WO2022246154A2 - Antibodies that bind to c1s and uses thereof - Google Patents

Antibodies that bind to c1s and uses thereof Download PDF

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Publication number
WO2022246154A2
WO2022246154A2 PCT/US2022/030189 US2022030189W WO2022246154A2 WO 2022246154 A2 WO2022246154 A2 WO 2022246154A2 US 2022030189 W US2022030189 W US 2022030189W WO 2022246154 A2 WO2022246154 A2 WO 2022246154A2
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Prior art keywords
antibody
binding fragment
seq
antibody binding
sequence
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French (fr)
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WO2022246154A3 (en
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Vahe Bedian
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Dianthus Therapeutics Inc
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Dianthus Therapeutics Inc
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Priority to EP22805547.1A priority Critical patent/EP4340879A4/en
Priority to JP2023571586A priority patent/JP2024518844A/ja
Priority to CN202280048661.4A priority patent/CN117769434A/zh
Publication of WO2022246154A2 publication Critical patent/WO2022246154A2/en
Publication of WO2022246154A3 publication Critical patent/WO2022246154A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present application claims priority to U.S. Provisional Application No. 63/201,952, filed May 20, 2021, which is hereby incorporated by reference in its entirety.
  • Field of the Invention is immunology, in particular therapeutic antibodies, and treatment of disease with those antibodies.
  • the complement system is a well-known effector mechanism of the innate immune response, providing not only protection against pathogens and other harmful agents but also recovery from injury. Complement activation due to autoantibodies and alloantibodies can lead to damage to normal cells or rejection of transplanted tissue.
  • the complement pathway comprises a number of proteins that typically exist in the body in inactive form.
  • the classical complement pathway is triggered by activation of the first component of complement, referred to as the C1 complex, which consists of C1q, C1r, and C1s proteins.
  • the C1 complex consists of C1q, C1r, and C1s proteins.
  • the C1s component a diisopropyl fluorophosphate (DFP)- sensitive serine protease, cleaves complement components C4 and C2 to initiate activation of the classical complement pathway.
  • DFP diisopropyl fluorophosphate
  • sutimlimab an antibody that inhibits C1s
  • the dosing and lack of specificity for C1s, the active form, as opposed to the zymogen proC1s, and its physical properties, such as its lack of specificity, which requires a very high dose to be adminiterested may limits its use. Therefore, there is a need in the art for compounds that treat a complement classical pathway-mediated disease or disorder. The embodiments provided for here in satisfies these needs as well as others. Summary [0004] In some embodiments, antibodies, such as recombinant antibodies, or an antigen binding fragments thereof that binds to a C1s are provided.
  • the antibody or antigen binding fragment thereof comprises an amino acid sequence, or a variant thereof, as provided for herein.
  • isolated nucleic acid molecules encoding an antibody, or an antigen binding fragment thereof, a heavy chain variable region, a light chain variable region, heavy chain, or light chain as provided herein are provided.
  • expression vectors comprising a nucleic acid molecule as provided for herein are provided.
  • host cells comprising a nucleic acid molecule as provided for herein are provided.
  • antibodies or antigen-binding fragments produced by the host cells are provided.
  • methods of producing a polypeptide comprising a heavy chain variable region or light chain variable region as provided herein comprise growing a host cell under conditions so that the host cell expresses a polypeptide comprising the heavy chain variable region or the light chain variable region; and purifying the polypeptide comprising the heavy chain variable region and/or the light chain variable region.
  • methods of treating a subject with a C1s mediated disorder are provided.
  • the methods comprise administering to the subject an antibody, or antigen binding fragment thereof, as provided herein or a pharmaceutical composition comprising the same.
  • the C1s mediated disorder is selected from hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • ITP Immune Thrombocytopenia
  • Glomerulopaties Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • antibodies, or antigen binding fragments thereof, as provided herein, or or a pharmaceutical composition comprising the same, for use as a medicament are provided.
  • use of the antibodies, or antigen binding fragments thereof, as provided for herein, or a pharmaceutical composition comprising the same are provided for the treatment of of of a C1s mediated disorder, such as, but not limited to hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection. or as provided for herein.
  • a C1s mediated disorder such as, but not limited to hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection. or as provided for herein.
  • an antibody, or an antigen binding fragment thereof comprises: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 9; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 10 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 11 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 12; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 13; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 14; or variants of any of the foregoing; (b) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HC
  • an antibody, or an antigen binding fragment thereof comprises: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 27; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 28 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 11 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 29; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing; (b) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HC
  • an antibody, or an antigen binding fragment thereof comprises: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 42; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 43 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 44 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 45; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 14; or variants of any of the foregoing; (b) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HC
  • an antibody, or an antigen binding fragment thereof comprises: a.
  • the HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, respectively, from SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 11, respectively, and from SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, respectively
  • the LCDR1, LCDR2 and LCDR3 are selected from from SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, respectively, from SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, respectively, and from SEQ ID NO: 45, SEQ ID NO: 30, SEQ ID NO: 14, respectively; or b.
  • the HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, respectively, from SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 17, respectively, and from SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, respectively, and the LCDR1, LCDR2 and LCDR3 are selected from from SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, respectively, from SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, respectively, and from SEQ ID NO: 49, SEQ ID NO: 35, SEQ ID NO: 20, respectively; or c.
  • the HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, respectively, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 23, respectively, and SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, respectively, and the LCDR1, LCDR2 and LCDR3 are selected from SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, respectively, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, respectively, and SEQ ID NO: 53, SEQ ID NO: 40, SEQ ID NO: 26, respectively.
  • a variant of an antibody or antigen binding fragment thereof is provided, wherein the variant has 1-10 substitutions, deletions, or insertions.
  • a variant of an antibody or antigen binding fragment thereof is provided, wherein the variant has 1-10 conservaitve substitutions.
  • a recombinant antibody or antigen binding fragment thereof is provided, wherein the recombinant antibody or antigen binding fragment thereof binds to a C1s.
  • the recombinant antibody or antigen binding fragment thereof is an antibody or antigen binding fragment thereof as provided for herein.
  • an isolated nucleic acid molecule is provided.
  • the isolated nucleic acid molecule encodes an antibody or antigen binding fragment thereof, a heavy chain variable region, a light chain variable region, a heavy chain, a light chain, or a combination thereod.
  • the antibody or antigen binding fragment thereof, a heavy chain variable region, a light chain variable region, a heavy chain, or light chain are as provided for herein.
  • an expression vector is provided.
  • the expression vector comprises a nucleic acid molecule as provided for herein.
  • a host cell is provided.
  • the host cell comprises a nucleic acid molecule or expression vector as provided for herein.
  • the host cell comprises a nucleic acid molecule as provided for herein. In some embodiments, the host cell comprises an expression vector as provided for herein. [0023] In some embodiments, an antibody or antigen binding fragment thereof is provided, wherein the antibody or antigen binding fragment thereof is produced by the host cell. [0024] In some embodiments, a pharmaceutical composition is provided. In some embodiments, the pharmaceutical composition comprises an antibody or antigen binding fragment thereof as provided for herein. [0025] In some embodiments, a method of producing a polypeptide comprising a heavy chain variable region or a light chain variable region is provided.
  • the method comprises (a) growing a host cell as provided for herein under conditions so that the host cell expresses the polypeptide comprising the heavy chain variable region or the light chain variable region; and (b) purifying the polypeptide comprising the heavy chain or the light chain variable regions.
  • the heavy chain variable region is as provided for herein.
  • the light chain variable region is as provided for herein.
  • a method of producing an antibody or an antigen binding fragment of the antibody is provided. In some embodiments, the antibody or antigen binding fragment bind to human C1s.
  • the method comprises (a) growing a host cell as provided for herein under conditions so that the host cell expresses a polypeptide or polypeptides comprising the immunoglobulin heavy chain variable region and/or the immunoglobulin light chain variable region, thereby producing the antibody or the antigen binding fragment of the antibody; and (b) purifying the antibody or the antigen-binding fragment of the antibody.
  • a method of treating a subject with a C1s mediated disorder is provided.
  • the method comprises adiministering to the subject an antibody or antigen bindgin fragment thereof as provided for herein, or a pharmaceutical composition as provided for herein.
  • an antibody or antigen binding fragment thereof or a pharmaceutical composistion is provided, wherein the antibody or antigen binding fragment thereof or the pharmaceutical comnposition are for the use in the treatment of a C1s mediated disorder.
  • the antibody or antigen binding fragment thereof is as provided for herein.
  • the pharmaceutical composition is as provided for herein.
  • the C1s mediated disorder is as provided for herein.
  • the C1s mediated disorder is hemolysis or Cold Agglutinin Disease.
  • an antibody or antigen binding fragment thereof or a pharmaceutical composistion is provided, wherein the antibody or antigen binding fragment thereof or the pharmaceutical comnposition are for the use as a medicament.
  • the antibody or antigen binding fragment thereof is as provided for herein.
  • the pharmaceutical composition is as provided for herein.
  • a use of an antibody or antigen binding fragment thereof or a pharmaceutical composistion is provided, wherein the use is for the treatment of a C1s mediated disorder.
  • the antibody or antigen binding fragment thereof is as provided for herein.
  • the pharmaceutical composition is as provided for herein.
  • the C1s mediated disorder is as provided for herein.
  • Figure 1 shows the dose response of six 4O11g antibodies that differ in their Fc regions, along with TNT009 and TNT020, in the Wieslab classical pathway kit used according to manufacturer’s instruction.
  • Figure 2 shows the dose response of four 4O11g variants along with TNT009, TNT020 and ravulizumab in C3b deposition in a FACS based assay using rabbit antibody sensitized human RBCs and 5% human serum
  • Figure 3 shows the dose response of 4O11g antibody with TNT009, TNT020 and eculizumab in a human RBC lysis assay using 10% human serum
  • Figure 4 depicts SPR sensograms where anti-Fc coated surfaces were used to capture test antibodies, and human C1s or proC1s_RQ was used as analyte.
  • binding proteins e.g., antibodies, or fragments, thereof, that selectively bind to C1s and have low binding to the zymogen proC1s.
  • the antibodies inhibit activation of the classical complement pathway and can be used in methods to treat complement mediated disoders, such as, but not limited to those provided for herein.
  • the selectivity for C1s over proC1s can be used to reduce or prevent target mediated clearance of the therapeutic antibody, thus requiring lower doses and frequency of administration of the antibody.
  • “comprising” means “including” and the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise.
  • reference to “comprising a therapeutic agent” includes one or a plurality of such therapeutic agents.
  • the term “or” refers to a single element of stated alternative elements, unless the context clearly indicates otherwise.
  • the phrase “A or B” refers to A alone or B alone.
  • the phrase “A, B, or a combination thereof” refers to A alone, B alone, or a combination of A and B.
  • “one or more of A and B” refers to A, B, or a combination of both A and B.
  • a and B refers to a combination of A and B.
  • the various elements, features and steps discussed herein, as well as other known equivalents for each such element, feature or step can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in particular examples. [0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.
  • antibody refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • parent antibodies are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.
  • antibody fragment or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies (single domain antibody) and multispecific antibodies formed from antibody fragments.
  • a “Fab fragment” is comprised of one light chain and the CH1 and variable regions of one heavy chain.
  • An “Fc” region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the C H 3 domains.
  • a “Fab' fragment” contains one light chain and a portion or fragment of one heavy chain that contains the V H domain and the C H 1 domain and also the region between the C H 1 and C H2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab') 2 molecule.
  • a “F(ab') 2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains.
  • a F(ab')2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.
  • the “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
  • the term “single-chain Fv” or “scFv” antibody refers to antibody fragments comprising the V H and V L domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • a “single-domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more V H regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.
  • a “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).
  • monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al.
  • the present invention provides single domain antibodies comprising two V H domains with modifications such that single domain antibodies are formed.
  • the term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V H ) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH).
  • Diabodies are described more fully in, e.g., EP 404,097; WO 93/11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat. Biotechnol.23:1126-1136.
  • a variant antibody or antigen binding fragment of the antibodies provided herein retain at least 10% of its C1s binding activity (when compared to a parental antibody that is modified) when that activity is expressed on a molar basis.
  • a variant antibody (or antigen fragment thereof), or antigen binding fragment of an antibody provided herein retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the C1s binding affinity as the parental antibody.
  • an antibody or antigen binding fragment of the invention can include conservative or non-conservative amino acid substitutions, which can also be referred to as “conservative variants” or “function conserved variants” of the antibody, that do not substantially alter its biologic activity.
  • isolated antibody refers to the purification status of a binding compound and in such context means the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.
  • the term “monoclonal antibody”, as used herein, refers to population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations and/or post-translational modifications that may be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol.222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol.116:731.
  • a “chimeric antibody” is an antibody having the variable domain from a first antibody and constant domain from a second antibody, where the first and second antibodies are from different species.
  • the variable domains are obtained from an antibody from an experimental animal (the “parental antibody”), such as a rodent, and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibody will be less likely to elicit an adverse immune response in a human subject than the parental (e.g. rodent) antibody.
  • humanized antibody refers to forms of antibodies that contain sequences from both human and non-human (e.g., murine, rat) antibodies.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non- human immunoglobulin, and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence.
  • the humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).
  • Fc human immunoglobulin constant region
  • the term “fully human antibody” refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody refers to an antibody that comprises mouse immunoglobulin sequences only.
  • a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell.
  • rat antibody refers to an antibody that comprises rat immunoglobulin sequences only.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids.
  • the variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, not the same.
  • the variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem.
  • hypervariable region refers to the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (i.e.
  • CDRL1 residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.) and/or those residues from a “hypervariable loop” (i.e.
  • CDR1 residues 26-32 (CDRL1), 50-52 (CDRL2) and 91-96 (CDRL3) in the light chain variable domain and 26-32 (CDRH1), 53-55 (CDRH2) and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol.196: 901-917).
  • the CDRs can also be referenced according to the IMGT system for the identification of CDRs, which is described in Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509.
  • the term “framework” or “FR” residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues.
  • CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope.
  • CDRs of interest can be derived from donor antibody variable heavy and light chain sequences, and include analogs of the naturally occurring CDRs, which analogs also share or retain the same antigen binding specificity and/or neutralizing ability as the donor antibody from which they were derived.
  • “specific binding” or “immunospecific binding” or “binds immunospecifically” refer to antibody binding to a predetermined antigen at a much higher affinity than for another antigen(s) (e.g. selectively binds the active form of complement component C1s as compared to inactive C1s, which can also be referred to as proC1s zymogen).
  • the antibody binds the predetermined antigen with a dissociation constant (KD) of 10 -7 M or less, and such KD is at least two-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide).
  • KD dissociation constant
  • the phrases “an antibody recognizing C1s” and “an antibody specific for C1s” are used interchangeably herein with the term “an antibody which binds immunospecifically to C1s.”
  • the antibody binds specifically or preferentially to C1s, such as the active form of C1s over other proteins, such as, but not limited to, the inactive form of C1s (proC1s).
  • the degree of specificity necessary for an anti-C1s antibody may depend on the intended use of the antibody, and at any rate is defined by its suitability for use for an intended purpose.
  • the antibody, or binding compound derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen (active form of C1s), with an affinity that is at least two fold greater, at least ten times greater, at least 20-times greater, or at least 100- times greater than the affinity with any other antigen, including, but not limited to inactive C1s.
  • Percent identity between two peptide chains can be determined by pair wise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carlsbad, Calif.) or other suitable alignment software, such as BLAST.
  • the antibody, or antigen binding fragment thereof has, at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity to a sequence described herein.
  • the antibody has conservative substitutions as compared to a sequence described herein. Exemplary conservative substitutions are illustrated in Table 1 and are encompassed within the scope of the disclosed subject matter.
  • a variant comprises a substitution, deletions, or insertion. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions.
  • the substitutions can be conservative substitutions. In some embodiments, the substitution is non-conservative. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions. In some embodiments, the substitutions, deletions, or insertions are present in the CDRs provided for herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided for herein.
  • the term “in combination with” as used herein means that the described agents can be administered to an animal or subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.
  • the term “epitope” is meant to refer to that portion of any molecule capable of being recognized by and bound by an antibody at one or more of the Ab’s antigen binding regions. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three dimensional structural characteristics as well as specific charge characteristics [0069] “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
  • An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
  • Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., Sendai viruses, lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
  • the antibody is a monoclonal antibody which binds to C1s.
  • sequence of active C1s is as follows (SEQ ID NO: 56): Residues 1-15 (SEQ ID NO: 75) constitute the signal peptide which is cleaved during translation, and residues 16-688 (SEQ ID NO: 76) constitute the mature protein.
  • proC1s is a single chain 86,000 Da protein that is the native form of C1s proteins (e.g. serine protease).
  • C1s is a subunit of the C1 complex which is the first complement component in the cascade referred to as the classical pathway of complement.
  • ProC1s is an inactive zymogen until C1 is activated.
  • C1 complex binds to and is activated by antigen-antibody complexes (immune complexes) yielding C1r enzyme.
  • C1r enzyme in the C1 complex activates proC1s generating C1s enzyme.
  • C1 complex is a non-covalent calcium- dependent complex of one C1q, two C1r and two C1s molecules.
  • C1q binds through two or more of its six arms to the Fc domains of IgG or IgM.
  • the binding of multiple arms to immune complexes causes the two C1r proteins in the complex (protease zymogens) to activate producing two proteases that cleave and activate the two proC1s in the complex (Morikis, D. and Lambris, J.D. (2005)). This activation of proC1s is caused by cleavage into the two chain C1s enzyme with 58,000 and 28,000 dalton fragments.
  • the antibody comprises a Fc domain.
  • the Fc domain can be linked to the heavy or light chain of the antibody.
  • the Fc domain comprises a mutation to extend the half-life of the antibody.
  • the Fc domain comprises a mutation such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.
  • the constant region comprises a mutation at position at amino acid residue 428 relative to a wild-type human IgG constant domain, numbered according to the EU numbering index of Kabat.
  • an antibody comprising a mutation that corresponds to residue 428 can have an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain.
  • the mutation is a substitution of the native residue with a threonine, leucine, phenylalanine or serine.
  • the antibody further comprises one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the Kabat EU numbering index. The specific mutations or substitutions at these positions are described in U.S. Patent No.7,670,600, which is hereby incorporated by reference in its entirety. [0073] Other mutations can be used in the Fc domain, such as those provided for in U.S.
  • the Fc region is a variant Fc region comprising amino acid substitutions at positions 428 and 434, wherein the amino acid substitutions are a leucine that is not the wild-type amino acid at position 428 and a serine that is not the wild-type amino acid at position 434, wherein the polypeptide is an antibody and wherein numbering is according to the EU Index in Kabat et al.
  • the Fc region comprises a S228P, L235E, M428L, or N434S substitution.
  • the Fc region comprises a M428L substitution.
  • the Fc region comprises a N434S substitution.
  • the Fc region comprises a M428L and a N434S substitution. In some emboidments, the Fc region comprises a M252Y, S254T, and/or T256E substitution. [0074] In some embodiments, the antibody comprises a constant region as set forth below with or without the mutations provided for the list below.
  • the antibody comprises a constant region as set follows: >IgG4 S228P L235E LS-trunc ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVLHEALHSHYTQKSLSLSLG (SEQ ID NO: 57) >IgG4 S228P L235E YTE-t
  • the antibodies described herein are used to detect the presence of the antigen.
  • the present antibody can be used in any device or method to detect the presence of the antigen.
  • the antibodies are used to detect the active form of C1s.
  • the antibodies are used to detect the active form preferentially (specifically) over the inactive form of C1s.
  • the term “purified” with referenced to an antibody refers to an antibody that is substantially free of other material that associates with the molecule in its natural environment. For instance, a purified protein is substantially free of the cellular material or other proteins from the cell or tissue from which it is derived.
  • the term refers to preparations where the isolated protein is sufficiently pure to be analyzed, or at least 70% to 80% (w/w) pure, at least 80%-90% (w/w) pure, 90-95% pure; and, at least 95%, 96%, 97%, 98%, 99%, or 100% (w/w) pure.
  • the antibody is purified.
  • Antibody Conjugates [0080]
  • the antibodies provided for herein may also be conjugated to a chemical moiety.
  • the chemical moiety may be, inter alia, a polymer, a radionuclide or a cytotoxic factor. In some embodiments, this can be referred to as an antibody drug conjugate.
  • the chemical moiety is a polymer which increases the half-life of the antibody molecule in the body of a subject.
  • Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2kDa, 5 kDa, 10 kDa, 12kDa, 20 kDa, 30kDa or 40kDa), dextran and monomethoxypolyethylene glycol (mPEG).
  • PEG polyethylene glycol
  • mPEG monomethoxypolyethylene glycol
  • DTPA diethylenetriaminpentaacetic acid
  • chemical moieties include, but are not limited to, anti-mitotics, such as calicheamicins (e.g. ozogamicin), monomethyl auristatin E, mertansine, and the like.
  • Other exmaples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents and DNA minor groove binding agents. Other examples of are provided herein and below.
  • the chemical moiety can be linked to the antibody through a linking group (maleimide), a cleavable linker, such as a cathepsin cleavable linkers (valine-citrulline), and in some embodiments, one or more spacers (e.g. para- aminobenzylcarbamate).
  • a linking group maleimide
  • a cleavable linker such as a cathepsin cleavable linkers (valine-citrulline)
  • one or more spacers e.g. para- aminobenzylcarbamate
  • the antibodies and antibody fragments of the invention may also be conjugated with labels such as 99 Tc, 90 Y, 111 In, 32 P, 14 C, 125 I, 3 H, 131 I, 11 C, 15 O, 13 N, 18 F, 35 S, 51 Cr, 57 To, 226 Ra, 60 Co, 59 Fe, 57 Se, 152 Eu, 67 CU, 217 Ci, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, and 40 K, 157 Gd, 55 Mn, 52 Tr and 56 Fe.
  • labels such as 99 Tc, 90 Y, 111 In, 32 P, 14 C, 125 I, 3 H, 131 I, 11 C, 15 O, 13 N, 18 F, 35 S, 51 Cr, 57 To, 226 Ra, 60 Co, 59 Fe, 57 Se, 152 Eu, 67 CU, 217 Ci, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, and 40 K, 157 Gd, 55 Mn
  • the antibodies and antibody fragments may also be conjugated with fluorescent or chemiluminescent labels, including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin, phycocyanin, allophycocyanin, o-phthaladehyde, fluorescamine, 152 Eu, dansyl, umbelliferone, luciferin, luminal label, isoluminal label, an aromatic acridinium ester label, an imidazole label, an acridimium salt label, an oxalate ester label, an aequorin label, 2,3-dihydrophthalazinediones, biotin/avidin, spin labels and stable free radicals.
  • fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin,
  • the antibody molecules may also be conjugated to a cytotoxic factor such as diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dianthin proteins, Phytoiacca americana proteins PAPI, PAPII, and PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, and enomycin.
  • a cytotoxic factor such as diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dian
  • any method known in the art for conjugating the antibody molecules of the invention to the various moieties may be employed, including those methods described by Hunter, et al., (1962) Nature 144:945; David, et al., (1974) Biochemistry 13:1014; Pain, et al., (1981) J. Immunol. Meth.40:219; and Nygren, J., (1982) Histochem. and Cytochem.30:407. Methods for conjugating antibodies are conventional and very well known in the art.
  • antibodies e.g. an anti-C1s antibody
  • the antibody is a recombinant antibody that binds to C1s.
  • the antibody binds to the active form of C1s. In some embodiments, the antibody binds to active form preferentially over the inactive form of C1s. In some embodiments, the antibody binds to the active form with an affinity that is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200% higher as compared to its affinity for the inactive form of C1s.
  • the C1s protein is a human C1s protein, such as the active form of C1s. In some embodiments, the antibody does not specifically bind to the inactive form of the C1s protein.
  • the term “recombinant antibody” refers to an antibody that is not naturally occurring.
  • the term “recombinant antibody” refers to an antibody that is not isolated from a human subject. In some embodiments, the antibody binds with at least 100X more affinity to the active form of C1s as compared to proC1s.
  • an antibody, or antigen binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the following table, which illustrate the CDRs based on Kabat numbering. Table 2: Kabat CDRs Ab ID No HCDR1 HCDR2 HCDR3 LCDR1 LCDR2 LCDR3 [0087] The CDRs in the above-identified table can also be referred to according to Chothia CDRs or IMGT CDRs.
  • an antibody, or antibody binding fragment thereof comprises a heavy or light chain CDR as provided in the tables above.
  • an antibody, or antibody binding fragment thereof comprises a light chain LCDR having a sequence of SEQ ID NO: 12, 13, 14, 18, 19, 20, 24, 25, 26, 29, 30, 31, 34, 35, 36, 39, 40, 41, 45, , , 49, , , 53, ,, or a combination thereof.
  • the light chain LCDR comprises a sequence of SEQ ID NO: 12.
  • the light chain LCDR comprises a sequence of SEQ ID NO: 13.
  • the light chain LCDR comprises a sequence of SEQ ID NO: 14. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 18. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 19. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 20. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 24. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 25. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 26. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 29.
  • the light chain LCDR comprises a sequence of SEQ ID NO: 30. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 31. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 34. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 35. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 36. In some embodiments, the light chainLCDR comprises a sequence of SEQ ID NO: 39. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 40. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 41.
  • the light chain LCDR comprises a sequence of SEQ ID NO: 45. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 49. In some embodiments, the light chain LCDR comprises a sequence of SEQ ID NO: 53. In some embodiments, the light chain LCDR comprises a sequence that is a combination of one or more of SED ID NO: 12, 13, 14, 18, 19, 20, 24, 25, 26, 29, 30, 31, 34, 35, 36, 39, 40, 41, 45, 49, and 53.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain HCDR having a sequence of SEQ ID NO: 9, 10, 11, 15, 16, 17, 21, 22, 23, 27, 28, 32, 33, , 37, 38, , 42, 43, 44, 46, 47, 48, 50, 51, or 52.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 9.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 10.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 11.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 15.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 16.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 17. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 21. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 22. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 23. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 27. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 28. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 32. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 33.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 37. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 38. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 42. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 43. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 44. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 46. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 47. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 48.
  • the heavy chain HCDR comprises a sequence of SEQ ID NO: 50. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 51. In some embodiments, the heavy chain HCDR comprises a sequence of SEQ ID NO: 52. In some embodiments, the heavy chain HCDR comprises a sequence that is a combination of one or more of SEQ ID NO: 9, 10, 11, 15, 16, 17, 21, 22, 23, 27, 28, 32, 33, 37, 38, 42, 43, 44, 46, 47, 48, 50, 51, and 52. It is to be understood that the CDRs referenced in the embodiments throughout the present specification can be interchanged with the CDRs that are characterized by different formats, such as Chothia and IMGT, which are illustrated in the tables above.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 12, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 18, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 13, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 19, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 14.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 20.
  • an antibody, or antibody binding fragment thereof comprises a light chain variable region having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 24, the LCDR2 has a sequence of SEQ ID NO: 25, and the LCDR3 has a sequence of SEQ ID NO: 26.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 9, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 15, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 10, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 16, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 11.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 17.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain variable region having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 21, the HCDR2 has a sequence of SEQ ID NO: 22, and the HCDR3 has a sequence of SEQ ID NO: 23.
  • the following tables are provided depicting non-limiting exemplary combinations of light chain (Table 5) and heavy chain (Table 6) CDRs.
  • an antibody or antibody binding fragment thereof comprises: (i) a light chain having any one of the foregoing recited combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any one of the foregoing reited combinations of HCDR1, HCDR2, and HCDR3 sequences. The following combinations are provided with reference to Table 5 and 6 above.
  • an antibody or antibody binding fragment thereof comprising VLA and VHA is understood to comprise a light chain having a LCDR1 of SEQ ID NO: 12, a LCDR2 of SEQ ID NO: 13, a LCDR3 of SEQ ID NO: 14, a HCDR1 of SEQ ID NO: 9, a HCDR2 of SEQ ID NO: 10, and a HCDR3 of SEQ ID NO: 11.
  • an antibody or antibody binding fragment thereof comprises V L A and V H A.
  • an antibody or antibody binding fragment thereof comprises V L B and V H A.
  • an antibody or antibody binding fragment thereof comprises VLC and VHA.
  • an antibody or antibody binding fragment thereof comprises V L D and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and V H A.
  • an antibody or antibody binding fragment thereof comprises VLM and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H A.
  • an antibody or antibody binding fragment thereof comprises V L V and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H A. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and VHA. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H A. [00146] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H B.
  • an antibody or antibody binding fragment thereof comprises VLD and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and V H B.
  • an antibody or antibody binding fragment thereof comprises V L M and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHB.
  • an antibody or antibody binding fragment thereof comprises V L V and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H B. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLAB and VHB. [00147] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H C.
  • an antibody or antibody binding fragment thereof comprises V L D and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHC.
  • an antibody or antibody binding fragment thereof comprises VLM and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H C.
  • an antibody or antibody binding fragment thereof comprises VLV and VHC. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H C. In some embodiments, an antibody or antibody binding fragment thereof comprises VLAB and VHC. [00148] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHD.
  • an antibody or antibody binding fragment thereof comprises V L D and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and V H D.
  • an antibody or antibody binding fragment thereof comprises V L M and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H D.
  • an antibody or antibody binding fragment thereof comprises V L V and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHD. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H D. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H D. [00149] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHE.
  • an antibody or antibody binding fragment thereof comprises VLD and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and V H E.
  • an antibody or antibody binding fragment thereof comprises V L M and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LN and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHE.
  • an antibody or antibody binding fragment thereof comprises V L V and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H E. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHE. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L AB and V H E. [00150] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H F.
  • an antibody or antibody binding fragment thereof comprises VLD and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and VHF.
  • an antibody or antibody binding fragment thereof comprises V L M and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LO and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHF.
  • an antibody or antibody binding fragment thereof comprises VLV and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHF. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H F. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and VHF. [00151] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHG.
  • an antibody or antibody binding fragment thereof comprises V L D and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and VHG.
  • an antibody or antibody binding fragment thereof comprises VLM and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H G.
  • an antibody or antibody binding fragment thereof comprises VLV and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHG. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H G. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H G. [00152] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHH.
  • an antibody or antibody binding fragment thereof comprises VLD and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHH.
  • an antibody or antibody binding fragment thereof comprises VLM and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHH.
  • an antibody or antibody binding fragment thereof comprises V L V and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H H. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHH. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H H. [00153] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H I.
  • an antibody or antibody binding fragment thereof comprises VLD and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and V H I.
  • an antibody or antibody binding fragment thereof comprises V L M and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L O and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHI.
  • an antibody or antibody binding fragment thereof comprises VLV and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHI. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H I. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and VHI. [00154] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H J.
  • an antibody or antibody binding fragment thereof comprises V L D and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and VHJ.
  • an antibody or antibody binding fragment thereof comprises V L M and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LO and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H J.
  • an antibody or antibody binding fragment thereof comprises VLV and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H J. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and VHJ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H J. [00155] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHK.
  • an antibody or antibody binding fragment thereof comprises V L D and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHK.
  • an antibody or antibody binding fragment thereof comprises VLM and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H K.
  • an antibody or antibody binding fragment thereof comprises V L V and V H K. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and VHK. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H K. [00156] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H L.
  • an antibody or antibody binding fragment thereof comprises VLD and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and V H L.
  • an antibody or antibody binding fragment thereof comprises V L M and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L N and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises VLU and VHL.
  • an antibody or antibody binding fragment thereof comprises V L V and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and V H L. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHL. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAB and VHL. [00157] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L C and V H M.
  • an antibody or antibody binding fragment thereof comprises V L D and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and V H M.
  • an antibody or antibody binding fragment thereof comprises V L M and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H M.
  • an antibody or antibody binding fragment thereof comprises VLV and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHM. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H M. In some embodiments, an antibody or antibody binding fragment thereof comprises VLAB and VHM. [00158] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHN.
  • an antibody or antibody binding fragment thereof comprises V L D and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and VHN.
  • an antibody or antibody binding fragment thereof comprises VLM and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H N.
  • an antibody or antibody binding fragment thereof comprises V L V and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H N. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and VHN. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H N. [00159] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H O.
  • an antibody or antibody binding fragment thereof comprises V L C and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHO.
  • an antibody or antibody binding fragment thereof comprises V L L and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L O and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHO.
  • an antibody or antibody binding fragment thereof comprises V L U and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L V and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H O. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHO. In some embodiments, an antibody or antibody binding fragment thereof comprises VLAB and VHO. [00160] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHP.
  • an antibody or antibody binding fragment thereof comprises V L C and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L D and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHP.
  • an antibody or antibody binding fragment thereof comprises VLL and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L M and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L O and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHP.
  • an antibody or antibody binding fragment thereof comprises VLU and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L V and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHP. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H P. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and VHP. [00161] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHQ.
  • an antibody or antibody binding fragment thereof comprises VLC and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L D and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H Q.
  • an antibody or antibody binding fragment thereof comprises VLL and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H Q.
  • an antibody or antibody binding fragment thereof comprises VLU and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and VHQ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H Q. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H Q. [00162] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H R.
  • an antibody or antibody binding fragment thereof comprises VLC and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H R.
  • an antibody or antibody binding fragment thereof comprises V L L and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H R.
  • an antibody or antibody binding fragment thereof comprises V L U and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H R. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and VHR. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H R. [00163] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LA and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHS.
  • an antibody or antibody binding fragment thereof comprises V L C and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises V L F and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLH and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLK and VHS.
  • an antibody or antibody binding fragment thereof comprises V L L and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L M and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises VLN and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L O and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises V L R and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLT and VHS.
  • an antibody or antibody binding fragment thereof comprises V L U and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L V and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises VLW and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHS. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Y and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H S. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and VHS. [00164] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises VLB and VHT.
  • an antibody or antibody binding fragment thereof comprises VLC and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L D and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises VLE and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L G and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises VLI and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L J and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H T.
  • an antibody or antibody binding fragment thereof comprises VLL and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L M and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LN and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L P and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQ and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L S and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H T.
  • an antibody or antibody binding fragment thereof comprises VLU and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises V L V and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHT. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Z and V H T. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L AB and V H T. [00165] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H U.
  • an antibody or antibody binding fragment thereof comprises VLC and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H U.
  • an antibody or antibody binding fragment thereof comprises V L L and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H U.
  • an antibody or antibody binding fragment thereof comprises V L U and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHU. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H U. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H U. [00166] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H V.
  • an antibody or antibody binding fragment thereof comprises VLC and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H V.
  • an antibody or antibody binding fragment thereof comprises V L L and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H V.
  • an antibody or antibody binding fragment thereof comprises V L U and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHV. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H V. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H V. [00167] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H W.
  • an antibody or antibody binding fragment thereof comprises V L B and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHW.
  • an antibody or antibody binding fragment thereof comprises V L K and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHW.
  • an antibody or antibody binding fragment thereof comprises V L T and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHW. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H W. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H W.
  • an antibody or antibody binding fragment thereof comprises V- L A and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H X.
  • an antibody or antibody binding fragment thereof comprises V L I and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H X.
  • an antibody or antibody binding fragment thereof comprises VLR and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H X. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHX. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H X.
  • an antibody or antibody binding fragment thereof comprises V L AB and V H X. [00169] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H Y.
  • an antibody or antibody binding fragment thereof comprises V L I and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H Y.
  • an antibody or antibody binding fragment thereof comprises VLR and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H Y. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHY. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H Y.
  • an antibody or antibody binding fragment thereof comprises V L AB and V H Y. [00170] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L H and V H Z.
  • an antibody or antibody binding fragment thereof comprises V L I and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises V L L and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLM and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L N and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Q and V H Z.
  • an antibody or antibody binding fragment thereof comprises VLR and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLV and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises V L X and V H Z. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHZ. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZ and V H Z.
  • an antibody or antibody binding fragment thereof comprises V- L AB and V H Z. [00171] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L A and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L B and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLC and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLD and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L E and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLF and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLG and VHAB.
  • an antibody or antibody binding fragment thereof comprises V L H and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L I and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJ and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L K and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLL and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L M and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L N and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLO and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLP and VHAB.
  • an antibody or antibody binding fragment thereof comprises V L Q and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLR and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLS and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L T and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L U and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L V and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L W and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLX and VHAB. In some embodiments, an antibody or antibody binding fragment thereof comprises VLY and VHAB.
  • an antibody or antibody binding fragment thereof comprises V L Z and V H AB. In some embodiments, an antibody or antibody binding fragment thereof comprises V L AB and V H AB.
  • the different CDR motifs can be combined in any combination including those not depicted in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain LCDRl, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO: 12; the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 13; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 14 and (ii) a heavy chain variable region comprising heavy chain HCDR1, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 9; the heavy chain HCDR2 sequence has the amino acid sequence of SEQ ID NO: 10; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 11; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain LCDRl, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 19; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 20 and (ii) a heavy chain variable region comprising heavy chain HCDR1, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 15; the heavy chain HCDR2 sequence has the amino acid sequence of SEQ ID NO: 16; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 17; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain LCDRl, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO: 24; the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 25; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 26 and (ii) a heavy chain variable region comprising heavy chain HCDR1, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 21; the heavy chain HCDR2 sequence has the amino acid sequence of SEQ ID NO: 22; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 23; or variants of any of the foregoing.
  • an antibody or antibody binding fragment thereof comprises: (i) a light chain having any one of the foregoing recited combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any one of the foregoing reited combinations of HCDR1, HCDR2, and HCDR3 sequences.
  • an antibody or antibody binding fragment thereof comprising VLAa and VHAa is understood to comprise a light chain having a LCDR1 of SEQ ID NO: 45, a LCDR2 of SEQ ID NO: 30, a LCDR3 of SEQ ID NO: 14, a HCDR1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 43, and a HCDR3 of SEQ ID NO: 44.
  • an antibody or antibody binding fragment thereof comprises VLAa and VHAa.
  • an antibody or antibody binding fragment thereof comprises V L Ba and V H Aa.
  • an antibody or antibody binding fragment thereof comprises VLCa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fa and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and VHAa.
  • an antibody or antibody binding fragment thereof comprises V L Ka and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Oa and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and VHAa.
  • an antibody or antibody binding fragment thereof comprises VLSa and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Aa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHAa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Aa.
  • an antibody or antibody binding fragment thereof comprises V L ABa and V H Aa. [00179] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHBa.
  • an antibody or antibody binding fragment thereof comprises V L Ha and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ka and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHBa.
  • an antibody or antibody binding fragment thereof comprises V L Qa and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLTa and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ba. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xa and V H Ba.
  • an antibody or antibody binding fragment thereof comprises VLYa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZa and VHBa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ba. [00180] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ca and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ca.
  • an antibody or antibody binding fragment thereof comprises V L Fa and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ka and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHCa.
  • an antibody or antibody binding fragment thereof comprises V L Na and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Oa and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ca.
  • an antibody or antibody binding fragment thereof comprises VLWa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ya and V H Ca. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZa and VHCa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABa and VHCa. [00181] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ca and V H Da.
  • an antibody or antibody binding fragment thereof comprises V L Da and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ja and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Da.
  • an antibody or antibody binding fragment thereof comprises V L Ma and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Oa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHDa.
  • an antibody or antibody binding fragment thereof comprises V L Va and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHDa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Da. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABa and VHDa. [00182] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ea.
  • an antibody or antibody binding fragment thereof comprises VLCa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ea.
  • an antibody or antibody binding fragment thereof comprises V L Ka and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pa and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHEa.
  • an antibody or antibody binding fragment thereof comprises VLSa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xa and V H Ea. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHEa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZa and VHEa.
  • an antibody or antibody binding fragment thereof comprises V L ABa and V H Ea.In some embodiments, an antibody or antibody binding fragment thereof comprises VLAa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ca and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fa and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHFa.
  • an antibody or antibody binding fragment thereof comprises V L Ha and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNa and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Oa and V H Fa.
  • an antibody or antibody binding fragment thereof comprises VLPa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLTa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and V H Fa.
  • an antibody or antibody binding fragment thereof comprises V L Ya and V H Fa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZa and VHFa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABa and VHFa. [00183] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ca and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEa and VHGa.
  • an antibody or antibody binding fragment thereof comprises V L Fa and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ja and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNa and VHGa.
  • an antibody or antibody binding fragment thereof comprises V L Oa and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pa and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLTa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ga.
  • an antibody or antibody binding fragment thereof comprises VLXa and VHGa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ya and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ga. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABa and VHGa. [00184] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and V H Ha.
  • an antibody or antibody binding fragment thereof comprises V L Ea and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ja and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ha.
  • an antibody or antibody binding fragment thereof comprises VLNa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ha.
  • an antibody or antibody binding fragment thereof comprises V L Wa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xa and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHHa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ha. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ha. [00185] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHIa.
  • an antibody or antibody binding fragment thereof comprises VLDa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fa and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Ia.
  • an antibody or antibody binding fragment thereof comprises VLLa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHIa.
  • an antibody or antibody binding fragment thereof comprises V L Ta and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xa and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ya and V H Ia. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZa and VHIa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ia.
  • an antibody or antibody binding fragment thereof comprises V- LAa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ca and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fa and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHa and VHJa.
  • an antibody or antibody binding fragment thereof comprises V L Ia and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ja and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Oa and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHJa.
  • an antibody or antibody binding fragment thereof comprises VLQa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ra and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLTa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWa and VHJa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xa and V H Ja.
  • an antibody or antibody binding fragment thereof comprises V L Ya and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ja. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABa and VHJa. [00187] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Da and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEa and VHKa.
  • an antibody or antibody binding fragment thereof comprises VLFa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ga and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIa and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ja and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L La and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNa and VHKa.
  • an antibody or antibody binding fragment thereof comprises VLOa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pa and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sa and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWa and VHKa.
  • an antibody or antibody binding fragment thereof comprises VLXa and VHKa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ya and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ka. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ka. [00188] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHLa.
  • an antibody or antibody binding fragment thereof comprises V L Ea and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H La.
  • an antibody or antibody binding fragment thereof comprises V L Na and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H La.
  • an antibody or antibody binding fragment thereof comprises V L Wa and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHLa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H La. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H La. [00189] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHMa.
  • an antibody or antibody binding fragment thereof comprises VLDa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHMa.
  • an antibody or antibody binding fragment thereof comprises V L Ma and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ta and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHMa.
  • an antibody or antibody binding fragment thereof comprises V L Va and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHMa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ma. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ma. [00190] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Na.
  • an antibody or antibody binding fragment thereof comprises VLCa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Na.
  • an antibody or antibody binding fragment thereof comprises V L Ka and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHNa.
  • an antibody or antibody binding fragment thereof comprises VLSa and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Na. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHNa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Na.
  • an antibody or antibody binding fragment thereof comprises V L ABa and V H Na. [00191] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHOa.
  • an antibody or antibody binding fragment thereof comprises V L Ha and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHOa.
  • an antibody or antibody binding fragment thereof comprises VLPa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Oa.
  • an antibody or antibody binding fragment thereof comprises VLXa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHOa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Oa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Oa. [00192] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHPa.
  • an antibody or antibody binding fragment thereof comprises V L Ea and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Pa.
  • an antibody or antibody binding fragment thereof comprises V L Na and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Pa.
  • an antibody or antibody binding fragment thereof comprises V L Wa and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHPa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Pa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Pa. [00193] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHQa.
  • an antibody or antibody binding fragment thereof comprises VLDa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Qa.
  • an antibody or antibody binding fragment thereof comprises VLLa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Qa.
  • an antibody or antibody binding fragment thereof comprises V L Ta and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHQa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Qa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Qa.
  • an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ra.
  • an antibody or antibody binding fragment thereof comprises V L Ia and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ka and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHRa.
  • an antibody or antibody binding fragment thereof comprises V L Qa and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHRa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHRa.
  • an antibody or antibody binding fragment thereof comprises V L Za and V H Ra. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ra. [00195] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHSa.
  • an antibody or antibody binding fragment thereof comprises VLGa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHSa.
  • an antibody or antibody binding fragment thereof comprises VLPa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHSa.
  • an antibody or antibody binding fragment thereof comprises VLYa and VHSa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Sa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Sa. [00196] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ta.
  • an antibody or antibody binding fragment thereof comprises VLFa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ta.
  • an antibody or antibody binding fragment thereof comprises VLOa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ta.
  • an antibody or antibody binding fragment thereof comprises VLXa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHTa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ta. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ta. [00197] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHUa.
  • an antibody or antibody binding fragment thereof comprises V L Ea and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHUa.
  • an antibody or antibody binding fragment thereof comprises V L Ma and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Ua.
  • an antibody or antibody binding fragment thereof comprises VLUa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHUa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ua. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Ua. [00198] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Va.
  • an antibody or antibody binding fragment thereof comprises V L Ba and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHVa.
  • an antibody or antibody binding fragment thereof comprises VLJa and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Va.
  • an antibody or antibody binding fragment thereof comprises VLRa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHVa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHVa.
  • an antibody or antibody binding fragment thereof comprises V L Za and V H Va. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Va. [00199] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHWa.
  • an antibody or antibody binding fragment thereof comprises VLGa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Wa.
  • an antibody or antibody binding fragment thereof comprises VLOa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ta and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Wa.
  • an antibody or antibody binding fragment thereof comprises V L Wa and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHWa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Wa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Wa. [00200] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHXa.
  • an antibody or antibody binding fragment thereof comprises VLDa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Xa.
  • an antibody or antibody binding fragment thereof comprises VLLa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Xa.
  • an antibody or antibody binding fragment thereof comprises V L Ta and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHXa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Xa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Xa.
  • an antibody or antibody binding fragment thereof comprises V- L Aa and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H Ya.
  • an antibody or antibody binding fragment thereof comprises V L Ia and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Ya.
  • an antibody or antibody binding fragment thereof comprises VLRa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Ya. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHYa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Ya.
  • an antibody or antibody binding fragment thereof comprises V L ABa and V H Ya. [00202] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ea and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHZa.
  • an antibody or antibody binding fragment thereof comprises V L Ha and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJa and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ma and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHZa.
  • an antibody or antibody binding fragment thereof comprises VLPa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ua and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H Za.
  • an antibody or antibody binding fragment thereof comprises VLXa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHZa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H Za. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H Za. [00203] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Aa and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ba and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDa and VHABa.
  • an antibody or antibody binding fragment thereof comprises V L Ea and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ha and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ia and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ja and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ka and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLa and VHABa.
  • an antibody or antibody binding fragment thereof comprises V L Ma and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Na and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qa and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Sa and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ta and V H ABa.
  • an antibody or antibody binding fragment thereof comprises VLUa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Va and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wa and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYa and VHABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Za and V H ABa. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABa and V H ABa. [00204] The equivalent CDRs may also be used from the CHOTHIA designation.
  • an antibody or antibody binding fragment thereof comprises: (i) a light chain having any one of the foregoing recited combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any one of the foregoing reited combinations of HCDR1, HCDR2, and HCDR3 sequences.
  • an antibody or antibody binding fragment thereof comprising VLAb and VHAb is understood to comprise a light chain having a LCDR1 of SEQ ID NO: 29, a LCDR2 of SEQ ID NO: 30, a LCDR3 of SEQ ID NO: 31, a HCDR1 of SEQ ID NO: 27, a HCDR2 of SEQ ID NO: 28, and a HCDR3 of SEQ ID NO: 11.
  • an antibody or antibody binding fragment thereof comprises VLAb and VHAb.
  • an antibody or antibody binding fragment thereof comprises V L Bb and V H Ab.
  • an antibody or antibody binding fragment thereof comprises VLCb and VHAb.
  • an antibody or antibody binding fragment thereof comprises VLDb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Ab.
  • an antibody or antibody binding fragment thereof comprises VLLb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ob and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Sb and V H Ab.
  • an antibody or antibody binding fragment thereof comprises V L Tb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHAb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Ab. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and VHAb.
  • an antibody or antibody binding fragment thereof comprises V- L Ab and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Cb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Db and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Gb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHb and VHBb.
  • an antibody or antibody binding fragment thereof comprises VLIb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pb and V H Bb.
  • an antibody or antibody binding fragment thereof comprises V L Qb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHBb.
  • an antibody or antibody binding fragment thereof comprises VLYb and VHBb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Bb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Bb. [00208] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Db and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Cb.
  • an antibody or antibody binding fragment thereof comprises VLFb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Cb.
  • an antibody or antibody binding fragment thereof comprises V L Nb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Cb.
  • an antibody or antibody binding fragment thereof comprises VLVb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Cb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZb and VHCb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Cb. [00209] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Db.
  • an antibody or antibody binding fragment thereof comprises V L Cb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and VHDb.
  • an antibody or antibody binding fragment thereof comprises V L Kb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ob and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Db.
  • an antibody or antibody binding fragment thereof comprises V L Sb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LTb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHDb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Yb and V H Db. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZb and VHDb.
  • an antibody or antibody binding fragment thereof comprises VLABb and VHDb.
  • an antibody or antibody binding fragment thereof comprises V- L Ab and V H Eb.
  • an antibody or antibody binding fragment thereof comprises VLBb and VHEb.
  • an antibody or antibody binding fragment thereof comprises V L Cb and V H Eb.
  • an antibody or antibody binding fragment thereof comprises V L Db and V H Eb.
  • an antibody or antibody binding fragment thereof comprises VLEb and VHEb.
  • an antibody or antibody binding fragment thereof comprises V L Fb and V H Eb.
  • an antibody or antibody binding fragment thereof comprises V L Gb and V H Eb.
  • an antibody or antibody binding fragment thereof comprises VLHb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ob and V H Eb.
  • an antibody or antibody binding fragment thereof comprises V L Pb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Eb.
  • an antibody or antibody binding fragment thereof comprises VLXb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHEb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Eb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABb and VHEb. [00211] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Db and V H Fb.
  • an antibody or antibody binding fragment thereof comprises V L Eb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Gb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LKb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHFb.
  • an antibody or antibody binding fragment thereof comprises V L Mb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Fb.
  • an antibody or antibody binding fragment thereof comprises V L Ub and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Fb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZb and VHFb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Fb. [00212] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAb and VHGb.
  • an antibody or antibody binding fragment thereof comprises V L Bb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Cb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHGb.
  • an antibody or antibody binding fragment thereof comprises VLJb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ob and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Gb.
  • an antibody or antibody binding fragment thereof comprises V L Rb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Gb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Yb and V H Gb.
  • an antibody or antibody binding fragment thereof comprises VLZb and VHGb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABb and VHGb. [00213] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Cb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Db and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fb and V H Hb.
  • an antibody or antibody binding fragment thereof comprises V L Gb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLKb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNb and VHHb.
  • an antibody or antibody binding fragment thereof comprises V L Ob and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- LTb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Hb.
  • an antibody or antibody binding fragment thereof comprises V L Wb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHHb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Yb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Hb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABb and VHHb. [00214] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHIb.
  • an antibody or antibody binding fragment thereof comprises V L Db and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Gb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and VHIb.
  • an antibody or antibody binding fragment thereof comprises VLLb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sb and V H Ib.
  • an antibody or antibody binding fragment thereof comprises V L Tb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHIb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Ib. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Ib.
  • an antibody or antibody binding fragment thereof comprises V- LAb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Fb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Jb.
  • an antibody or antibody binding fragment thereof comprises V L Ib and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHJb.
  • an antibody or antibody binding fragment thereof comprises V L Qb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLVb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Jb.
  • an antibody or antibody binding fragment thereof comprises V L Yb and V H Jb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLZb and VHJb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Jb. [00216] In some embodiments, an antibody or antibody binding fragment thereof comprises V- LAb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Cb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEb and VHKb.
  • an antibody or antibody binding fragment thereof comprises V L Fb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Gb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLHb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLMb and VHKb.
  • an antibody or antibody binding fragment thereof comprises VLNb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ob and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Rb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Sb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Kb.
  • an antibody or antibody binding fragment thereof comprises VLVb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWb and VHKb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Xb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Yb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Kb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLABb and VHKb. [00217] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLBb and VHLb.
  • an antibody or antibody binding fragment thereof comprises VLCb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Db and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLEb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Gb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLIb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Jb and V H Lb.
  • an antibody or antibody binding fragment thereof comprises VLKb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Lb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLNb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Pb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLQb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHLb.
  • an antibody or antibody binding fragment thereof comprises V L Sb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ub and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLWb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHLb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Yb and V H Lb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Lb.
  • an antibody or antibody binding fragment thereof comprises V L ABb and V H Lb. [00218] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHMb.
  • an antibody or antibody binding fragment thereof comprises V L Hb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Jb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHMb.
  • an antibody or antibody binding fragment thereof comprises VLPb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Sb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Mb.
  • an antibody or antibody binding fragment thereof comprises VLXb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHMb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Mb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Mb. [00219] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHNb.
  • an antibody or antibody binding fragment thereof comprises V L Eb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHNb.
  • an antibody or antibody binding fragment thereof comprises V L Mb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Nb.
  • an antibody or antibody binding fragment thereof comprises VLUb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHNb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Nb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Nb. [00220] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Ob.
  • an antibody or antibody binding fragment thereof comprises V L Bb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHOb.
  • an antibody or antibody binding fragment thereof comprises VLJb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Ob.
  • an antibody or antibody binding fragment thereof comprises VLRb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHOb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHOb.
  • an antibody or antibody binding fragment thereof comprises V L Zb and V H Ob. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Ob. [00221] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHPb.
  • an antibody or antibody binding fragment thereof comprises VLGb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Kb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Pb.
  • an antibody or antibody binding fragment thereof comprises VLOb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Pb.
  • an antibody or antibody binding fragment thereof comprises V L Wb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHPb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Pb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Pb. [00222] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHQb.
  • an antibody or antibody binding fragment thereof comprises VLDb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Qb.
  • an antibody or antibody binding fragment thereof comprises VLLb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Qb.
  • an antibody or antibody binding fragment thereof comprises V- L Tb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHQb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Qb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Qb.
  • an antibody or antibody binding fragment thereof comprises V- L Ab and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Rb.
  • an antibody or antibody binding fragment thereof comprises V L Ib and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHRb.
  • an antibody or antibody binding fragment thereof comprises V L Qb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHRb.
  • an antibody or antibody binding fragment thereof comprises VLYb and VHRb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Rb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Rb. [00224] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Sb.
  • an antibody or antibody binding fragment thereof comprises VLFb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Kb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Sb.
  • an antibody or antibody binding fragment thereof comprises V L Nb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHSb.
  • an antibody or antibody binding fragment thereof comprises V L Vb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHSb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Sb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Sb. [00225] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Tb.
  • an antibody or antibody binding fragment thereof comprises VLCb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Tb.
  • an antibody or antibody binding fragment thereof comprises V L Kb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHTb.
  • an antibody or antibody binding fragment thereof comprises VLSb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Tb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHTb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Tb.
  • an antibody or antibody binding fragment thereof comprises V L ABb and V H Tb. [00226] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHUb.
  • an antibody or antibody binding fragment thereof comprises V L Hb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHUb.
  • an antibody or antibody binding fragment thereof comprises VLPb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Ub.
  • an antibody or antibody binding fragment thereof comprises VLXb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHUb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Ub. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Ub. [00227] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHVb.
  • an antibody or antibody binding fragment thereof comprises V L Eb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHVb.
  • an antibody or antibody binding fragment thereof comprises V L Mb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Vb.
  • an antibody or antibody binding fragment thereof comprises VLUb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHVb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Vb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Vb. [00228] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Wb.
  • an antibody or antibody binding fragment thereof comprises V L Bb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHWb.
  • an antibody or antibody binding fragment thereof comprises V- L Jb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Wb.
  • an antibody or antibody binding fragment thereof comprises VLRb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Sb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHWb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHWb.
  • an antibody or antibody binding fragment thereof comprises V L Zb and V H Wb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Wb. [00229] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHXb.
  • an antibody or antibody binding fragment thereof comprises VLGb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Xb.
  • an antibody or antibody binding fragment thereof comprises VLOb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Tb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Xb.
  • an antibody or antibody binding fragment thereof comprises V L Wb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHXb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Xb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Xb. [00230] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHYb.
  • an antibody or antibody binding fragment thereof comprises VLDb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Yb.
  • an antibody or antibody binding fragment thereof comprises VLLb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Yb.
  • an antibody or antibody binding fragment thereof comprises V- L Tb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHYb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Yb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Yb.
  • an antibody or antibody binding fragment thereof comprises V- L Ab and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLFb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H Zb.
  • an antibody or antibody binding fragment thereof comprises V L Ib and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLJb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Nb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHZb.
  • an antibody or antibody binding fragment thereof comprises V L Qb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLSb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Vb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHZb.
  • an antibody or antibody binding fragment thereof comprises VLYb and VHZb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H Zb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H Zb. [00232] In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Ab and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Bb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLCb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLDb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Eb and V H ABb.
  • an antibody or antibody binding fragment thereof comprises VLFb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLGb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Hb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Ib and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Jb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Kb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLLb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Mb and V H ABb.
  • an antibody or antibody binding fragment thereof comprises V L Nb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLOb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLPb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Qb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLRb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V- L Sb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Tb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLUb and VHABb.
  • an antibody or antibody binding fragment thereof comprises V L Vb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Wb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLXb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises VLYb and VHABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L Zb and V H ABb. In some embodiments, an antibody or antibody binding fragment thereof comprises V L ABb and V H ABb. [00233] In some embodiments, the light chain variable region LCDR1 is replaced with any of the other light chain LCDR1 sequences.
  • the light chain variable region LCDR2 is replaced with any of the other light chain LCDR2 sequences. In some embodiments, the light chain variable region LCDR3 is replaced with any of the other light chain LCDR3 sequences. In some embodiments, the heavy chain variable region HCDR1 is replaced with any of the other heavy chain HCDR1 sequences. In some embodiments, the heavy chain variable region HCDR2 is replaced with any of the other heavy chain HCDR2 sequences. In some embodiments, the heavy chain variable region HCDR3 is replaced with any of the other heavy chain HCDR3 sequences.
  • any LCDR1, LCDR2, and LCDR3 pairing from any of the Kabat, IMGT, or CHOTHIA designations may be paired with any HCDR1, HCDR2, and HCDR3 pairing from any of the Kabat, IMGT, or CHOTHIA designations.
  • an antibody or antibody fragment may comprise V L A and any one of VHA, VHB, VHC, VHD, VHE, VHF, VHG, VHH, VHI, VHJ, VHK, VHL, VHM, VHN, V H O, V H P, V H Q, V H R, V H S, V H T, V H U, V H V, V H W, V H X, V H Y, V H Z, V H AB, V H Aa, V H Ba, V H Ca, V H Da, V H Ea, V H Fa, V H Ga, V H Ha, V H Ia, V H Ja, V H Ka, V H La, V H Ma, V H Na, V H Oa, V H Pa, VHQa, VHRa, VHSa, VHTa, VHUa, VHVa, VHWa, VHXa, VHYa, VHZa, VHABa, VHAb, VHBb
  • VLA V L B, V L C, V L D, V L E, V L F, V L G, V L H, V L I, V L J, V L K, V L L, V L M, V L N, V L O, V L P, V L Q, V L R, V L S, V L T, V L U, V L V, V L W, V L X, V L Y, V L Z, V L AB, V L Aa, V L Ba, V L Ca, V L Da, VLEa, VLFa, VLGa, VLHa, VLIa, VLJa, VLKa, VLLa, VLMa, VLNa, VLOa, VLPa, VLQa, VLRa, V L Sa, V L Ta, V L Ua, V L Va, V L Wa
  • an antibody or antigen-binding fragment thereof is provided, wherein the HCDR1, HCDR2, and HCDR3 are selected from SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively, from SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 11, resepectively, or from SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44, respectively, and the LCDR1, LCDR2, and LCDR3 are selected from SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively, from SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31, respectively, or from SEQ ID NO: 45, SEQ ID NO: 30, and SEQ ID NO: 14 respectively.
  • an antibody or antigen-binding fragment thereof is provided, wherein the HCDR1, HCDR2, and HCDR3 are selected from SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, from SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 17, resepectively, or from SEQ ID NO: 46, SEQ ID NO: 47, and SEQ ID NO: 48, respectively, and the LCDR1, LCDR2, and LCDR3 are selected from SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, from SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, or from SEQ ID NO: 49, SEQ ID NO: 35, and SEQ ID NO: 20 respectively.
  • an antibody or antigen-binding fragment thereof is provided, wherein the HCDR1, HCDR2, and HCDR3 are selected from SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, respectively, from SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 23, resepectively, or from SEQ ID NO: 50, SEQ ID NO: 51, and SEQ ID NO: 52, respectively, and the LCDR1, LCDR2, and LCDR3 are selected from SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26, respectively, from SEQ ID NO: 39, SEQ ID NO: 40, and SEQ ID NO: 41, respectively, or from SEQ ID NO: 53, SEQ ID NO: 40, and SEQ ID NO: 26 respectively.
  • the antibody comprises a heavy chain variable region peptide having one of the following sequences, or a variant thereof: Table 11: SEQ ID NO: AB ID NO. Sequence 1 MAB1 QVQLVQSGAEVKKPGASVKVSCKVSGDTLTELSMHWVRQ SEQ ID NO: AB ID NO. Sequence 5 MAB3 EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQA [00239] In some embodiments, the antibody comprises a light chain variable region peptide having one of the following sequences, or a variant thereof: Table 12: SEQ ID NO: AB ID NO.
  • an antibody, or antigen binding fragment thereof comprises a sequence selected from one or more of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or any variants thereof.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide of SEQ ID NO: 1, 3, or 5, or any variant thereof.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide having at least 85% identitiy to SEQ ID NO: 1, 3, or 5.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, 3, or 5.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide of SEQ ID NO: 1, 3, or 5.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide of SEQ ID NO: 1.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide having at least 85% identitiy to SEQ ID NO: 1.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide of SEQ ID NO: 3.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide having at least 85% identitiy to SEQ ID NO: 3.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 3.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide of SEQ ID NO: 5.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide having at least 85% identitiy to SEQ ID NO: 5.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide of SEQ ID NO: 2, 4, or 6, or any variant thereof.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide having at least 85% identitiy to SEQ ID NO: 2, 4, or 6.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 2, 4, or 6.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide of SEQ ID NO: 2, 4, or 6.
  • an antibody, or antigen binding fragment thereof comprises a VL peptide of SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a VL peptide having at least 85% identitiy to SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a VL peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide of SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a VL peptide having at least 85% identitiy to SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a VL peptide of SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide having at least 85% identitiy to SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the wherein the V H peptide comprises a sequence of SEQ ID NO: 1, 3, or 5 or a variant thereof; and the V L peptide comprises a sequence of SEQ ID NO: 2, 4, or 6 or a variant thereof.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide and a VL peptide, wherein the wherein the V H peptide has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 1, 3, or 5; and the VL peptide has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitiy to SEQ ID NO: 2, 4, or 6.
  • the V H peptide comprises a sequence of SEQ ID NO: 1, 3, or 5; and the V L peptide comprises a sequence of SEQ ID NO: 2, 4, or 6.
  • the heavy chain of the antibody or antigen binding fragment thereof comprises a heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 1, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO: 11 or SEQ ID NO: 44, maintains a LCDR1 sequence of SEQ ID NO: 12, SEQ ID NO: 29, or SEQ
  • the heavy chain of the antibody or antigen binding fragment thereof comprises a heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 3, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO: 17 or SEQ ID NO: 48, maintains a LCDR1 sequence of SEQ ID NO: 18, SEQ ID NO: 34, or SEQ ID NO: 49, maintains a LCDR2 sequence of SEQ ID NO: 19, or SEQ ID NO: 35, and maintains a LCDR3 sequence SEQ ID NO: 20, or SEQ ID
  • the heavy chain of the antibody or antigen binding fragment thereof comprises a heavy chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 5, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of SEQ ID NO: 23 or SEQ ID NO: 52, maintains a LCDR1 sequence of SEQ ID NO: 24, SEQ ID NO: 39, or SEQ ID NO: 53, maintains a LCDR2 sequence of SEQ ID NO: 25, or SEQ ID NO: 40, and maintains a LCDR3 sequence SEQ ID NO: 26, or SEQ
  • the light chain of the antibody or antigen binding fragment thereof comprises a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 2, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO: 11 or SEQ ID NO: 44, maintains a LCDR1 sequence of SEQ ID NO: 12, SEQ ID NO: 29, or SEQ ID NO: 45, maintains a LCDR2 sequence of SEQ ID NO: 13, or SEQ ID NO: 30, and maintains a LCDR3 sequence SEQ ID NO: 14, or SEQ ID NO: 31
  • the light chain of the antibody or antigen binding fragment thereof comprises a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 4, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO: 17 or SEQ ID NO: 48, maintains a LCDR1 sequence of SEQ ID NO: 18, SEQ ID NO: 34, or SEQ ID NO: 49, maintains a LCDR2 sequence of SEQ ID NO: 19, or SEQ ID NO: 35, and maintains a LCDR3 sequence SEQ ID NO: 20, or SEQ
  • the light chain of the antibody or antigen binding fragment thereof comprises a light chain variable region having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 6, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of SEQ ID NO: 23 or SEQ ID NO: 52, maintains a LCDR1 sequence of SEQ ID NO: 24, SEQ ID NO: 39, or SEQ ID NO: 53, maintains a LCDR2 sequence of SEQ ID NO: 25, or SEQ ID NO: 40, and maintains a LCDR3 sequence SEQ ID NO: 26, or SEQ
  • the VH and the VL sequences can be in any format, including, but not limited to an scFv format where the VH and VL regions are linked with a peptide linker.
  • peptide linkers that can be used to link various peptides provided for herein include, but are not limited to: (GGGGS)n (SEQ ID NO: 54); (GGGGA)n (SEQ ID NO: 55), or any combination thereof, wherein each n is independently 1-5.
  • each n is, independently, 1.
  • each n is, independently, 2.
  • each n is, independently, 3.
  • each n is, independently, independently, independently, 4.
  • each n is, independently, 5.
  • the variable regions are not linked with a peptide linker.
  • the antibody comprises SEQ ID NO: 1 and SEQ ID NO: 2.
  • the antibody comprises SEQ ID NO: 3 and SEQ ID NO: 4.
  • the antibody comprises SEQ ID NO: 5 and SEQ ID NO: 6.
  • the different peptides (V H or V L ) described herein can be linked with a peptide linker or not linked with a peptide linker and instead form a contiguous sequence.
  • the heavy chain variable region and the light chain variable region are not linked by a linker.
  • the heavy chain variable region and the light chain variable region are linked via a peptide linker.
  • the peptide linker comprises a sequence of (GGGGS)n (SEQ ID NO: 54); (GGGGA)n (SEQ ID NO: 55), or any combination thereof, wherein each n is independently 1-5.
  • each n is, independently, 1.
  • each n is, independently, 2.
  • each n is, independently, 3.
  • each n is, independently, 4.
  • each n is, independently, 5.
  • the linked peptide format can be represented by a formula of V H -Z-V L or V L -Z-V H , wherein Z is the peptide linker.
  • Z is (GGGGS) n (SEQ ID NO: 54); (GGGGA) n (SEQ ID NO: 55), or any combination thereof, wherein each n is independently 1-5.
  • each n is, independently, 1.
  • each n is, independently, 2.
  • each n is, independently, 3.
  • each n is, independently, 4.
  • each n is, independently, independently, 5.
  • the VH and VL polypeptides are linked to a Fc region, such as “IgG4 S228P L235E LS” or “IgG4 S228P L235E YTE”.
  • the Fc region is as provided for herein.
  • the Fc region is “IgG4 S228P L235E LS”.
  • the Fc region is “IgG4 S228 L235E YTE”.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 1, 3, or 5, and the VL peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 2, 4, or 6.
  • the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 1.
  • the V H peptide comprises a sequence of SEQ ID NO: 1.
  • the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 3.
  • the V H peptide comprises a sequence of SEQ ID NO: 3. In some embodiments, the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 5. In some embodiments, the V H peptide comprises a sequence of SEQ ID NO: 5.
  • the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 2.
  • the V L peptide comprises a sequence of SEQ ID NO: 2.
  • the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 4.
  • the V L peptide comprises a sequence of SEQ ID NO: 4. In some embodiments, the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 6. In some embodiments, the VL peptide comprises a sequence of SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 1, 3, or 5, and the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 2, 4, or 6 provided that the VH peptide and a VL peptide comprises a light chain LCDR having a sequence of SEQ ID NO: 12, 13, 14, 18, 19, 20, 24, 25, 26, 29, 30, 31, 34, 35, 36, 39, 40, 41, 45, 49, or 53; and/or a
  • an antibody, or antigen binding fragment thereof comprises a VH peptide and a VL peptide, wherein the VH peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 1, 3, or 5, and the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 2, 4, or 6 provided that the V L peptide comprises a LCDR1 having a sequence selected from SEQ ID NO: 12, 18, 24, 29, 34, 39, 45, 49, or 53;
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 1, 3, or 5, and the V L peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence of SEQ ID NO: 2, 4, or 6, provided that the VL peptide comprises a LCDR1 having a sequence selected from SEQ ID NO: 12, 18, 24, 29, 34, 39, 45, 49, or 53, wherein the LCDR1 comprises at most 1 conservative amino acid substitution, a LCDR2 having a sequence selected from SEQ ID NO:
  • the antibody or antigen-binding fragment fragment thereof comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region of the light chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 1, the heavy chain variable region of the heavy chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 2, and wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO:
  • the antibody or antigen-binding fragment fragment thereof comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region of the light chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 3, the heavy chain variable region of the heavy chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 4, and wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO:
  • the antibody or antigen-binding fragment fragment thereof comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region of the light chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 5, the heavy chain variable region of the heavy chain has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 6, and wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of
  • an antibody, or antigen binding fragment thereof comprises a VH peptide and a VL peptide, wherein the VH peptide comprises a sequence of SEQ ID NO: 1 and the V L peptide comprises a sequence of SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide and a VL peptide, wherein the VH peptide comprises a sequence of SEQ ID NO: 1 and the VL peptide comprises a sequence of SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a VH peptide and a VL peptide, wherein the VH peptide comprises a sequence of SEQ ID NO: 1 and the VL peptide comprises a sequence of SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 3 and the VL peptide comprises a sequence of SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 3 and the VL peptide comprises a sequence of SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 3 and the VL peptide comprises a sequence of SEQ ID NO: 6.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 5 and the VL peptide comprises a sequence of SEQ ID NO: 2.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 5 and the VL peptide comprises a sequence of SEQ ID NO: 4.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence of SEQ ID NO: 5 and the V L peptide comprises a sequence of SEQ ID NO: 6.
  • the antibody comprises a heavy chain as set forth below, which includes the variable region and the constant domain: Table 13: SEQ ID NO: AB ID NO. Sequence 66 MAB1 ith n t nt QVQLVQSGAEVKKPGASVKVSCKVSGDTLTELSMHWVRQ SEQ ID NO: AB ID NO.
  • the antibody comprises a light chain as set forth below, which includes the variable region and a constant domain, such as the human kappa constant domain: Table 14: SEQ ID NO: AB ID NO.
  • Sequence 72 MAB1 lus ka a DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKL
  • the antibody or antigen binding fragment thereof of any of the embodiments as provided for herein may comprise any constant domain known, such as but not limited to an IgG constant domain.
  • the constant domain is as provided for herein.
  • the constant domain is selected from the group including, but not limited to, SEQ ID NO: 7, 8, 57, 58, 65, or a variant thereof as provided for herein.
  • the constant domain has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to a sequence selected from the group including, but not limited to, SEQ ID NO: 7, 8, 57, 58, 65, or a variant thereof as provided for herein.
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB1.
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO: 11 or SEQ ID NO: 44, maintains a LCDR1 sequence of SEQ ID NO: 12, SEQ ID NO: 29, or SEQ ID NO: 45, maintains a LCDR2 sequence of SEQ ID NO: 13, or SEQ ID NO: 30, and maintains a LCDR3 sequence SEQ ID NO: 14, or SEQ
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB2.
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO: 17 or SEQ ID NO: 48, maintains a LCDR1 sequence of SEQ ID NO: 18, SEQ ID NO: 34, or SEQ ID NO: 49, maintains a LCDR2 sequence of SEQ ID NO: 19, or SEQ ID NO: 35, and maintains a LCDR3 sequence SEQ ID NO:
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB3.
  • the antibody, or antigen-binding fragment thereof comprises a heavy chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of SEQ ID NO: 23 or SEQ ID NO: 52, maintains a LCDR1 sequence of SEQ ID NO: 24, SEQ ID NO: 39, or SEQ ID NO: 53, maintains a LCDR2 sequence of SEQ ID NO: 25, or SEQ ID NO: 40, and maintains a LCDR3 sequence SEQ ID NO:
  • the antibody, or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:72, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB1.
  • the antibody, or antigen- binding fragment thereof comprises a light chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 72, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO: 11 or SEQ ID NO: 44, maintains a LCDR1 sequence of SEQ ID NO: 12, SEQ ID NO: 29, or SEQ ID NO: 45, maintains a LCDR2 sequence of SEQ ID NO: 13, or SEQ ID NO: 30, and maintains a LCDR3 sequence SEQ ID NO: 14, or SEQ ID NO: 31.
  • the antibody, or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:73, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB2.
  • the antibody, or antigen- binding fragment thereof comprises a light chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 73, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO: 17 or SEQ ID NO: 48, maintains a LCDR1 sequence of SEQ ID NO: 18, SEQ ID NO: 34, or SEQ ID NO: 49, maintains a LCDR2 sequence of SEQ ID NO: 19, or SEQ ID NO: 35, and maintains a LCDR3 sequence SEQ ID NO: 20, or SEQ ID NO: 36
  • the antibody, or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:74, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB3.
  • the antibody, or antigen- binding fragment thereof comprises a light chain that has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 74, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of SEQ ID NO: 23 or SEQ ID NO: 52, maintains a LCDR1 sequence of SEQ ID NO: 24, SEQ ID NO: 39, or SEQ ID NO: 53, maintains a LCDR2 sequence of SEQ ID NO: 25, or SEQ ID NO: 40, and maintains a LCDR3 sequence SEQ ID NO: 26, or SEQ ID NO: 41
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:72, and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67 (HC of MAB1), wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB1.
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:72, and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 9, SEQ ID NO: 27, or SEQ ID NO: 42, maintatins a HCDR2 sequence of SEQ ID NO: 10, SEQ ID NO: 28, or SEQ ID NO: 43, maintains a HCDR3 sequence of SEQ ID NO: 11 or SEQ ID NO: 44, maintains a LCDR1 sequence of SEQ ID NO: 12, SEQ ID NO: 29, or SEQ ID NO: 45, maintains a LCDR2 sequence of SEQ ID NO:
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:73, and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB2.
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:73, and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 15, SEQ ID NO: 32, or SEQ ID NO: 46, maintatins a HCDR2 sequence of SEQ ID NO: 16, SEQ ID NO: 33, or SEQ ID NO: 47, maintains a HCDR3 sequence of SEQ ID NO: 17 or SEQ ID NO: 48, maintains a LCDR1 sequence of SEQ ID NO: 18, SEQ ID NO: 34, or SEQ ID NO: 49, maintains a LCDR2 sequence of
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:74 (LC of MAB3), and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains the sequences of the heavy chain and light chain CDRs of MAB3.
  • the antibody or antigen-binding fragment thereof comprises a light chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:74, and a heavy chain that has at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO:70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains a HCDR1 sequence of SEQ ID NO: 21, SEQ ID NO: 37, or SEQ ID NO: 50, maintatins a HCDR2 sequence of SEQ ID NO: 22, SEQ ID NO: 38, or SEQ ID NO: 51, maintains a HCDR3 sequence of SEQ ID NO: 23 or SEQ ID NO: 52, maintains a LCDR1 sequence of SEQ ID NO: 24, SEQ ID NO: 39, or SEQ ID NO: 53, maintains a LCDR2 sequence of
  • the antibody, or antigen-binding fragment thereof comprises a light chain having a sequence of SEQ ID NO:72 and a heavy chain that comprises a sequence of SEQ ID NO: 66 or SEQ ID NO: 67.
  • the antibody, or antigen-binding fragment thereof comprises a light chain having a sequence of SEQ ID NO:73 and a heavy chain that comprises a sequence of SEQ ID NO: 68 or SEQ ID NO: 69.
  • the antibody, or antigen-binding fragment thereof comprises a light chain having a sequence of SEQ ID NO:74 and a heavy chain that comprises a sequence of SEQ ID NO: 70 or SEQ ID NO: 71.
  • the antibodies, or antigen binding fragments thereof can be variants of the sequences. Accordingly, in some embodiments, a variant of an antibody or antigen binding fragment thereof provided for herein is provided. In some embodiments, the variant comprises mutations selected from substitutions, deletions, insertions, or a combination thereof. In some embodiments, the variant comprises between 1 and 20 mutations. In some embodiments, the variant comprises between 1 and 10 mutations.
  • the variant comprises between 1 and 5 mutations. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mutations. In some embodiments, the variant comprises at least 1 mutation. Accordingly, in some embodiments, the variant comprises up to or more than 20 mutations. In some embodiments, the variant comprises 1-10 mutations, wherein the mutations are selected from substitutions, deletions, insertions, or a combination thereof. In some embodiments, the variant comprises 1-10 mutations, wherein the mutations are conservative substitutions. Examples of conservative substitutions are as provided for herein (Table 1). Further, one of skill in the art will recognize and understand the substutions that are encompassed by the term “conservative substitutions”.
  • the antibody or antigen binding fragment may comprise an antibody fragment as defined and provided for herein. In some embodiments, the antibody binding fragment is as provided for herein. In some embodiments, the antibody fragment is a scFv antibody, a Fab fragment, a Fab’ fragment, or a F(ab’) 2 fragment. In some embodiments, the antibody fragment is a scFv antibody. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is a Fab’ fragment. In some embodiments, the antibody fragment is a F(ab’) 2 fragment. [00284] The sequences of the antibodies can be modified to yield human IgG antibodies.
  • the conversion of the sequences provided herein can be modified to yield other types of antibodies.
  • the CDRs can also be linked to other antibodies, proteins, or molecules to create antibody fragments that bind C1s. This can be in the form of an antibody drug conjugate (“ADC”), or a multi-specific molecule.
  • ADC antibody drug conjugate
  • the sequences can also be made into chimeric antibodies as described herein.
  • the antibody comprises an amino acid sequence comprising a sequence provided for herein or a fragment thereof.
  • the antibody is a monoclonal antibody.
  • the antibody is a polyclonal antibody.
  • the antibody is a humanized antibody.
  • the antibody comprises one or more amino acid sequences as provided herein, an antigen binding fragments, thereof, or a human IgG variant thereof.
  • a human IgG variant thereof refers to an antibody that has been modified to be a human IgG when the starting antibody is not a human IgG antibody.
  • a nucleic acid molecule encoding an antibody or fragment thereof is provided.
  • the nucleic acid encodes a sequence provided for herein.
  • the antibodies can also be modified to be chimeric antibodies or human antibodies.
  • the antibodies can also be used in injectable pharmaceutical compositions.
  • the antibodies can be isolated antibodies or engineered antibodies.
  • an isolated nucleic acid molecule is provided.
  • the nucleic acid molecule encodes for an antibody, or antigen binding fregament thereof as provided for herein.
  • the nucleic acid molecule encodes for an antibody, or antigen binding fregament thereof comprising a heavy chain variable region, a light chain variable region, a heavy chain, a light chain or any combination thereof as provided for herein.
  • the nucleic acid molecule encoding the variable heavy chain is as set forth below: Table 15: SEQ ID NO: AB ID NO.
  • nucleic acid molecule encoding the variable light chain is as set forth below: Table 16: SEQ ID NO: AB ID NO. Sequence 60 MAB1 GACATACAAATGACTCAATCACCCTCTACACTTTCCGCCT [00289] In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 59, SEQ ID NO: 61, or SEQ ID NO: 63.
  • the nucleic acid molecule comprises a sequence of SEQ ID NO: 59. In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 61. In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 63. In some embodiments, a nucleic acid molecule is provided that comprises a sequence of SEQ ID NO: 60, SEQ ID NO: 62, or SEQ ID NO: 64. In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 60. In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 62. In some embodiments, the nucleic acid molecule comprises a sequence of SEQ ID NO: 64.
  • sequences of SEQ ID NO. 59, 60, 61, 62, 63, and 64 are exemplary sequences and are not meant to be limiting in any way. Due to the degenerate nature of codons, other nucleic acid molecules can be used.
  • the nucleic acid molecule is codon optimized for expression in a bacterial system.
  • the nucleic acid molecule is codon optimized for expression in a eukaryotic system or cell.
  • the nucleic acid molecule is a DNA or RNA molecule that encodes a polypeptide as provided for herein.
  • the RNA molecule is a mRNA molecule. Accordingly, in some embodiments, the nucleic acid molecule comprises a sequence that is substantially similar to SEQ ID NO: 59, SEQ ID NO: 61, or SEQ ID NO: 63. In some embodiments, the nucleic acid molecule comprises a sequence that has at least 60% % identity to SEQ ID NO: 59, SEQ ID NO: 61, or SEQ ID NO: 63.
  • the nucleic acid molecule comprises a sequence that has at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 59, SEQ ID NO: 61, or SEQ ID NO: 63, or any percent identity falling within any of the recited percent identities.
  • the nucleic acid molecule comprises a sequence that is substantially similar to SEQ ID NO: 60, SEQ ID NO: 62, or SEQ ID NO: 64.
  • the nucleic acid molecule comprises a sequence that has at least 60% % identity to SEQ ID NO: 60, SEQ ID NO: 62, or SEQ ID NO: 64.
  • the nucleic acid molecule comprises a sequence that has at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 60, SEQ ID NO: 62, or SEQ ID NO: 64, or any percent identity falling within any of the recited percent identities.
  • an expression vector is provided.
  • the expression vector comprises a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof as provided for herein.
  • the expression vector comprises a nucleic acid molecule as provided for herein.
  • the vector may be any vector known in the art. In some embodiments the vector is as provided for herein.
  • the vector is a plasmid. In some embodiments the vector is a virus.
  • “derivatives” of the antibodies, fragments, regions or derivatives thereof, which term includes those proteins encoded by truncated or modified genes to yield molecular species functionally resembling the immunoglobulin fragments are provided.
  • the modifications include, but are not limited to, addition of genetic sequences coding for cytotoxic proteins such as plant and bacterial toxins.
  • the modification can also include a reporter protein, such as a fluorescent or chemiluminescent tag.
  • the fragments and derivatives can be produced in any manner.
  • the identification of these antibodies, or antigen binding fragments thereof, provide the information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility that parallel the embodiments of this application.
  • the antibodies can be generated according the examples provided herein. Once the sequences are known, the antibodies can also be generated according to known methods. The antibodies can also be converted to different types, such as being converted to Human IgGs and the like. By converting the antibodies to a human antibody, a human subject should not identify the antibodies as foreign. The conversion of a non-human IgG antibody to a human IgG antibody is well known and can routinely be done once the native sequence is known. As discussed herein, the antibodies can be modified according to known methods.
  • a host cell comprises an antibody or antigen-binding fragment thereof as provided for herein.
  • the host cell comprises a nucleic acid molecule encoding for antibody or antigen- binding fragment thereof as provided for herein.
  • the host cell comprises nucleic acid molecules selected from the group including, but not limited to, SEQ ID NO.59, 60, 61, 62, 63, 64, any variats thereof as provided for herein, or any combination thereof.
  • the host cell comprises a vector, said vector comprising comprises a nucleic acid molecule encoding for antibody or antigen-binding fragment thereof as provided for herein.
  • the vector comprises nucleic acid molecules selected from the group including, but not limited to, SEQ ID NO.59, 60, 61, 62, 63, 64, any variats thereof as provided for herein, or any combination thereof.
  • the host cell produces an antibody or antigen-binding fragment thereof as provided for herein.
  • an antibody or antigen-binding fragment thereof as provided for herein is provided, wherein the antibody or antigen-binding fragment thereof as provided for herein is produced by the host cell.
  • a method of producing a polypeptide is provided.
  • the polypeptide comprises a heavy chain variable region as provided for herein, a light chain variable region as provided for herein, or a combination thereof.
  • the method comprises growing a host cell under conditions so that the host cell expresses the polypeptide comprising the heavy chain variable region, light chain variable region, or combination thereof, and purifying the polypeptide comprising the heavy chain variable region, the light chain variable region, or a combination thereof, thereby producing the polypeptide.
  • the host cell is a host cell as provided for herein.
  • a method of producing an antibody or antigen binding fragment thereof is provided.
  • the antibody binds human C1s.
  • the antigen binding fragment binds human C1s.
  • the method comprises growing a host cell under conditions so that the host cell expresses a polypeptide or polypeptides comprising the immunoglobulin heavy chain variable region and/or the immunoglobulin light chain variable region, thereby producing the antibody or the antigen binding fragment of the antibody, and purifying the antibody or the antigen binding fragment of the antibody.
  • the polypeptide or polypeptides comprise the immunoglobulin heavy chain variable region.
  • the polypeptide or polypeptides comprise the immunoglobulin light chain variable region.
  • the polypeptide or polypeptides comprise the immunoglobulin heavy chain variable region and the immunoglobulin light chain variable region.
  • the host cell is a host cell as provided for herein.
  • the antibody or antigen binding fragment thereof is as provided for herein.
  • the polypeptide or antibody-producing cell contributing the nucleotide sequences encoding the antigen-binding region of the chimeric antibody can also be produced by transformation of a non-human, such as a primate, or a human cell.
  • a B lymphocyte which produces the antibody can be infected and transformed with a virus such as Epstein-Barr virus to yield an immortal antibody producing cell (Kozbor et al., Immunol. Today 4:72 79 (1983)).
  • the B lymphocyte can be transformed by providing a transforming gene or transforming gene product, as is well-known in the art.
  • the cell fusions are accomplished by standard procedures well known to those skilled in the field of immunology, such as producing cells can also be a hybridoma which is generated by fusing a B-cell with an immortal myeloma cell. Fusion partner cell lines and methods for fusing and selecting hybridomas and screening for mAbs are well known in the art. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.
  • the nucleic acid sequence encoding an antibody described herein can be genomic DNA or cDNA, or RNA (e.g. mRNA) which encodes at least one of the variable regions described herein.
  • RNA e.g. mRNA
  • a convenient alternative to the use of chromosomal gene fragments as the source of DNA encoding the V region antigen-binding segment is the use of cDNA for the construction of chimeric immunoglobulin genes, e.g., as reported by Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), which references are hereby entirely incorporated herein by reference.
  • cDNA requires that gene expression elements appropriate for the host cell be combined with the gene in order to achieve synthesis of the desired protein.
  • the use of cDNA sequences is advantageous over genomic sequences (which contain introns), in that cDNA sequences can be expressed in bacteria or other hosts which lack appropriate RNA splicing systems.
  • a cDNA encoding a V region antigen-binding segment able to detect, bind, to or neutralize C1s can be provided using known methods based on the use of the amino acid sequences provided herein. Because the genetic code is degenerate, more than one codon can be used to encode a particular amino acid (Watson, et al., infra).
  • oligonucleotides can be identified, each of which would be capable of encoding the amino acid.
  • the probability that a particular oligonucleotide will, in fact, constitute the actual XXX-encoding sequence can be estimated by considering abnormal base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic or prokaryotic cells expressing an antibody or fragment.
  • Such “codon usage rules” are disclosed by Lathe, et al., J. Molec. Biol. 183:1 12 (1985).
  • variable regions described herein can be combined with any type of constant region including a human constant region or murine constant region.
  • Human genes which encode the constant (C) regions of the antibodies, fragments and regions can be derived from a human fetal liver library, by known methods. Human C region genes can be derived from any human cell including those which express and produce human immunoglobulins.
  • the human C H region can be derived from any of the known classes or isotypes of human H chains, including gamma, ⁇ , ⁇ , ⁇ or ⁇ , and subtypes thereof, such as G1, G2, G3 and G4. Since the H chain isotype is responsible for the various effector functions of an antibody, as well as antibody recycling by interaction with FcRn, the choice of CH region will be guided by the desired effector functions, such as complement fixation, or activity in antibody-dependent cellular cytotoxicity (ADCC).
  • the CH region is derived from gamma 1 (IgG1), gamma 3 (IgG3), gamma 4 (IgG4), or ⁇ (IgM).
  • the human CL region can be derived from either human L chain isotype, kappa or lambda.
  • Methods of purifying polypeptides or proteins are known in the art, and any such method is within the scope of the present application. Further, the host cell is not limited by the examples recited above. Any suitable cell may be used to generate the polypeptides or proteins of the present disclosure.
  • Pharmaceutical Compositions [00304] In some embodiments, a pharmaceutical composition is provided. In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof as provided for herein.
  • the antibody or antigen binding fragment thereof or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).
  • Formulations of therapeutic or the antibodies provided herein may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al.
  • the antibodies are diluted to an appropriate concentration in a sodium acetate solution pH 5-6, and NaCl or sucrose is added for tonicity. Additional agents, such as polysorbate 20 or polysorbate 80, may be added to enhance stability.
  • Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index (LD50/ ED50).
  • antibodies exhibiting high therapeutic indices are desirable.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • a composition is administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).
  • the mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.
  • the composition is an injectable pharmaceutical composition.
  • the composition is formulated for intravenous or subcutaneous injection. In some embodiments, the composition is formulated for intravenous injection. In some embodiments, the composition id formulated for subcutaneous injection.
  • the antibody or antigen binding fragment thereof can be administered by an invasive route such as by injection. In some embodiments, the antibodies or antigen binding fragment thereof, or pharmaceutical composition thereof, is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g. in arthritis joints), intratumorally, or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., orally; for example, in a pill, capsule or tablet) is also within the scope of the present embodiments.
  • the anti-C1s antibody, or antigen binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to any therapeutic used to treat the disorders provided for herein.
  • the antibody is administered in combination with another treatment for the disorders provided for herein.
  • Compositions can be administered with medical devices known in the art.
  • a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.
  • the pharmaceutical compositions may also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent Nos.
  • compositions may also be administered by infusion.
  • implants and modules form administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No.
  • one may administer the antibody in a targeted drug delivery system for example, in a liposome coated with a tissue-specific antibody, targeting, for example, arthritic joint or pathogen-induced lesion characterized by immunopathology.
  • the liposomes will be targeted to and taken up selectively by the afflicted tissue.
  • the administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix.
  • the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects. Accordingly, the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated.
  • Determination of the appropriate dose can be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced.
  • a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent.
  • chimeric, humanized and fully human antibodies are may be desirable.
  • Antibodies or antigen binding fragments thereof can be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, or quarterly.
  • a total weekly dose is generally at least 0.05 ⁇ g/kg body weight, more generally at least 0.2 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.25 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 5.0 mg/ml, 10 mg/kg, 25 mg/kg, 50 mg/kg or more (see, e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych.
  • Doses may also be provided to achieve a pre-determined target concentration of the antibody in the subject’s serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300 ⁇ g/ml or more.
  • a fully human antibody is administered subcutaneously or intravenously, on a weekly, biweekly, “every 4 weeks,” monthly, bimonthly, or quarterly basis at 10, 20, 50, 80, 100, 200, 500, 1000 or 2500 mg/subject.
  • inhibitor or “treat” or “treatment” includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder.
  • the terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.
  • terapéuticaally effective amount refers to an amount of the antibody, or antigen binding fragment thereof, that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition.
  • a therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a therapeutically effective dose refers to that ingredient alone.
  • a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • An effective amount of a therapeutic will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%.
  • An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity.
  • an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate tumors or gastric tumors.
  • subject as used throughout includes any organism, such as an animal, including a mammal (e.g., rat, mouse, dog, cat, rabbit) and, for example, a human.
  • the subject is a human.
  • a subject can also be referred to as a patient.
  • the subject is a subject in need thereof.
  • a subject that is “in need thereof” refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition.
  • the conditions can be, for example, any of the conditions described herein.
  • the methods comprise administering a therapeutically or prophylactically effective amount of one or more antibodies or antigen binding fragments of the antibodies described herein to a susceptible subject or to one exhibiting a condition in which C1s is known to have caused the pathology observed.
  • Any active form of the antibody can be administered, including, but not limited to scFv, Fab and F(ab')2 fragments and other forms of antibodies provided for herein.
  • the present disclosure provides a method to treat an individual having a complement- mediated disease or disorder, the method comprising administering to the individual an anti-C1s antibody of any of the embodiments disclosed herein or a pharmaceutical composition thereof.
  • the individual is a mammal.
  • the individual is a human.
  • the administering is intravenous.
  • the administering is intrathecal.
  • the administering results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho- Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition, (i) a reduction in glial cell loss; (j) a reduction in oligodendrocyte loss; (k) a reduction in dendritic cell infiltration; (l) a reduction in neutrophil infiltration; (m) a reduction in red blood cell lysis; (n) a reduction in red blood cell phagocytosis; (o) a reduction in platelet phagocytosis
  • the reduction in glial cell activation comprises reduction in astrocyte activation or reduction in microglia activation.
  • a method of treating a subject with a C1s mediated disorder comprises administering to the subject an antibody or antigen-binding fragment thereof as provided for herein or a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as provided for herein, thereby treating the C1s mediated disorder.
  • the an antibody or antigen-binding fragment thereof of any of the embodiments provided for herein or the pharmaceutical compositions of any of the embodiments provided for herein inhibit complement C1s activity in an individual having a complement-mediated disease or disorder.
  • the individual is a mammal.
  • the individual is a human.
  • the administering is intravenous.
  • the administering is intrathecal.
  • the administering results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho-Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition, (i) a reduction in glial cell loss; (j) a reduction in oligodendrocyte loss; (k) a reduction in dendritic cell infiltration; (l) a reduction in neutrophil infiltration; (m) a reduction in red blood cell lysis; (n) a reduction in red blood cell phagocytosis; (o) a reduction in platelet phagocytos
  • the reduction in glial cell activation comprises reduction in astrocyte activation or reduction in microglia activation.
  • the C1s mediated disorder is selected from the group including, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease.
  • the C1s mediated disorder is Immune Thrombocytopenia (ITP).
  • the C1s mediated disorder is Myastenia Gravis. In some embodiments, the C1s mediated disorder is Glomerulopaties. In some embodiments, the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection. [00325] In some embodiments, the antibody or antigen-binding fragment thereof of any of the embodiments as provided for herein, or a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any of the embodiments as provided for herein is for the use in the treatment of a complement-mediated disease or disorder. .
  • the complement-mediated disorder is selected from the group including, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease.
  • the C1s mediated disorder is Immune Thrombocytopenia (ITP).
  • the C1s mediated disorder is Myastenia Gravis.
  • the C1s mediated disorder is Glomerulopaties.
  • the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection. In some embodiments, the C1s mediated disorder is selected from the group including, but not limited to, hemolysis and Cold Agglutinin Disease. In some embodiments, the C1s mediated disorder is hemolysis. In some embodiments, the C1s mediated disorder is Cold Agglutinin Disease. [00326] The present disclosure provides use of an anti-C1s antibody of any of the embodiments in the manufacture of a medicament for the treatment of an individual having a complement- mediated disease or disorder.
  • an antibody or binding fragment thereof or a pharmaceutical composition is provided for use as a medicament.
  • an antibody or binding fragment thereof is provided for use as a medicament.
  • a pharmaceutical composition is procided for use as a medicament.
  • the antibody or binding fragment thereof is an antibody or antigen binding fragment as provided for herein.
  • the pharmaceutical composition comprises an antibody or antigen binding fragment as provided for herein.
  • the pharmaceutical composition is as provided for herein.
  • the medicament is for use in treatment of a C1s mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease.
  • the C1s mediated disorder is Immune Thrombocytopenia (ITP).
  • the C1s mediated disorder is Myastenia Gravis.
  • the C1s mediated disorder is Glomerulopaties.
  • the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection. [00327] In some embodiments, a use of an antibody or antigen binding fragment as provided for herein or a pharmaceutical composition as provided for herein is provided. In some embodiments, the use is for the treatment of a C1a mediated disorder. In some embodiments, a use of an antibody or antigen binding fragment as provided for herein is provided, the use for the treatment of a C1a mediated disorder.
  • a use of a pharmaceutical composition comprising an antibody or antigen binging fragment as provided for herein is provided, the use for the treatment of a C1a mediated disorder.
  • the pharmaceutical composition is as provided for herein.
  • the antibody of any of the embodiments or pharmaceutical compositions thereof inhibit complement C1s activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease. In some embodiments, the C1s mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the C1s mediated disorder is Myastenia Gravis. In some embodiments, the C1s mediated disorder is Glomerulopaties. In some embodiments, the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection.
  • ITP Immune Thrombocytopenia
  • the C1s mediated disorder is Myastenia Gravis.
  • the C1s mediated disorder is Glomerulopaties.
  • the C1s mediated disorder is Atypical Hemolytic uremic syndrome.
  • the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection.
  • the present disclosure provides use of an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting complement C1s activity.
  • the present disclosure provides use of an anti- C1s antibody of any of the embodiments or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting complement C1s activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the present disclosure provides an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof for use in medical therapy.
  • the present disclosure provides an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof for treating an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease.
  • the C1s mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the C1s mediated disorder is Myastenia Gravis. In some embodiments, the C1s mediated disorder is Glomerulopaties. In some embodiments, the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection. [00331] The present disclosure provides an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof for inhibiting complement C1s protein activity.
  • the present disclosure provides an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof for inhibiting complement C1s protein activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • the C1s mediated disorder is hemolysis.
  • the C1s mediated disorder is Cold Agglutinin Disease.
  • the C1s mediated disorder is Immune Thrombocytopenia (ITP).
  • the C1s mediated disorder is Myastenia Gravis. In some embodiments, the C1s mediated disorder is Glomerulopaties. In some embodiments, the C1s mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the C1s mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the C1s mediated disorder is transplant rejection.
  • the present disclosure provides a method to diagnose a complement-mediated disease or disorder in an individual, the method comprising: (a) determining the amount of a complement C1s protein in a biological sample obtained from the individual, wherein the step of determining comprises: (i) contacting the biological sample with an anti-C1s antibody of any of the embodiments; and (ii) quantitating binding of the antibody to complement C1s protein present in the sample; and (b) comparing the amount of the complement C1s protein to a normal control value that indicates the amount of complement C1s protein in a normal control individual, wherein a significant difference between the amount of C1s protein in the biological sample and the normal control value indicates that the individual has a complement-mediated disease or disorder.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the present disclosure provides a method to monitor progression of a complement- mediated disease or disorder in an individual, the method comprising: (a) determining a first amount of complement a C1s protein in a biological sample obtained from the individual at a first time point; (b) determining a second amount of complement a C1s protein in a biological sample obtained from the individual at a second time point; and (c) comparing the second amount of complement C1s protein with the first amount of complement C1s protein.
  • the steps of determining comprise: (i) contacting the biological sample with an anti-C1s antibody of any of the embodiments; and (ii) quantitating binding of the antibody to complement C1s protein present in the sample.
  • the first time point is a time point before initiation of a treatment regimen
  • the second time point is a time point after initiation of a treatment regimen.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the present disclosure provides an in vitro method to detect complement C1s protein in a biological sample obtained from an individual, the method comprising: (a) contacting the biological sample with an anti-C1s antibody of any of the embodiments; and (b) detecting binding of the antibody to complement C1s protein present in the sample.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the method is quantitative.
  • the present disclosure provides a method to detect complement C1s protein in a living individual in vivo, the method comprising: (a) administering to the individual an anti-C1s antibody of any of the embodiments; and (b) detecting binding of the antibody to complement C1s protein in the individual using an imaging method.
  • the binding is detected in the individual at a site altered by a complement-mediated disease or disorder.
  • the binding is detected in the brain of the individual.
  • the antibody comprises a contrast agent suitable for use in the imaging method.
  • the imaging method is selected from the group consisting of magnetic resonance imaging, positron emission tomography, and IVIS instrumentation. In some embodiments, the method is quantitative.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and a cellular sample.
  • the methods of the present disclosure provide that the individual is suspected of having a complement-mediated disease or disorder, has been diagnosed as having a complement-mediated disease or disorder, or has a genetic predisposition to developing a complement-mediated disease or disorder.
  • the present disclosure provides a composition comprising: (a) an anti-C1s antibody of any of the embodiments; and (b) a solution comprising one or more agents that maintain an organ or a tissue intended for transplantation into a recipient individual.
  • the solution is an organ preservation solution or a tissue preservation solution.
  • the solution is an organ perfusion solution or a tissue perfusion solution.
  • the solution comprises: i) a salt; ii) an agent that reduces edema; iii) an oxygen free radical scavenger; and iii) an energy supply system component.
  • the composition comprises potassium lactobionate, KH2PO4, MgSO4, raffinose, adenosine, glutathione, allopurinol, and/or hydroxyethyl starch.
  • the present disclosure provides an organ or tissue preservation solution comprising an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof.
  • the present disclosure provides an organ or tissue perfusion solution comprising an anti-C1s antibody of any of the embodiments or a pharmaceutical composition thereof.
  • the present disclosure provides a method for maintaining an organ or tissue for transplant, the method comprising contacting the organ or the tissue with a composition comprising: (a) an anti-C1s antibody of any of the embodiments; and (b) an organ or tissue preservation solution of any of the embodiments or an organ or tissue perfusion solution of any of the embodiments.
  • a composition comprising: (a) an anti-C1s antibody of any of the embodiments; and (b) an organ or tissue preservation solution of any of the embodiments or an organ or tissue perfusion solution of any of the embodiments.
  • the organ is selected from the group consisting of an eye, a heart, an intestine, a kidney, a liver, a lung, a pancreas, a stomach, and a thymus.
  • the tissue is selected from the group consisting of bone, bone marrow, cornea, heart valve, islet of Langerhans, tendon, skin, and vein.
  • the antibodies can be provided in a kit, such as those provided herein.
  • the antibodies can be used or administered alone or in admixture with another therapeutic, analgesic, or diagnostic agent, such as provided for herein.
  • another therapeutic, analgesic, or diagnostic agent such as provided for herein.
  • the dosage of administered agent will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, previous medical history, etc.
  • An antibody, capable treating a condition associated with C1s activity or use to treat a C1s related pathology is intended to be provided to subjects in an amount sufficient to affect a reduction, resolution, or amelioration in the C1s related symptom or pathology.
  • kits are also provided which are useful for carrying out embodiments described herein.
  • the present kits can comprise a first container containing or packaged in association with the above-described antibodies.
  • the kit may also comprise another container containing or packaged in association solutions necessary or convenient for carrying out the embodiments.
  • the containers can be made of glass, plastic or foil and can be a vial, bottle, pouch, tube, bag, etc.
  • the kit may also contain written information, such as procedures for carrying out the embodiments or analytical information, such as the amount of reagent contained in the first container means.
  • the container may be in another container apparatus, e.g. a box or a bag, along with the written information.
  • antibodies that bind to a C1s protein are provided.
  • the antibodies are antibodies or antigen binding fragments as provided for herein.
  • the antibodies or antigen binding fragments comprise an amino acid sequence as provided for herein, or a variant thereof as provided for herein. In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically to the active form of C1s. [00350] In some embodiments, the antibody inhibits or neutralizes the function of an active form of C1s protein. As used herein, the term “neutralize” means that the activity or function of the protein is inhibited. The inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The percent inhibition can be based upon the function or activity of the protein in the absence of the antibody.
  • the antibody inhibits the function facilitated by C1s.
  • the following embodiments are provided.
  • An antibody, or an antigen binding fragment thereof, wherein the antibody or antibody fragment comprises: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 9; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 10 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 11 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 12; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 13; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO
  • an antibody, or an antigen binding fragment thereof comprising: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 27; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 28 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 11 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 29; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing; (b) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain
  • an antibody, or an antigen binding fragment thereof comprising: (a) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 42; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 43 and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 44 or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2, and LCDR3 sequences, wherein the light chain LCDR1 sequence has the amino acid sequence SEQ ID NO: 45; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 14; or variants of any of the foregoing; (b) a heavy chain variable region comprising heavy chain HCDRl, HCDR2, and HCDR3 sequences, wherein the heavy chain
  • HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, respectively, from SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 11, respectively, and from SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, respectively, and the LCDR1, LCDR2 and LCDR3 are selected from from SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, respectively, from SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, respectively, and from SEQ ID NO: 45, SEQ ID NO: 30, SEQ ID NO: 14, respectively; or b.
  • the HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, respectively, from SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 17, respectively, and from SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, respectively, and the LCDR1, LCDR2 and LCDR3 are selected from from SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, respectively, from SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, respectively, and from SEQ ID NO: 49, SEQ ID NO: 35, SEQ ID NO: 20, respectively; or c.
  • the HCDR1, HCDR2 and HCDR3 are selected from SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, respectively, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 23, respectively, and SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, respectively, and the LCDR1, LCDR2 and LCDR3 are selected from SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, respectively, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, respectively, and SEQ ID NO: 53, SEQ ID NO: 40, SEQ ID NO: 26, respectively. 5.
  • the heavy chain comprises: a. a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:1, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b. a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:3, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart b of any one of embodiments 1-4; or c.
  • the light chain comprises: a. a light chain variable region having at least 90% sequence identity to SEQ ID NO:2, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b.
  • the antibody or antigen-binding fragment thereof of any one of embodiments 1-4, wherein the antibody or antigen binding fragment thereof comprises: a.
  • a light chain variable region of the light chain having at least 90% sequence identity to SEQ ID NO:2 and a heavy chain variable region of the heavy chain having at least 90% sequence identity to SEQ ID NO:1, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b.
  • a light chain variable region of the light chain having at least 90% sequence identity to SEQ ID NO:4 and a heavy chain variable region of the heavy chain having at least 90% sequence identity to SEQ ID NO:3, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart b of any one of embodiments 1-4; or c.
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b.
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart b of any one of embodiments 1-4; or c.
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart c of any one of embodiments 1-4.
  • the light chain comprises: a. the light chain has at least 90% sequence identity to SEQ ID NO:72, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b.
  • the light chain has least 90% sequence identity to SEQ ID NO:73, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart b of any one of embodiments 1-4; or c.
  • the light chain has at least 90% sequence identity to SEQ ID NO:74, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart c of any one of embodiments 1-4.
  • the light chain has at least 90% sequence identity to SEQ ID NO:72
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:66 or SEQ ID NO: 67, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart a of any one of embodiments 1-4; or b.
  • the light chain has at least 90% sequence identity to SEQ ID NO:73
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:68 or SEQ ID NO: 69, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart b of any one of embodiments 1-4; or c.
  • the light chain has at least 90% sequence identity to SEQ ID NO:74
  • the heavy chain has at least 90% sequence identity to SEQ ID NO:70 or SEQ ID NO: 71, wherein the antibody or antigen binding fragment thereof maintains the sequences of HCDR1, HCDR2, HCDR2, LCDR1, LCD2, and LCDR3 set forth in subpart c of any one of embodiments 1-4. 12.
  • the light chain comprises SEQ ID NO:72, and the heavy chain comprises SEQ ID NO: 66 or SEQ ID NO: 67; the light chain comprises SEQ ID NO:73, and the heavy chain comprises SEQ ID NO: 68 or SEQ ID NO: 69; or the light chain comprises SEQ ID NO:74, and the heavy chain comprises SEQ ID NO: 70 or SEQ ID NO: 71; 13.
  • the antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody is a monoclonal antibody. 15. The antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody is a humanized antibody. 16. The antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof comprises the sequence selected from one or more of the following sequences: SEQ ID NO: 1; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5, SEQ ID NO: 6, or a variant thereof. 17.
  • the antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody, or antigen binding fragment thereof, comprises a V L peptide of SEQ ID NOs: 2, 4, or 6, or any variant thereof. 18.
  • the antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody, or antigen binding fragment thereof, comprises a V H peptide of SEQ ID NOs: 1, 3, or 5, or any variant thereof.
  • the antibody or antigen binding fragment thereof of any one of the preceding embodiments, wherein the antibody, or antigen binding fragment thereof comprises a constant region as provided for herein. 20.
  • the isolated nucleic acid sequence of embodiment 26 comprising SEQ ID NO:59, SEQ ID NO:61, or SEQ ID NO:63. 28.
  • the isolated nucleic acid sequence of embodiment 27 comprising SEQ ID NO:59. 29.
  • the isolated nucleic acid sequence of embodiment 26 comprising SEQ ID NO:60, SEQ ID NO:62, or SEQ ID NO:64.
  • the isolated nucleic acid sequence of embodiment 29 comprising SEQ ID NO:60.
  • An expression vector comprising the nucleic acid molecule of any one of embodiments 26-30.
  • a host cell comprising the nucleic acid molecule of any one of embodiments 26-30 or the vector of embodiment 31.
  • a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, of any one of embodiments 1-25.
  • 35. The pharmaceutical composition of embodiment 34, wherein the composition is formulated for intravenous or subcutaneous injection.
  • 36. The pharmaceutical composition of embodiment 34, wherein the composition is an injectable pharmaceutical composition.
  • 37. A method of producing a polypeptide comprising a heavy chain variable region or light chain variable region, the method comprising: (a) growing the host cell of embodiment 32 under conditions so that the host cell expresses the polypeptide comprising the heavy chain variable region or the light chain variable region; and (b) purifying the polypeptide comprising the heavy chain variable region or the light chain variable region. 38.
  • a method of producing an antibody that binds human C1s, or an antigen binding fragment of the antibody comprising: (a) growing the host cell of embodiment 32 under conditions so that the host cell expresses a polypeptide or polypeptides comprising the immunoglobulin heavy chain variable region and/or the immunoglobulin light chain variable region, thereby producing the antibody or the antigen-binding fragment of the antibody; and (b) purifying the antibody or the antigen-binding fragment of the antibody.
  • a method of treating a subject with C1s mediated disorder the method comprising administering to the subject an antibody, or antigen binding fragment thereof, of any one of embodiments 1-25 or 33 or a pharmaceutical composition of any one of embodiments 34-36. 40.
  • the disorder is hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • ITP Immune Thrombocytopenia
  • Myastenia Gravis Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
  • 41. An antibody or antigen binding fragment thereof of any one of embodiments 1-25 or 33, or a pharmaceutical composition comprising the antibody or antigen binding fragment thereof, for the use in the treatment of a C1s mediated disorder, such as those provided for herein, such as hemolysis, Cold Agglutinin Disease.
  • the antibody or binding fragment thereof, or pharmaceutical composition of embodiment 42 for use in the treatment of a C1s mediated disorder, such as those provided for herein. 44.
  • Example 1 Production of monoclonal antibodies
  • Human immunoglobulin variable domain transgenic mice (Alloy Therapeutics) were immunized at LakePharma with human C1s (active form, Complement Technologies Cat. #A104, 10 ug per dose) via hock route using proprietary adjuvants once weekly for 4 weeks. Serum titers were monitored over time using an ELISA assay with 1 ug/ml C1s coated Maxisorb plates.
  • mice received a final boost with recombinant CCP2-SP, a fragment of C1s consisting of the second CCP domain and the serine protease domain, amino acids 358-688 of Uniprot P09871).
  • Highest titer mice were sacrificed and lymphocytes from draining lymph nodes were harvested.
  • One hundred million lymphocytes were transferred to Single Cell Technologies (SCT) for plasma cell enrichment and single cell screening. Thirty million lymphocytes were fused to generate hybridomas at LakePharma.
  • SCT Single Cell Technologies
  • Hybridomas produced by electrofusion were plated in eight 384-well plates at an average density of 2.0 hybridomas per well. Supernatants were screened by ELISA for binding to C1s and proC1s (Complement Technologies Cat.
  • Hybridomas with inhibitory signal in either assay were subcloned, expanded, IgG purified from spent supernatants, and heavy and light chain variable domains determined. Purified IgG from hybridomas were tested at varying concentrations to determine potency in CP Wieslab assay. Recombinantly expressed anti-C1s antibodies TNT009 or TNT020, anti-C5 antibody eculizumab, as well as human plasma C1INH were used as reference standards. [00359] Example 3: Single plasma cell screening [00360] Lymphocytes harvested from immunized mice and transferred to SCT were enriched for plasma cells, which were distributed into the microfluidics device and cultured for 3 hrs.
  • Example 4 C3b deposition and RBC lysis assays
  • C3b deposition To evaluate ability of antibodies to inhibit C3b deposition which leads to extravascular hemolysis select antibodies were tested by Flow Contract Site (Bothel, WA) for inhibition of C3b deposition on human red blood cells (RBCs) sensitized with rabbit anti-human RBC serum in the presence of 5% human serum.
  • RBCs red blood cells
  • MAB1 Four Fc variants of MAB1 were tested along side C1s inhibitory antibodies TNT009 and TNT020, as well as the C5 inhibitory antibody Ravulizumab.
  • Lead antibodies of the invention inhibited C3b deposition in a dose dependent manner ( Figure 2), with IC50 values ranging between 0.63 and 3.92 nM.
  • RBC lysis as a measure of ability of antibodies to inhibit intravascular lysis O-negative human red blood cells (RBCs) were washed 3 times in Gelatin Veronal Buffer (GVB) and sensitized with 1:60 dilution of rabbit anti-human RBC antibody (LSBio LS-C63000-2) for 30 min, centrifuged, and resuspended in GVB++ (GVB + 0.15 mM CaCl2, 0.5 mM MgCl2).
  • Example 5 Assessment of selectivity against proC1s
  • Hybridoma and single-cell hits that demonstrated good inhibition of the Classical Pathway were evaluated for selectivity by SPR at Biosensor Tools (Salt Lake City, UT).
  • a non-cleavable version of proC1s (proC1s_RQ) was used to avoid artifacts due to partial activation of proC1s during experimental manipulation.
  • Test IgGs were captured on an anti-Fc surface, and C1s or proC1s_RQ binding was evaluated at various concentrations.
  • Kinetic parameters and equilibrium dissociation constants were derived by global fitting of the data ( Figure 4).
  • the Fc region of lead antibodies was engineered in several ways. IgG4 and IgG2/4 chimeric scaffolds were tested to avoid effector function, and half-life extension mutations (Xencor LS or MedImmune YTE) were introduced to improve pharmacokinetic properties. [00370]
  • Example 7 Pharmacokinetics in cynomolgus monkeys [00371] Lead antibodies and TNT009 were administered to cynomolgus monkeys at relatively low doses (0.05-0.1 mg/kg) where impact of target mediated clearance would be seen clearly.
  • the panel consisted of C1r, Protein C, Cathepsin G, Chymase, Factor VIIa, Factor Xa, Factor XIa, Granzyme B, Kallikrein 1, plasma kallikrein, Matripase 2, Plasmin, Thrombin, TPA and Urokinase.
  • Enzyme and substrate concentrations were optimized in preliminary assays, followed by screening of lead antibodies. Inhibition by lead antibodies at 1 uM concentration was less than 50% in all cases.
  • lead antibodies were tested in Complement Lectin Pathway and Alternative Pathway Wieslab kits as a surrogate for inhibition of MASP1, MASP2, MASP3 and Factor D.

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WO2025255340A2 (en) 2024-06-05 2025-12-11 Genzyme Corporation BINDING PROTEINS THAT TARGET aC1s, TfR, OR BOTH, AND COMPOSITIONS THEREOF

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