.1 nM to about 0.5 nM, e.g., about 0.25 nM to about 0.5 nM, e.g., about 0.001 nM, about 0.005 nM, about 0.01 nM, about, about 0.05 nM, about 0.1 nM, about 0.15 nM, about 0.2 nM, about 0.25 nM, about 0.3 nM, about 0.35 nM, about 0.4 nM, about 0.45 nM, about 0.5 nM, about 0.55 nM, about 0.6 nM, about 0.65 nM, about 0.7 nM, about 0.75 nM, about 0.8 nM, about 0.85 nM, about 0.9 nM, about 0.95 nM, or about 1 nM.

[0201] Embodiment 9. The antibody of any one of Embodiments 1-8, wherein the antibody is a human antibody.

[0202] Embodiment 10. The antibody of any one of Embodiments 1-8, wherein the antibody is a humanized antibody.

[0203] Embodiment 11. The antibody of any one of Embodiments 1-10, wherein the antibody is a monoclonal antibody.

[0204] Embodiment 12. A nucleic acid sequence encoding the antibody or antigen- binding fragment thereof of any one of Embodiments 1-11.

[0205] Embodiment 13. A vector comprising the nucleic acid sequence of Embodiment 12.

[0206] Embodiment 14. A host cell comprising the nucleic acid sequence of Embodiment 12 or the vector of Embodiment 13. Page 59 of 82 12621951v1Attorney Docket No.: 2017284-0018

[0207] Embodiment 15. A method of treating an autoimmune disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody, or antigen-binding fragment thereof, of any one of Embodiments 1-11.

[0208] Embodiment 16. The method of Embodiment 15, wherein the autoimmune disease is systemic lupus erythematosus, lupus nephritis, Sjogren’s syndrome, IgA nephropathy, pemphigus vulgaris, neuromyelitis optica spectrum disorders, multiple myeloma, rheumatoid arthritis, or multiple sclerosis.

[0209] Embodiment 17. A pharmaceutical composition comprising the antibody of any one of Embodiments 1-11.

[0210] Embodiment 18. The pharmaceutical composition of Embodiment 17, further comprising one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

[0211] Embodiment 19. The pharmaceutical composition of Embodiment 17 or 18 for pharmaceutical use.

[0212] Embodiment 20. The pharmaceutical composition of Embodiment 19, wherein the pharmaceutical use comprises a therapeutic or prophylactic treatment of a disease or disorder.

[0213] Embodiment 21. The pharmaceutical composition of Embodiment 20, wherein the therapeutic or prophylactic treatment of a disease or disorder comprises treating or preventing an autoimmune disorder.

[0214] Embodiment 22. The pharmaceutical composition of Embodiment 21, wherein the autoimmune disorder is systemic lupus erythematosus, lupus nephritis, Sjogren’s syndrome, IgA nephropathy, pemphigus vulgaris, neuromyelitis optica spectrum disorders, multiple myeloma, rheumatoid arthritis, or multiple sclerosis.

[0215] Embodiment 23. The pharmaceutical composition of any one of Embodiments 17- 22, which is for administration to a human.

[0216] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by Page 60 of 82 12621951v1Attorney Docket No.: 2017284-0018 one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0217] The disclosure is further illustrated by the following examples. The examples are provided for illustrative purposes only. They are not to be construed as limiting the scope or content of the disclosure in any way. EXAMPLES Example 1: Engineering of an Anti-BLyS Antibody

[0218] A primary screen was conducted of 6,287 hybridomas with FACS-based blocking of BLyS binding to TACI on IM-9 cells. The primary screen was followed by a confirmation screen of 93 hybridomas. The confirmation screen included: 1) a FACS-based blocking assay of BLyS binding to TACI on IM-9 cells, 2) FACS-based binding to BAFF-R on stable HEK293T:huBAFF-R cells, 3) a FACS-based binding assay to HEK293T:huBLyS and HEK293T:cyBLyS cells, and / or 4) Octet© off-rate analysis to huBLyS active trimer and cyBLyS hFc . After the confirmation screen, 29 anti-BLyS antibodies were subcloned and screened by ELISA-based blocking of huBLyS to TACI-hFc. After subcloning, 25 anti-BLyS antibodies (antibodies 1 and 3-26 listed in Table 3 below) were then expressed and purified at 20 mL scale. Table 3. Anti-BLyS Antibodies Antibody Heavy Chain Light Chain 0 2Page 61 of 82 12621951v1Attorney Docket No.: 2017284-0018 Antibody Heavy Chain Light Chain 7 E ID N 1 E ID N 14 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 612621951v1Attorney Docket No.: 2017284-0018 Antibody Heavy Chain Light Chain 2 E ID N 7 E ID N 8 0   Example 2: BLyS Antbody n vtro oc ng ssay

[0219] The anti-BLyS antibodies 1 and 3-30, described in Example 1, were subjected to blocking assays. Antibodies were mixed with huBLyS-His-FLAG and added to 293T:huBAFFR cells or IM-9 cells. Rat anti-FLAG-488 was used to detect BLyS by flow cytometry. Table 4. Antibody IM9 Inhibition huBAFF-R (IC50; nM) Inhibition12621951v1Attorney Docket No.: 2017284-0018 Antibody IM9 Inhibition huBAFF-R (IC50; nM) Inhibition I MExample 3: BLyS Antibody Binding in HEK293T

[0220] The anti-BLyS antibodies 1 and 3-30, described in Example 1, were subjected to binding assays. HEK293T:huBLYS and HEK293T:cyBLyS cells were incubated with antibodies overnight at 4oC . Cells were washed and stained with a secondary antibody and viability dye and analyzed by flow cytometry. Table 5. Antibody 293T:huBLyS 293T:cyBLySPage 64 of 82 12621951v1Attorney Docket No.: 2017284-0018 Antibody 293T:huBLyS 293T:cyBLyS EC50(nM) EC50(nM)12621951v1Attorney Docket No.: 2017284-0018 Other Embodiments

[0221] While a number of embodiments of this invention are described herein, the present disclosure and examples may be altered to provide other methods and compositions of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims in addition to the specific embodiments that have been represented by way of example. Page 66 of 82 12621951v1Attorney Docket No.: 2017284-0018 LISTING OF SEQUENCES SEQ ID NO:1 VH (underlining denotes CDR1 (SEQ ID NO: 100), CDR2 (SEQ ID NO: 101), CDR3 (SEQ ID NO: 102), sequentially)VTVSS SEQ ID NO:2 VL (underlining denotes CDR1 (SEQ ID NO: 103), CDR2 (SEQ ID NO: 104), CDR3 (SEQ ID NO: 105), sequentially) QSVLTQPPSASGTPGQRVTISCSGSTSNIGFKTVNWYQQLPGTAPKLLICCNNQRPSGVP DRFSGSKSDTSASLAISGLQSEDEADYYCAAWDDRLNGPVFGGGTKLTVL SEQ ID NO:5 VH (underlining denotes CDR1 (SEQ ID NO: 112), CDR2 (SEQ ID NO: 113), CDR3 (SEQ ID NO: 114), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSLRSYYWSWIRQPAGKGLEWIGRIYTSGSTNY NPSLKSRVTMSVDTSKNQFSLKLNSVTAADTAVYYCVRDRYLTWGGLDYWGQGTLVT VSS SEQ ID NO:6 VL (underlining denotes CDR1 (SEQ ID NO: 115), CDR2 (SEQ ID NO: 116), CDR3 (SEQ ID NO: 117), sequentially) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSSLAWYQQKPGQAPRLLIYGASSRATGIPD RFSGSGSGTDFTLTISRLEPEDFAVYYCQQCGSSPPSTFGQGTKLEIK SEQ ID NO:7 VH (underlining denotes CDR1 (SEQ ID NO: 118), CDR2 (SEQ ID NO: 119), CDR3 (SEQ ID NO: 120), sequentially) QVQLQESGPGLVKPSETLSLTCAVSGGSISSDYWSWIRQPAGKGLEWIGHIYASGNTNY NPSLKSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARLNRRFDVFDIWGQGTMVTVS T SEQ ID NO:8 VL (underlining denotes CDR1 (SEQ ID NO: 121), CDR2 (SEQ ID NO: 122), CDR3 (SEQ ID NO: 123), sequentially) DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSLGYNYLDWYLQKPGQSPQLLIYLGSIRAS GVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK SEQ ID NO:9 VH (underlining denotes CDR1 (SEQ ID NO: 124), CDR2 (SEQ ID NO: 125), CDR3 (SEQ ID NO: 126), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISDYYWSWIRQPPGKGLEWNGHIYYSGYTNS NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARVNRYDAFDIWGQGTMVTVSS Page 67 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NO:10 VL (underlining denotes CDR1 (SEQ ID NO: 127), CDR2 (SEQ ID NO: 128), CDR3 (SEQ ID NO: 129), sequentially) IVMTQSPLSLPVTPGEPASISCRSSQSLLHSYGHNSLDWYLQRPGQSPQLLIYLGSNRASG VPDRFSGSGSGTDFTLKISRVEAADVGVYYCMQSLQTPWTFGQGTKVEIK SEQ ID NO:11 VH (underlining denotes CDR1 (SEQ ID NO: 130), CDR2 (SEQ ID NO: 131), CDR3 (SEQ ID NO: 132), sequentially) EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDG GTTDYAAPVKGSFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTDTYSDILTGYSHFDYW GQGTLVTVSS SEQ ID NO:12 VL (underlining denotes CDR1 (SEQ ID NO: 133), CDR2 (SEQ ID NO: 134), CDR3 (SEQ ID NO: 135), sequentially) DIQMTQSPSSLSASVGDRVTITCRASQGIRKYLAWYQQKPGKVPKLLIYAASALQSGVPS RFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPLTFGQGTRLEIK SEQ ID NO:13 VH (underlining denotes CDR1 (SEQ ID NO: 136), CDR2 (SEQ ID NO: 137), CDR3 (SEQ ID NO: 138), sequentially) QVQLQESGPGLVKPSETLSLTCAVSGGSISSDYWSWIRQPAGKGLEWIGRIYTSGSTNYN PSLKSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARLNRRFDVFDIWGQGTMVTVST SEQ ID NO:14 VL (underlining denotes CDR1 (SEQ ID NO: 139), CDR2 (SEQ ID NO: 140), CDR3 (SEQ ID NO: 141), sequentially) DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSLGYNYLDWYLQKPGQSPQLLIYLGSIRAS GVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK SEQ ID NO:15 VH (underlining denotes CDR1 (SEQ ID NO: 142), CDR2 (SEQ ID NO: 143), CDR3 (SEQ ID NO: 144), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPAGKGLEWIGHIYTSGNTNYN PSLKSRVTMSVDTPKNQFSLKLSSVTAADTAVYYCARGRHYDILTGYSPDVFDIWGQGT MVTVSS SEQ ID NO:16 VL (underlining denotes CDR1 (SEQ ID NO: 145), CDR2 (SEQ ID NO: 146), CDR3 (SEQ ID NO: 147), sequentially) DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWFQQKPGKAPKSLIYAASGLQSGVPS KFSGSGSGTDFTLTISSLQPEDFATYFCQQYNSYPYTFGQGTKLEIK SEQ ID NO:17 VH (underlining denotes CDR1 (SEQ ID NO: 148), CDR2 (SEQ ID NO: 149), CDR3 (SEQ ID NO: 150), sequentially) Page 68 of 82 12621951v1Attorney Docket No.: 2017284-0018 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYDMHWVRQATGKGLEWVSAIGTAGDTY YPGSVKGRFTISRENAKNSLYLQMNSLRAGDTAVYYCARGYYDILTKYYLHAFDIWGQ GTMVTVSS SEQ ID NO:18 VL (underlining denotes CDR1 (SEQ ID NO: 151), CDR2 (SEQ ID NO: 152), CDR3 (SEQ ID NO: 153), sequentially) DIQMTQSPSAMSASVGDRVTITCRASQGISYYLSWFQQKPGKVPKRLIYAASSLQSGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNTYPFTFGPGTKVDIK SEQ ID NO:19 VH (underlining denotes CDR1 (SEQ ID NO: 154), CDR2 (SEQ ID NO: 155), CDR3 (SEQ ID NO: 156), sequentially) EVQLVESGGGLVKPGGSLRLSCAASGFSFRNAWMSWVRQAPGKGLEWVGRIKSKTDG VTTDFTAPVNDRFIISRDDSKNTLYLQMISLKTEDTAVYYCTTDEFHDILTGYSYFDYWG QGTLVTVSS SEQ ID NO:20 VL (underlining denotes CDR1 (SEQ ID NO: 157), CDR2 (SEQ ID NO: 158), CDR3 (SEQ ID NO: 159), sequentially) DIQMTQSPSTLSASVGDRVTITCRASQNISSLLAWYQQKPGKAPKLLIYKASSLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQHYNSYSRTFGQGTKVEIK SEQ ID NO:21 VH (underlining denotes CDR1 (SEQ ID NO: 160), CDR2 (SEQ ID NO: 161), CDR3 (SEQ ID NO: 162), sequentially) EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMNWVRQAPGKGLEWVSTIRGSGGST YYADSVKGRFTVSRDNSKNTLYLLMVSLRAEDTAVYYCASLTGDAFDVWGQGTMVT VSS SEQ ID NO:22 VL (underlining denotes CDR1 (SEQ ID NO: 163), CDR2 (SEQ ID NO: 164), CDR3 (SEQ ID NO: 165), sequentially) QSVLTQPPSVSAAPGQKVTISCSGSNSNIGNNYVSWYHQLPGTAPKLLIYDNNKRPSGIP DRFSGSKSGTSATLGITGLQTGDEADYYCGTWDGSLNPTWMFGGGTKLTVL SEQ ID NO:23 VH (underlining denotes CDR1 (SEQ ID NO: 166), CDR2 (SEQ ID NO: 167), CDR3 (SEQ ID NO: 168), sequentially) EVQLVESGGGVVKPGGSLRLSCAASGFTFSNAWMNWVRQAPGKGLEWVGRFKSKTDG GTIDYAAPVKDRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTDYDILTGYLFDYWGQ GTLVTVSS SEQ ID NO:24 VL (underlining denotes CDR1 (SEQ ID NO: 169), CDR2 (SEQ ID NO: 170), CDR3 (SEQ ID NO: 171), sequentially) Page 69 of 82 12621951v1Attorney Docket No.: 2017284-0018 DIQMTQSPSTLSASVGDRVTITCRASQSIGNWLAWYQQKPGKAPKLLIYKASSLESGVPS RFSGSGSGTEFTLTISSLQPDDFITYYCQHYNSYSRTFGQGTKVEIK SEQ ID NO:25 VH (underlining denotes CDR1 (SEQ ID NO: 172), CDR2 (SEQ ID NO: 173), CDR3 (SEQ ID NO: 174), sequentially) EVQLVESGGGLVKPGGSLRLSCAASGFTFSSAWMSWVRQAPGKGLEWVGRIKSKTEGG TTDYAAPVKGRFTISRDDSKNTLYVQMNSLKTEDTAVYYCTTDEYYDILTGYSYFDYW GQGTLVTVSS SEQ ID NO:26 VL (underlining denotes CDR1 (SEQ ID NO: 175), CDR2 (SEQ ID NO: 176), CDR3 (SEQ ID NO: 177), sequentially) DIQMTQSPSTLSASVGDRVTITCRASQSISRWLAWYQQKPGKAPKLLIYKASSLESGVPS RFSGSGSGTEFTLTISNLQPDDFATYYCQHYNSYSRTFGQGTKVEIK SEQ ID NO:27 VH (underlining denotes CDR1 (SEQ ID NO: 178), CDR2 (SEQ ID NO: 179), CDR3 (SEQ ID NO: 180), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGDSISSHHWSWIRQPPGKGLEWIGYIYNSGSTNYN LSLKSRVTISIDTSKNQFFLKLSSVTAADTAVYYCARQYYDILTGYYLGFDIWGQGTMV TVSS SEQ ID NO:28 VL (underlining denotes CDR1 (SEQ ID NO: 181), CDR2 (SEQ ID NO: 182), CDR3 (SEQ ID NO: 183), sequentially) QSVLTQPPSVSAAPGQKVTISCSGRISNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSATSATLGITGLLTGDEADYYCGTWDSSLSAWVFGGGTKVTVL SEQ ID NO:29 VH (underlining denotes CDR1 (SEQ ID NO: 184), CDR2 (SEQ ID NO: 185), CDR3 (SEQ ID NO: 186), sequentially) QVQLQESGPGLVKPSVTLSLTCTVSGGSISSYCWSWVRQPAGKGLEWIGRIYTSGNTNY NPSLKSRVTMSVDTSKNQFSLNLRSVTAADTAVYYCAREREYKDILTGYYLSNGMDVW GQGTTVTVSS SEQ ID NO:30 VL (underlining denotes CDR1 (SEQ ID NO: 187), CDR2 (SEQ ID NO: 188), CDR3 (SEQ ID NO: 189), sequentially) DIQLTQSPSFLSASVGDRVTITCRASQGISSFLAWYQQRPGKAPKLLIYGASTLQSGVPSR FSGSGSGTEFTLTISSLQPEDFASYYCQQLISYPRTFGQGTKVEIK SEQ ID NO:31 VH (underlining denotes CDR1 (SEQ ID NO: 190), CDR2 (SEQ ID NO: 191), CDR3 (SEQ ID NO: 192), sequentially) Page 70 of 82 12621951v1Attorney Docket No.: 2017284-0018 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGPPN YAQKFQGRVTITADKSTTTAYMELSSLRSEDTAVYFCARERAGDGYFDLWGRGTLVTV SS SEQ ID NO:32 VL (underlining denotes CDR1 (SEQ ID NO: 193), CDR2 (SEQ ID NO: 194), CDR3 (SEQ ID NO: 195), sequentially) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLTWYQQKPGQAPRVFIYDASSRATGIPD RFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGQGTKVEIK SEQ ID NO:33 VH (underlining denotes CDR1 (SEQ ID NO: 196), CDR2 (SEQ ID NO: 197), CDR3 (SEQ ID NO: 198), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISSHYWSWIRQPPGKGLEWIGYIYDSGSTNYN PSLKSRVTISVDTSENQFSLKLSSVTAADTAVYYCSRQYYDILTGYYLAFNIWGQGTMV TVSS SEQ ID NO:34 VL (underlining denotes CDR1 (SEQ ID NO: 199), CDR2 (SEQ ID NO: 200), CDR3 (SEQ ID NO: 201), sequentially) DIQLTQSPSFLSASVGDRVTITCRASQGISRYLAWYQQRPGKAPKLLIYVASTLQSGVPSR FSGSGSGTEFTLTISSLQPEDFATYSCQQFNTYPFTFGPGTKVDIK SEQ ID NO:35 VH (underlining denotes CDR1 (SEQ ID NO: 202), CDR2 (SEQ ID NO: 203), CDR3 (SEQ ID NO: 204), sequentially) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGPPN YAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAREVPGDGTFDIWGQGTMVTV SS SEQ ID NO:36 VL (underlining denotes CDR1 (SEQ ID NO: 205), CDR2 (SEQ ID NO: 206), CDR3 (SEQ ID NO: 207), sequentially) QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNDYVSWYQQLPGTAPKLLIYDNNKRPSGVP DRFSGSKSGTSATLGITGLQTGDEADYYCGTWDRSLSANVVFGGGTKLTVL SEQ ID NO:37 VH (underlining denotes CDR1 (SEQ ID NO: 208), CDR2 (SEQ ID NO: 209), CDR3 (SEQ ID NO: 210), sequentially) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSG GTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARTFYDILIGYYDPFDYW GQGTLVTVSS SEQ ID NO:38 VL (underlining denotes CDR1 (SEQ ID NO: 211), CDR2 (SEQ ID NO: 212), CDR3 (SEQ ID NO: 213), sequentially) Page 71 of 82 12621951v1Attorney Docket No.: 2017284-0018 DIQMTQSPSAMSASVGDRVTITCRTSQDIRNYLAWFQQKPGKVPKRLIYAASGLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPYTFGQGTKLEIK SEQ ID NO:39 VH (underlining denotes CDR1 (SEQ ID NO: 214), CDR2 (SEQ ID NO: 215), CDR3 (SEQ ID NO: 216), sequentially) QVQLRESGPGLVKPSETLSLTCTVSGDSISRYYWSWIRQPAGKGLEWIGRFYTSGNTNY NPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCAREVGMKDWYFDLWGRGTLVT VSS SEQ ID NO:40 VL (underlining denotes CDR1 (SEQ ID NO: 217), CDR2 (SEQ ID NO: 218), CDR3 (SEQ ID NO: 219), sequentially) SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPD RFSGSRSGNTASLTITGAQAEDEADYYCHSRDSSGNYVVFGGGTKLTVL SEQ ID NO:41 VH (underlining denotes CDR1 (SEQ ID NO: 220), CDR2 (SEQ ID NO: 221), CDR3 (SEQ ID NO: 222), sequentially) QVQLQESGPGLVKPSETLSLTCTVAGGSISGYYWSWIRQPPGKGLEWVGYFYYSGITNY NPSLKSRVTISVDTSKNQFSLNLSSLTAADTAVYYCARQYYDILTGYHIAFDIWGQGTM VTVSS SEQ ID NO:42 VL (underlining denotes CDR1 (SEQ ID NO: 223), CDR2 (SEQ ID NO: 224), CDR3 (SEQ ID NO: 225), sequentially) DIQLTQSPSFLSASVGDRATITCRASQGISRYLAWYQQKPGKAPKLLIYAASTLQSGVPS RFSGSGSGTEFTLTISSLQPEDFASYHCQQFNSYPFTFGPGTKVDIK SEQ ID NO:43 VH (underlining denotes CDR1 (SEQ ID NO: 226), CDR2 (SEQ ID NO: 227), CDR3 (SEQ ID NO: 228), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISNYYWSWIRQPPGKGLEWIGYIYYSGSTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGPFYDILTGYYNPYFDYWGQGT LVTVSS SEQ ID NO:44 VL (underlining denotes CDR1 (SEQ ID NO: 229), CDR2 (SEQ ID NO: 230), CDR3 (SEQ ID NO: 231), sequentially) QSALTQPASVSGSPGQSITISCTGTSSDVGSYHLVSWYQQHPGKAPKLMIYEDIKRPSGV SNRFSGSKSGSTASLTISGLQAEDEADYYCCSYAGSSTLVFGGGTKLTVL SEQ ID NO:45 VH (underlining denotes CDR1 (SEQ ID NO: 232), CDR2 (SEQ ID NO: 233), CDR3 (SEQ ID NO: 234), sequentially) Page 72 of 82 12621951v1Attorney Docket No.: 2017284-0018 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSAWMSWVRQAPGKGLEWVGRIKTKTDG GTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCSTDHTYYDILTGYSPFDY WGQGTLVTVSS SEQ ID NO:46 VL (underlining denotes CDR1 (SEQ ID NO: 235), CDR2 (SEQ ID NO: 236), CDR3 (SEQ ID NO: 237), sequentially) DIVMTQSPDSLTVSLGERATMNCKSSQSILYRSNNKNYLAWYQQKPGQPPKLLIYWASI RESGVPDRFSGRGSGTDFTLTISSLQAEDVAVYYCQQYYSAPNTFGQGTKLEIK SEQ ID NO:47 VH (underlining denotes CDR1 (SEQ ID NO: 238), CDR2 (SEQ ID NO: 239), CDR3 (SEQ ID NO: 240), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWNWIRQPAGKGLEWIGRIYTSGNTNYN PSLKSRVTMSVDTSKNQFSLNLSSVTAADTAVYYCAGDYYDFLTGYSIPFDYWGQGTL VTVSS SEQ ID NO:48 VL (underlining denotes CDR1 (SEQ ID NO: 241), CDR2 (SEQ ID NO: 242), CDR3 (SEQ ID NO: 243), sequentially) DIVMTQSPLSLPVTPGESASISCRSSQSLLKRNGYNHLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPITFGQGTRLEIK SEQ ID NO:49 VH (underlining denotes CDR1 (SEQ ID NO: 244), CDR2 (SEQ ID NO: 245), CDR3 (SEQ ID NO: 246), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGVSISTYYWSWIRQSPGKGLEWIGYIYYSGNTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTAEYYCARGPFYDILTGYFLNWFDPWGQGT LVTVSS SEQ ID NO:50 VL (underlining denotes CDR1 (SEQ ID NO: 247), CDR2 (SEQ ID NO: 248), CDR3 (SEQ ID NO: 249), sequentially) QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYASWYQKIPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGAWDISLNPGVVFGGGTKLTVL SEQ ID NO:51 VH (underlining denotes CDR1 (SEQ ID NO: 250), CDR2 (SEQ ID NO: 251), CDR3 (SEQ ID NO: 252), sequentially) EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSLNWVRQAPGRGLEWVSFISSSSSNTYY ADSVKGRFTISRDNAKNSLYLQLNSLRDEDAAVYYCARDRHYDILTGYSLSAMDVWG QGTTVTVSS SEQ ID NO:52 VL (underlining denotes CDR1 (SEQ ID NO: 253), CDR2 (SEQ ID NO: 254), CDR3 (SEQ ID NO: 255), sequentially) Page 73 of 82 12621951v1Attorney Docket No.: 2017284-0018 QSVLTQPPSASGTPGQRVTISCSGSSSNIGSHYVYWFQQLPGTAPKLLIYSYNQRPSGVPD RFSGTKSGTSASLAISGLRSEDEADYYCATWDDSLSGWVFGGGTKLTVL SEQ ID NO:53 VH (underlining denotes CDR1 (SEQ ID NO: 256), CDR2 (SEQ ID NO: 257), CDR3 (SEQ ID NO: 258), sequentially) QVQLQESGPGLVKPSETLSLTCTVSGGSISNYYWSWIRQPAGKGLEWIGRIYSSGSTNYN PSLKSRVTMSVDTSMNQFSLNLSSVTAADTAVYYCARGWAWGGSYSGYFDYWGQGT LVTVSS SEQ ID NO:54 VL (underlining denotes CDR1 (SEQ ID NO: 259), CDR2 (SEQ ID NO: 260), CDR3 (SEQ ID NO: 261), sequentially) DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTECTLTISSLQPEDFATYYCQQLNSYPWTFGQGTKVEIK SEQ ID NO:55 VH (underlining denotes CDR1 (SEQ ID NO: 262), CDR2 (SEQ ID NO: 263), CDR3 (SEQ ID NO: 264), sequentially) EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDT RYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGNYLDTFDIWGQGTMVTV SS SEQ ID NO:56 VL (underlining denotes CDR1 (SEQ ID NO: 265), CDR2 (SEQ ID NO: 266), CDR3 (SEQ ID NO: 267), sequentially) DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPWTFGQGTKVEIK SEQ ID NO:57 VH (underlining denotes CDR1 (SEQ ID NO: 268), CDR2 (SEQ ID NO: 269), CDR3 (SEQ ID NO: 270), sequentially) QVQLVQSGAEVKKPGSSVKVSCKASGGIFSSYAIDWVRQAPGQGLEWMGGILPLFGTA NYAQNFQGRVTITADKSTTTAYMELSSLRSEDTAVYYCANLVGEVDYWGQGTLVTVSS SEQ ID NO:58 VL (underlining denotes CDR1 (SEQ ID NO: 271), CDR2 (SEQ ID NO: 272), CDR3 (SEQ ID NO: 273), sequentially) DIQMTQSPSAMSASVGDRVTITCRASQGISNYLAWFQQKPGKVPKRLIFAASSLQSGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGPGTKVDIK SEQ ID NO:59 VH (underlining denotes CDR1 (SEQ ID NO: 274), CDR2 (SEQ ID NO: 275), CDR3 (SEQ ID NO: 276), sequentially) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNWGSFDYWGQGTLVTVSS Page 74 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NO:60 VL (underlining denotes CDR1 (SEQ ID NO: 277), CDR2 (SEQ ID NO: 278), CDR3 (SEQ ID NO: 279), sequentially) QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSYRPSGV PDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDNSLSGVVFGGGTKLTVL Page 75 of 82 12621951v1

Claims

Attorney Docket No.: 2017284-0018 CLAIMS 1. An antibody that binds B lymphocyte stimulator (BLyS), or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence selected from any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence selected from any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60.

2. An antibody that binds BLyS, or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 1, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59; and (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of the amino acid sequence of any one of SEQ ID NOs: 2, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58.

3. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising a heavy chain variable domain (VH) comprising three complementarity determining regions CDR- H1, CDR-H2, and CDR-H3, wherein the CDR-H1, CDR-H2, and CDR-H3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100, 101, and 102; SEQ ID NOs: 112, 113, and 114; SEQ ID NOs: 118, 119, and 120; SEQ ID NOs: 124, 125, and 126; SEQ ID NOs: 130, 131, and 132; Page 76 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 136, 137, and 138; SEQ ID NOs: 142, 143, and 144; SEQ ID NOs: 148, 149, and 150; SEQ ID NOs: 154, 155, and 156; SEQ ID NOs: 160, 161, and 162; SEQ ID NOs: 166, 167, and 168; SEQ ID NOs: 172, 173, and 174; SEQ ID NOs: 178, 179, and 180; SEQ ID NOs: 184, 185, and 186; SEQ ID NOs: 190, 191, and 192; SEQ ID NOs: 196, 197, and 198; SEQ ID NOs: 202, 203, and 204; SEQ ID NOs: 208, 209, and 210; SEQ ID NOs: 214, 215, and 216; SEQ ID NOs: 220, 221, and 222; SEQ ID NOs: 226, 227, and 228; SEQ ID NOs: 232, 233, and 234; SEQ ID NOs: 238, 239, and 240; SEQ ID NOs: 244, 245, and 246; SEQ ID NOs: 250, 251, and 252; SEQ ID NOs: 256, 257, and 258; SEQ ID NOs: 262, 263, and 264; SEQ ID NOs: 268, 269, and 270; or SEQ ID NOs: 274, 275, and 276.

4. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising a light chain variable domain (VL) comprising three complementarity determining regions CDR- L1, CDR-L2, and CDR-L3, wherein the CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 103, 104, and 105; Page 77 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 115, 116, and 117; SEQ ID NOs: 121, 122, and 123; SEQ ID NOs: 127, 128, and 129; SEQ ID NOs: 133, 134, and 135; SEQ ID NOs: 139, 140, and 141; SEQ ID NOs: 145, 146, and 147; SEQ ID NOs: 151, 152, and 153; SEQ ID NOs: 157, 158, and 159; SEQ ID NOs: 163, 164, and 165; SEQ ID NOs: 169, 170, and 171; SEQ ID NOs: 175, 176, and 177; SEQ ID NOs: 181, 182, and 183; SEQ ID NOs: 187, 188, and 189; SEQ ID NOs: 193, 194, and 195; SEQ ID NOs: 199, 200, and 201; SEQ ID NOs: 205, 206, and 207; SEQ ID NOs: 211, 212, and 213; SEQ ID NOs: 217, 218, and 219; SEQ ID NOs: 223, 224, and 225; SEQ ID NOs: 229, 230, and 231; SEQ ID NOs: 235, 236, and 237; SEQ ID NOs: 241, 242, and 243; SEQ ID NOs: 247, 248, and 249; SEQ ID NOs: 253, 254, and 255; SEQ ID NOs: 259, 260, and 261; SEQ ID NOs: 265, 266, and 267; SEQ ID NOs: 271, 272, and 273; or SEQ ID NOs: 277, 278, and 279. Page 78 of 82 12621951v1Attorney Docket No.: 2017284-0018 5. An antibody that binds BLyS, or an antigen-binding portion thereof, comprising (a) a heavy chain variable domain (VH) comprising three complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and (b) a light chain variable domain (VL) comprising three complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 100-105; SEQ ID NOs: 112-117; SEQ ID NOs: 118-123; SEQ ID NOs: 124-129; SEQ ID NOs: 130-135; SEQ ID NOs: 136-141; SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 154-159; SEQ ID NOs: 160-165; SEQ ID NOs: 166-171; SEQ ID NOs: 172-177; SEQ ID NOs: 178-183; SEQ ID NOs: 184-189; SEQ ID NOs: 190-195; SEQ ID NOs: 196-201; SEQ ID NOs: 202-207; SEQ ID NOs: 208-213; SEQ ID NOs: 214-219; SEQ ID NOs: 220-225; SEQ ID NOs: 226-231; SEQ ID NOs: 232-237; SEQ ID NOs: 238-243; SEQ ID NOs: 244-249; Page 79 of 82 12621951v1Attorney Docket No.: 2017284-0018 SEQ ID NOs: 250-255; SEQ ID NOs: 256-261; SEQ ID NOs: 262-267; SEQ ID NOs: 268-273; or SEQ ID NOs: 274-279.

6. The antibody of claim 5, or antigen-binding portion thereof, wherein the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences, respectively, of: SEQ ID NOs: 136-141; SEQ ID NOs: 142-147; SEQ ID NOs: 148-153; SEQ ID NOs: 160-165; or SEQ ID NOs: 202-207.

7. An antibody that competes for binding to BLyS with the antibody of any one of claims 1-6.

8. The antibody of any one of claims 1-7, wherein the antibody has an in vitro binding (KD) to BLyS of about 0.001 nM to about 1 nM.

9. The antibody of any one of claims 1-8, wherein the antibody is a human antibody.

10. The antibody of any one of claims 1-8, wherein the antibody is a humanized antibody.

11. The antibody of any one of claims 1-10, wherein the antibody is a monoclonal antibody. Page 80 of 82 12621951v1Attorney Docket No.: 2017284-0018 12. A nucleic acid sequence encoding the antibody or antigen-binding fragment thereof of any one of claims 1-11.

13. A vector comprising the nucleic acid sequence of claim 12.

14. A host cell comprising the nucleic acid sequence of claim 12 or the vector of claim 13.

15. A method of treating an autoimmune disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody, or antigen-binding fragment thereof, of any one of claims 1-11.

16. The method of claim 15, wherein the autoimmune disorder is systemic lupus erythematosus, lupus nephritis, Sjogren’s syndrome, IgA nephropathy, pemphigus vulgaris, neuromyelitis optica spectrum disorders, multiple myeloma, rheumatoid arthritis, or multiple sclerosis. Page 81 of 82 12621951v1

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