Anti-il-18BP antibodies, compositions comprising Anti-il-18BP antibodies and methods of using Anti-il-18BP antibodies

Abstract

Provided herein are antibodies that selectively bind to IL-18BP and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as in therapeutics.

Description

ANTI-IL-18BP ANTIBODIES, COMPOSITIONS COMPRISING ANTI-IL-18BP ANTIBODIES AND METHODS OF USING ANTI-IL-18BP ANTIBODIES 1. RELATED APPLICATIONS

[0001] This application claims benefit of and priority to U.S. Provisional Application No.63 / 575,237, filed April 5, 2024, the disclosure of which is incorporated herein by reference in its entirety. 2. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format compliant with WIPO Standard ST.26 and is hereby incorporated by reference in its entirety. Said XML copy, created on February 28, 2025, is named 1107368.00140 PRO.xml and is 302,846 bytes in size. 3. FIELD

[0003] Provided herein are antibodies with binding specificity for IL-18BP and compositions comprising the antibodies, including pharmaceutical compositions, and kits. Also provided are methods of using anti-IL-18BP antibodies for therapeutic and diagnostic purposes. 4. BACKGROUND

[0004] Interleukin-18 (IL-18) is a member of the IL-1 family that was identified based on its ability to induce natural killer (NK) and T cell production of interferon (IFN)-g and promote Th1 immunity. IL- 18 acts synergistically with IL-12 to optimize production of IFN-g and tumor necrosis factor (TNF)-a by innate lymphoid cells (ILCs) and T cells. Endogenous IL-18 contributes to optimal resistance to diverse intracellular pathogens that include Mycobacterium tuberculosis, Salmonella tymphimurium, Cryptosporidium parvum, and Leishmania major.

[0005] However, sustained IL-18 activity is associated with autoinflammatory pathologies that include cryopyrinopathies, hereditary periodic fever syndromes, familial hemophagocytic lymphohistiocytosis, and macrophage activation syndromes, as well as viral and bacterial sepsis. These examples illustrate the need for endogenous mechanisms to optimize host protective activity of IL-18 while limiting aberrant pathological effect of IL-18 signaling.

[0006] Interleukin 18 (IL-18) is a pro-inflammatory cytokine that can stimulate T cells, NK cells, and myeloid cells. IL-18 has been proposed as an immunotherapeutic agent for the treatment of cancer, given its ability to stimulate anti-tumor immune cells. However, the clinical efficacy of IL-18 has been limited.

[0007] Two distinct checkpoints exist to limit IL-18 production and activity. First, IL-18 is produced as a pro-cytokine without biological activity and requires caspase-mediated processing. Second, the ability of IL-18 to induce the production of IFNγ results in the synthesis of a dedicated IL-18 bindingprotein (IL-18BP), which blocks the ability of IL-18 to signal.

[0008] IL-18BP is a high-affinity IL-18 decoy receptor. IL-18 is negatively regulated by IL-18BP, a secreted antagonist that binds IL-18 with extremely high affinity (KD < 1 nM). IL 18-BP binds IL-18, prevents the binding of IL-18 to its receptor and thus functions as an inhibitor of IL-18.

[0009] IL18-BP inhibits IL-18 induced T and NK cell activation and proliferation and pro- inflammatory cytokine production, resulting in reduced T and NK cell activity and T-helper type 1 immune responses. IL-18BP is frequently upregulated in diverse human and mouse tumors and limits the anti-tumor activity of IL-18 in mice.

[0010] What is needed is a therapeutic antibody that binds specifically to a human IL-18BP that could limit the effect of IL-18BP and thus promote the anti-tumor activity of IL-18. 5. SUMMARY

[0011] A first aspect provides an antibody that binds IL18BP (IL-18BP) and is capable of one or more of the following: a) in-vivo enhancement, such as restoration, of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) restimulation of tumor specific T cells; f) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; g) an increase in frequency of CD8 T cells in the tumor; h) an increase in CD11c activated T cells in the tumor; i) a decrease in CD4 Tregs in the tumor; j) an increase in Granzyme B staining in tumor specific CD8 T cells; k) inhibiting poxvirus, chikungunya, and / or hepatitis C; l) activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22; m) promoting barrier functions; n) promoting antigen presentation; o) enhancing response to parasites and bacterial infection; and / or p) promoting neutrophil activation and effector function.

[0012] In some embodiments, the binds specifically to human, murine, or cynomolgus IL-18BP. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a human antibody, a humanized antibody, or a chimeric antibody.

[0013] In some embodiments, the antibody is a bispecific antibody, a multi-specific antibody, adiabody, or a multivalent antibody. In some embodiments, the antibody is of the IgA, IgD, IgG1, IgG2, IgG3, IgG4, or IgM type. In some embodiments, the antibody is an antigen-binding antibody fragment.

[0014] In some embodiments, the antibody is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment. In some embodiments, the antibody is a single chain antibody, a single domain antibody, or a nanobody.

[0015] In some embodiments, one or more antibodies is capable of binding to human IL-18BP (hIL- 18BP). In some embodiments, the one or more antibodies is an isolated antibody. In some embodiments, the isolated antibody comprises, consists of, or consists essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18- 29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47- 58; and a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58; and a VHCDR3 having the sequence set forth in SEQ ID NOS: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153.

[0016] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and / or a light chain variable region (VL), the VH comprising at least one sequence set forth in any one of SEQ ID NOs: 157-172 and the VL comprising at least one sequence set forth in any one of SEQ ID NOs: 176-203. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID Nos: 129-153. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID Nos: 129-153.

[0017] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more VH molecules having a sequence consisting of one of SEQ ID NOs: 157-172 and the light chain comprising one or more VL molecules having a sequence consisting of one of SEQ ID NOs: 176-203.

[0018] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more HC molecules having a sequence consisting of one of SEQ ID NOs: 207-222 and the light chain comprising one or more LC molecules having a sequence consisting of one of SEQ ID NOs: 226-253.

[0019] A second aspect provides an isolated nucleic acid encoding an antibody provided herein. In some embodiments, the isolated nucleic acid comprises an expression vector. Some embodiments provide a prokaryotic or eukaryotic host cell transformed with the one or more expression vectors. Some embodiments provide an oncolytic virus encoding the nucleic acid. Some embodiments provide a method for the production of an antibody of the invention comprising the steps of expressing a nucleic acid provided herein in a prokaryotic or eukaryotic host cell and recovering the protein from the cell or the cell culture supernatant.

[0020] A third aspect provides a method of treating an individual having a disease or condition comprising administering any of the antibodies set forth herein to an individual in need thereof. In some embodiments, the disease or condition is cancer, autoimmune disease, and infection.

[0021] In some embodiments, the method further comprises administering one or more additional compounds or more additional cell therapies. In some embodiments, the one or more additional compounds comprise or consist of one or more of IL-12, IL-2, IL-15, IL-1β, IFNα, IFNγ, IL-18, IL-21 IL-22, IL-3, IL-4, IL-13, IL-9, and / or IL-5. In some embodiments, the one or more additional cell therapies comprise or consist of CAR-T or NK cell therapies. In some embodiments, the one or moreadditional compounds comprises or consist of an effective amount of an anti-PD-1, anti-PD-L1 antibody, anti-CTLA4 antibody, and / or anti-LAG-3 antibody.

[0022] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is a hematological cancer.

[0023] In some embodiments, the subject is a human subject. In some embodiments, treatment achieves one or more of the following: a) restoration of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; f) increasing frequency of tumor specific CD8 T cells; g) increasing CD11c activated tumor specific CD8 T cells; h) decreasing tumor CD4 Tregs; i) inhibiting poxvirus, chikungunya, and / or hepatitis C; j) activating local and / or tumor infiltrating T cells and NK cells to produce IFNγ and / or IL-22. k) promoting barrier functions; l) promoting antigen presentation; m) enhancing response to parasites and bacterial infection; and / or n) promoting neutrophil activation and effector function.

[0024] A fourth aspect provides a pharmaceutical composition comprising any of the antibodies set forth herein. In some embodiments, the pharmaceutical composition is adopted to any suitable route of administration. In some embodiments, the pharmaceutical composition comprises one or more excipients. Some embodiments further comprise parenteral dosage forms. 6. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1A shows antibody binding to human, murine, and cynomolgus IL-18BP by biolayer interferometry. A summary table is inserted into FIG. 1A. FIG. 1B shows human IL-18BP binding with a summary table inserted. FIG.1C shows murine IL-18BP binding. FIG.1D shows cyno IL-18BP binding.

[0026] FIG.2 shows a multiantigen ELISA to assess non-specific binding of anti-IL-18BP antibodies.

[0027] FIG.3 shows determination of anti-IL 18BP antibody blocking by ELISA.

[0028] FIG. 4 shows the results of the assay where isotype-matched antibody was unable to restorereporter functional activity while anti-IL-18BP antibodies all showed restoration of IL-18 function.

[0029] FIG.5 shows the enhancement of IL-18 activity in-vivo via anti-IL18BP antibodies.

[0030] FIG.6 depicts the enhancement of tumor specific T-cell function following treatment with anti- IL-18BP antibody TZ-2349 in combination with anti-PD1.

[0031] FIG. 7 shows that the combination of anti-PD1 and anti-IL18BP clone 2349 resulted in an increased frequency of tumor-specific AH1-tetramer staining CD8 T cells and a decrease in the frequency of CD4 Tregs (FOXP3+) amongst the CD45-staining lymphocytes in the tumor when compared to isotype antibody treatment or anti-PD1 alone.

[0032] FIG.8 shows the concentrations of interferon gamma following stimulation in the presence of anti-IL-18BP antibodies. 7. DETAILED DESCRIPTION

[0033] Provided herein are antibodies that selectively bind to IL-18BP and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as therapeutic methods. 7.1 Definitions

[0034] Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0035] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0036] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value.

[0037] The term “combinations thereof” includes every possible combination of elements to which the term refers.

[0038] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, CH1, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0039] The term “IL-18,” interleukin-18,” or “interferon-gamma inducing factor” is a protein which in humans is encoded by the IL-18 gene. The protein encoded by this gene is a proinflammatory cytokine.

[0040] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VLdimer. An “IL-18BP antibody,” “anti-IL-18BP antibody,” “IL-18BP Ab,” “IL-18BP-specific antibody,” or “anti-IL-18BP Ab” is an antibody, as described herein, which binds specifically to the antigen IL-18BP.

[0041] The VHand VLregions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VHand VLgenerally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0042] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0043] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and µ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgD, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0044] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia”numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0045] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR- H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0046] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat / Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia. Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes. CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H31-H35B H1 (Kabat Numbering) H26-H32 or H34* H1 (Chothia Numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102 * The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0047] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0048] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab′)2fragments, Fab′ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0049] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0050] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. A fabfragment can be composed of one constant and one variable domain of each of the heavy and light chains. Fab fragments may be generated, for example, by papain digestion of a full-length antibody.

[0051] “F(ab′)2” fragments contain two Fab′ fragments joined, near the hinge region, by disulfide bonds. F(ab′)2fragments may be generated, for example, by pepsin digestion of an intact antibody. The F(ab′) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol. A Fab’ fragment is a Fab fragment that has been modified with disulfide bonds.

[0052] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VHdomain and a VLdomain in a single polypeptide chain. The VHand VLare generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety.

[0053] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VHor VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VLor VL-VH). Any suitable Fc domain known in the art or described herein may be used.

[0054] A “single domain antibody” or “nanobody” is an antibody fragment consisting of a single monomeric variable antibody domain, often a peptide of about 110 amino acids, comprising one variable domain, often of a heavy chain. The single domain antibody often also comprises a common IgG.

[0055] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0056] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0057] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a humanimmunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0058] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0059] An “isolated antibody” is one that has been separated and / or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present. In some embodiments, an isolated antibody is prepared by at least one purification step.

[0060] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent.

[0061] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore®instrument, or using bio-layer interferometry technology, such as an Octet®instrument.

[0062] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0063] The term “kd” (sec−1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koffvalue.

[0064] The term “ka” , as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the konvalue.

[0065] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD= kd / ka.

[0066] The term “KA” (M−1), as used herein, refers to the association equilibrium constant of a particular antibody- KA= ka / kd.

[0067] An “affinity matured” antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s). In one embodiment, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in the art. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VHand VLdomain shuffling. Random mutagenesis of CDR and / or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is incorporated by reference in its entirety.

[0068] When used herein in the context of two or more antibodies, the term “competes with” or “cross- competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., IL- 18BP). In one exemplary assay, IL-18BP is coated on a plate and allowed to bind a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, then the antibodies compete. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. Insome embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0069] The term “epitope” means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL-18BP variants with different point-mutations.

[0070] Percent “identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0071] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” By way of example, the following groups of amino acids are considered conservative substitutions for one another. Acidic Residues D and EAliphatic Residues I, L, V, and M Cycloalkenyl-associated Residues F, H, W, and Y Hydrophobic Residues A, C, F, G, H, I, L, M, V, W, and Y Negatively Charged Residues D and E Polar Residues C, D, E, H, K, N, Q, R, S, and T Positively Charged Residues H, K, and R Small Residues A, C, D, G, N, P, S, T, and V Very Small Residues A, G, and S Residues Involved in Turn Formation A, C, D, E, G, H, K, N, Q, R, S, P, and T Flexible Residues Q, T, K, S, G, P, D, E, and R Group 1 A, S, and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L, and M Group 6 F, Y, and W Group A A and Gand Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.”

[0072] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe;F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0073] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.

[0074] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder.

[0075] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and / or an infection that can be treated with an antibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and / or an acute infection and chronic infection. 7.2 Antibodies

[0076] Provided are antibodies that selectively bind human IL-18BP. In some embodiments, the antibody selectively binds to the extracellular domain of human IL-18BP.

[0077] A first aspect provides an antibody that binds IL18BP (IL-18BP) and is capable of one or more of the following: a) in-vivo enhancement, such as restoration, of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) restimulation of tumor specific T cells; f) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; g) an increase in frequency of CD8 T cells in the tumor; h) an increase in CD11c activated T cells in the tumor; i) a decrease in CD4 Tregs in the tumor; j) an increase in Granzyme B staining in tumor specific CD8 T cells;k) inhibiting poxvirus, chikungunya, and / or hepatitis C; l) activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22; m) promoting barrier functions; n) promoting antigen presentation; o) enhancing response to parasites and bacterial infection; and / or p) promoting neutrophil activation and effector function.

[0078] In some embodiments, the anti-IL-18BP antibody is capable of providing in-vivo enhancement, such as, for example, with limitation, restoration, of IL-18 responses. In some embodiments, the anti- IL-18BP antibody is capable of blocking and / or inhibiting binding of IL-18BP to IL-18. In some embodiments, the anti-IL-18BP antibody is capable of reversing suppression of IFNγ. In some embodiments, the anti-IL-18BP antibody is capable of enhancing tumor specific T-cell function. In some embodiments, the anti-IL-18BP antibody is capable of restimulating tumor specific T cells. In some embodiments, the anti-IL-18BP antibody is capable of activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells. In some embodiments, the anti-IL-18BP antibody is capable of providing / inducing an increase in frequency of CD8 T cells in the tumor. In some embodiments, the anti-IL-18BP antibody is capable of providing / inducing an increase in CD11c activated T cells in the tumor. In some embodiments, the anti-IL-18BP antibody is capable of providing / inducing a decrease in CD4 Tregs in the tumor. In some embodiments, the anti-IL-18BP antibody is capable of providing / inducing an increase in Granzyme B staining in tumor specific CD8 T cells. In some embodiments, the anti-IL-18BP antibody is capable of inhibiting poxvirus, chikungunya, and / or hepatitis C. In some embodiments, the anti-IL-18BP antibody is capable of activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22. In some embodiments, the anti-IL-18BP antibody is capable of promoting barrier functions. In some embodiments, the anti-IL-18BP antibody is capable of promoting antigen presentation. In some embodiments, the anti-IL-18BP antibody is capable of enhancing response to parasites and bacterial infection. In some embodiments, the anti-IL- 18BP antibody is capable of promoting neutrophil activation and effector function.

[0079] In some embodiments, the anti-IL-18BP antibody is capable of enhancing restoration of IL-18 response, blocking and / or inhibiting binding of IL-18BP to IL-18, reversing suppression of IFNγ, enhancing tumor specific T-cell function, restimulating tumor specific T cells, activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells, providing / inducing an increase in frequency of CD8 T cells in the tumor, providing / inducing an increase in CD11c activated T cells in the tumor, providing / inducing a decrease in CD4 Tregs in the tumor, providing / inducing an increase in Granzyme B staining in tumor specific CD8 T cells, inhibiting poxvirus, chikungunya, and / or hepatitis C, activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22, promoting barrier functions, promoting antigen presentation, enhancing response to parasites and bacterial infection, and / or promoting neutrophil activation and effector function by at least 10%, at least 20%, at least 30%,at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 99%.

[0080] In some embodiments, one or more antibodies is capable of binding to human IL-18BP (hIL- 18BP). In some embodiments, the one or more antibodies is an isolated antibody. In some embodiments, the isolated antibody comprises, consists of, or consists essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18- 29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47- 58; and a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153. In some embodiments, In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31- 43 or SEQ ID NOs: 47-58; and a VHCDR3 having the sequence set forth in SEQ ID NOS: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153.

[0081] In some embodiments, In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and / or a light chain variable region (VL), the VH comprising at least one sequence set forth in any one of SEQ ID NOs: 157-172 and the VL comprising at least one sequence set forth in any one of SEQ ID NOs: 176-203. In some embodiments, the antibody molecule capable of binding to human IL-18BP (hIL-18BP) comprises, consists of, or consists essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and a VHCDR3 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID Nos: 129-153.

[0082] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more VH molecules having a sequence consisting of one of SEQ ID NOs: 157-172 and the light chain comprising one or more VL molecules having a sequence consisting of one of SEQ ID NOs: 176-203.

[0083] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more HC molecules having a sequence consisting of one of SEQ ID NOs: 207-222 and the light chain comprising one or more LC molecules having a sequence consisting of one of SEQ ID NOs: 226-253.

[0084] In some embodiments, the antibody has one or more CDRs having particular lengths, in terms of the number of amino acid residues. In some embodiments, the Chothia CDR-H1 of the antibody is 6, 7, 8, or 9 residues in length. In some embodiments, the Kabat CDR-H1 of the antibody is 4, 5, 6, or 7 residues in length. In some embodiments, the Chothia CDR-H2 of the antibody is 5, 6, or 7 residues in length. In some embodiments, the Kabat CDR-H2 of the antibody is 15, 16, 17, or 18 residues in length. In some embodiments, the Kabat / Chothia CDR-H3 of the antibody is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 residues in length.

[0085] In some embodiments, the Kabat / Chothia CDR-L1 of the antibody is 9, 10, 11, 12, 13, 14, 15, or 16 residues in length. In some embodiments, the Kabat / Chothia CDR-L2 of the antibody is 6, 7, or 8 residues in length. In some embodiments, the Kabat / Chothia CDR-L3 of the antibody is 8, 9, 10, 11, or 12 residues in length.

[0086] In some embodiments, the antibody comprises a light chain. In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain.

[0087] In some embodiments, the antibody comprises a heavy chain. In some embodiments, the heavy chain is an IgA. In some embodiments, the heavy chain is an IgD. In some embodiments, the heavy chain is an IgE. In some embodiments, the heavy chain is an IgG. In some embodiments, the heavy chain is an IgM. In some embodiments, the heavy chain is an IgG1. In some embodiments, the heavy chain is an IgG2. In some embodiments, the heavy chain is an IgG3. In some embodiments, the heavy chain is an IgG4. In some embodiments, the heavy chain is an IgA1. In some embodiments, the heavy chain is an IgA2.

[0088] In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment.In some embodiments, the antibody fragment is a F(ab′)2fragment. In some embodiments, the antibody fragment is a Fab′ fragment. In some embodiments, the antibody fragment is an scFv (sFv) fragment. In some embodiments, the antibody fragment is an scFv-Fc fragment.

[0089] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

[0090] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0091] In some embodiments, the antibody is an affinity matured antibody. In some embodiments, the antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure.

[0092] In some embodiments, the antibody is an anti-IL-18BP antibody. In some embodiments, the antibody binds IL-18 specifically with high binding affinities. FIG.1 shows representative raw curves of binding by time and a summary table showing recombinant IL-18BP binding by IL-18BP antibodies and demonstrating characterization of antibody / IL-18BP binding affinities and cross reactivity. FIG. 1A shows antibody binding to human, murine, and cynomolgus IL-18BP by biolayer interferometry. A summary table is inserted into FIG.1A. FIG.1B shows human IL-18BP binding with a summary table inserted; FIG.1C shows murine IL-18BP binding; FIG.1D shows cyno IL-18BP binding. The majority of the anti-IL-18BP antibodies were capable of binding to human, mouse, and cynomolgus IL-18BP. FIG. 2 shows that anti-IL-18BP antibodies TZ-2349 and TZ-2367 perform similarly to the negative control and have minimal binding to the multiantigen panel. FIG. 3 shows the results of biophysical characterization of the anti-IL-18BP antibody.

[0093] In some embodiments, the antibody is capable of blocking IL-18 expressing cells. FIG.4 shows the results of testing anti-IL18BP antibodies in a suppression assay using an IL-18 reporter cell line, HEK-Blue™ IL-18. In some embodiments, the anti-IL-18BP antibody is effective in blocking the suppression of IL-18 signaling via IL-18BP.

[0094] In some embodiments, the antibody when administered to a subject and evaluated in an in vitro assay, restores IL-18 function. In some embodiments, the antibody is capable of effectively blocking the suppression of IL-18 signaling via IL-18BP. For example, FIG.4 shows the results of testing anti- IL18BP antibodies in a suppression assay using an IL-18 reporter cell line.

[0095] In some embodiments, the antibody enhances response to systemically administered IL-18. FIG. 5 shows the results of testing anti-IL18BP antibodies in a suppression assay with in-vivo enhancement of IL-18 responses by anti-IL-18BP antibodies. As shown in FIG.5, the IL18BP antibody clones were able to reverse suppression of IFN-gamma production by IL-18BP demonstrating that clones against IL-18BP were active in vivo. Mice were injected with anti-IL18BP antibodies clonesand recombinant mouse IL-18 as depicted. Serum was collected and tested for IFN-gamma levels by ELISA. In some embodiments, the IL-18BP antibodies are functional in vivo and are cross reactive to mouse IL-18BP in an in vivo experiment. In some embodiments, the antibody productively alter the tumor microenvironment.

[0096] FIG.6 depicts the enhancement of tumor specific T-cell function following treatment with anti- IL-18BP antibody TZ-2349 in combination with anti-PD1. Tumor bearing mice were treated with isotype controls, anti-PD-1, or the combination of anti-PD-1 anti-IL-18BP. Tumor and spleen cells were stimulated with media or the immunodominant epitope AH1. Shown are the FACS plots for Interferon gamma and CCL5 of tumor lymphocytes stimulated with AH1 peptide (A) and the frequencies of Interferon gamma and CCL5 positive cells in the spleen and tumors from treated mice (B). Data were analyzed by one-way ANOVA with Tukey’s multiple comparisons test. *p < 0.05, **p < 0.01, ***p < 0.001. In some embodiments, administration or treatment with the anti-18-BP antibody and an anti-PD1 antibody (or an equivalent anti-checkpoint inhibitor antibody) significantly enhances cytokine positive cells compared to administration of the anti-PD1 antibody alone.

[0097] FIG. 7 shows that the combination of anti-PD1 and anti-IL18BP clone 2349 resulted in an increased frequency of tumor-specific AH1-tetramer staining CD8 T cells, a decrease in the frequency of CD4 Tregs (FOXP3+) amongst the CD45-staining lymphocytes in the tumor when compared to isotype antibody treatment or anti-PD1 alone. Peripheral blood mononuclear cells were stimulated over night with IL-18, IL-12, IL-18BP and anti-IL18BP antibodies. Supernatants were collected and tested for concentrations of Interferon gamma Data were analyzed by one-way ANOVA with Tukey’s multiple comparisons test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.

[0098] In some embodiments, administration or treatment with the anti-IL18BP antibody and an anti- PD1 antibody (or an equivalent anti-checkpoint inhibitor antibody) significantly increases the ratio of tumor-specific T cells to Tregs. In some embodiments, administration of the combination of anti-PD1 antibody and anti-IL18BP antibody alters the tumor microenvironment activates tumor-specific CD8 T cells and / or non-Treg CD4 T cells. In some embodiments, that anti-IL18-BP antibodies are functional in the tumor microenvironment.

[0099] In some embodiments, the IL-18BP antibody is capable of reversing suppression of IL18BP. FIG.8 shows the concentrations of interferon gamma following stimulation in the presence of the anti- IL-18BP antibodies. Controls, no IL-18, and no IL-18BP are the minimal and maximal signal for the assay respectively. All clones tested showed partial or complete restoration of signal compared to the stimulation in the absence of IL-18BP. 7.3 CDR-H3 Sequences

[0100] In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of,or consisting essentially of a sequence selected from SEQ ID NOS: 62-75. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 62. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 63. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 64. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 65. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 66. In some embodiments, the antibody comprises a CDR- H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 71. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 72. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 73. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 74. In some embodiments, the antibody comprises a CDR- H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 75.

[0101] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.1 VHSequences Comprising Illustrative CDRs

[0102] In some embodiments, the antibody comprises a VHsequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof. 7.3.2 VHSequences Comprising Illustrative Kabat CDRs

[0103] In some embodiments, the antibody comprises a VHsequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative KabatCDR-H sequences provided in this disclosure, and variants thereof. 7.3.2.1 Kabat CDR-H3

[0104] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 62-75. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 62. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 63. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 64. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 65. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 66. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 71. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 72. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 73. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 74. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 75. 7.3.2.2 Kabat CDR-H2

[0105] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 31-43. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 31. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 32. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 33. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 34. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 35. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 36. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 37. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 38. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 39. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 40. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 41. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 42. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 43. 7.3.2.3 Kabat CDR-H1

[0106] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-4 or 6-14. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR- H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 1. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 2. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 3. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 4. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 6. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 7. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 8. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 9. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 10. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 11. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 12. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 13. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 14. 7.3.2.4 Kabat CDR-H3 + Kabat CDR-H2

[0107] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 62-75 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 31-43. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 157-172. 7.3.2.5 Kabat CDR-H3 + Kabat CDR-H1

[0108] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 62-75 and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-4 or 6-14. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative VHsequence selected from SEQ ID NOS: 157-172. 7.3.2.6 Kabat CDR-H1 + Kabat CDR-H2

[0109] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-4 or 6-14 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 31-43. In some embodiments, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 157-172. 7.3.2.7 Kabat CDR-H1 + Kabat CDR-H2 + Kabat CDR-H3

[0110] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-4 or 6-14, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 31-43, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 62-75. In some embodiments, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative VHsequence selected from SEQ ID NOS: 157-172.

[0111] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 32, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 63. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 33, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 64. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 65. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 35, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 66. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 6, a Kabat CDR-H2 sequence comprising SEQ ID NO: 36, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 67. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 7, a Kabat CDR-H2 sequence comprising SEQ ID NO: 37, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 68. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 69. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 9, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 70. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 10, a Kabat CDR-H2 sequence comprising SEQ ID NO: 39, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 71. In some embodiments, the antibody comprises a VHsequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 11, a Kabat CDR-H2 sequence comprising SEQ ID NO: 40, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 72. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 12, a Kabat CDR-H2 sequence comprising SEQ ID NO: 41, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 73. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 13, a Kabat CDR-H2 sequence comprising SEQ ID NO: 42, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 74. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 14, a Kabat CDR-H2 sequence comprising SEQ ID NO: 73, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 75. 7.3.2.8 Variants of VHSequences Comprising Illustrative Kabat CDRs

[0112] In some embodiments, the VHsequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0113] In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0114] In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0115] In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H1 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in thisdisclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.3 VHSequences Comprising Illustrative Chothia CDRs

[0116] In some embodiments, the antibody comprises a VHsequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof. 7.3.3.1 Chothia CDR-H3

[0117] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 62-75. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 62. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 63. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 64. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 65. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 66. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 71. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 72. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 73. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 74. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 75.7.3.3.2 Chothia CDR-H2

[0118] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 47-58. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 47. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 48. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 49. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 50. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 51. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 52. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 53. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 54. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 55. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 56. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 57. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 58. 7.3.3.3 Chothia CDR-H1

[0119] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 18-29. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 18. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 19. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 20. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 21. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 22. In some embodiments, theantibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 23. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 24. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 25. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 26. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 27. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 28. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 29. 7.3.3.4 Chothia CDR-H3 + Chothia CDR-H2

[0120] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 62-75 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 47-58. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOs: 157-172. 7.3.3.5 Chothia CDR-H3 + Chothia CDR-H1

[0121] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 62-75 and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 18-29. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative VHsequence selected from SEQ ID NOs: 157-172. 7.3.3.6 Chothia CDR-H1 + Chothia CDR-H2

[0122] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 18-29 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 47-58. In some embodiments, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1 and Chothia CDR-H2 are bothfrom a single illustrative VHsequence selected from SEQ ID NOs: 157-172. 7.3.3.7 Chothia CDR-H1 + Chothia CDR-H2 + Chothia CDR-H3

[0123] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 18-29, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID Nos: 47-58, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 62-75. In some embodiments, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VHsequence selected from SEQ ID NOs: 157-172.

[0124] In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 19, a Chothia CDR- H2 sequence comprising SEQ ID NO: 48, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 63. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 20, a Chothia CDR-H2 sequence comprising SEQ ID NO: 49, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 64. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR- H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 65. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 22, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 66. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 29, a Chothia CDR- H2 sequence comprising SEQ ID NO: 49, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 67. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 23, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 68. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR- H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 70. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 54, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 75. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 25, a Chothia CDR- H2 sequence comprising SEQ ID NO: 55, and a Chothia CDR-H3 sequence comprising SEQ ID NO:72. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 28, a Chothia CDR-H2 sequence comprising SEQ ID NO: 56, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 73. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 26, a Chothia CDR- H2 sequence comprising SEQ ID NO: 57, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 74. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 27, a Chothia CDR-H2 sequence comprising SEQ ID NO: 58, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 75. 7.3.3.8 Variants of VHSequences Comprising Illustrative Chothia CDRs

[0125] In some embodiments, the VHsequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0126] In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0127] In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0128] In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.7.3.4 VHSequences

[0129] In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 157-172. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 157. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 158. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 159. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 160. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 161. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 162. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 163. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 164. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 165. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 166. In some embodiments, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 167. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 168. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 169. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 170. In some embodiments, the antibody comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 171. In some embodiments, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 172. 7.3.4.1 Variants of VHSequences

[0130] In some embodiments, the VHsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VHsequence provided in this disclosure.

[0131] In some embodiments, the VHsequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VHsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VHsequences provided in this disclosure.

[0132] In some embodiments, the VHsequence comprises, consists of, or consists essentially of any of the illustrative VHsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 orfewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.5 VLSequences Comprising Illustrative CDRs

[0133] In some embodiments, the antibody comprises a VLsequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof. 7.3.5.1 CDR-L3 Sequences

[0134] In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 129-153. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR- L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 132. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 133. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 134. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 135. In some embodiments, the antibody comprises a CDR- L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 136. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 137. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 138. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 139. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 140. In some embodiments, the antibody comprises a CDR- L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 141. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 142. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 144. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO:145. In some embodiments, the antibody comprises a CDR- L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 146. In someembodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 147. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 148. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 149. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 150. In some embodiments, the antibody comprises a CDR- L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 151. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 152. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 153.

[0135] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.5.2 CDR-L2

[0136] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 104-125. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 104. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 105. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 106. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 107. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 108. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 109. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 111. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 112. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 113. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 114. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 115. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 116. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 118. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 120. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 121. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 122. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 123. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 125. 7.3.5.3 CDR-L1

[0137] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 79-100. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 79. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 80. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 82. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 83. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 84.In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 85. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 86. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 87. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 88. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 91. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 92. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 93. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 94. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 95. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 96. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 97. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 98. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 99. In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 100. 7.3.5.4 CDR-L3 + CDR-L2

[0138] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 129-153 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 104-125. In some embodiments, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L2 are both from a single illustrative VLsequence selected from SEQ ID NOS: 176-203.7.3.5.5 CDR-L3 + CDR-L1

[0139] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 129-153 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 79-100. In some embodiments, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L1 are both from a single illustrative VLsequence selected from SEQ ID NOS: 176-203. 7.3.5.6 CDR-L1 + CDR-L2

[0140] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 79-100 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 104-125. In some embodiments, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L1 and CDR-L2 are both from a single illustrative VLsequence selected from SEQ ID NOs: 176-203. 7.3.5.7 CDR-L1 + CDR-L2 + CDR-L3

[0141] In some embodiments, the antibody comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 79-100, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 104-125, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 129-153. In some embodiments, the CDR-L1 sequence, CDR- L2 sequence, and CDR-L3 sequence are all from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VLsequence selected from SEQ ID NOs: 176-203.

[0142] In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence comprising SEQ ID NO: 129. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence comprising SEQ ID NO: 130. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence comprising SEQ ID NO: 131. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 80, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR-L3 sequence comprising SEQ ID NO: 133. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 81, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR-L3 sequence comprising SEQ ID NO: 133. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 82, a CDR-L2 sequence comprising SEQ ID NO: 106, and a CDR-L3 sequence comprising SEQ ID NO: 134. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 83, a CDR-L2 sequence comprising SEQ ID NO: 107, and a CDR-L3 sequence comprising SEQ ID NO: 135. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 84, a CDR-L2 sequence comprising SEQ ID NO: 108, and a CDR-L3 sequence comprising SEQ ID NO: 136. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 85, a CDR-L2 sequence comprising SEQ ID NO: 109, and a CDR-L3 sequence comprising SEQ ID NO: 137. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 86, a CDR-L2 sequence comprising SEQ ID NO: 110, and a CDR-L3 sequence comprising SEQ ID NO: 138. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 111, and a CDR-L3 sequence comprising SEQ ID NO: 139. In some embodiments, the antibody comprises a VL sequence comprising a CDR- L1 sequence comprising SEQ ID NO: 87, a CDR-L2 sequence comprising SEQ ID NO: 112, and a CDR-L3 sequence comprising SEQ ID NO: 140. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 88, a CDR-L2 sequence comprising SEQ ID NO: 113, and a CDR-L3 sequence comprising SEQ ID NO: 141. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 89, a CDR-L2 sequence comprising SEQ ID NO: 114, and a CDR-L3 sequence comprising SEQ ID NO: 142. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 90, a CDR-L2 sequence comprising SEQ ID NO: 115, and a CDR-L3 sequence comprising SEQ ID NO: 143. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 91, a CDR-L2 sequence comprising SEQ ID NO: 116, and a CDR-L3 sequence comprising SEQ ID NO: 144. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 92, a CDR-L2 sequence comprising SEQ ID NO: 117, and a CDR-L3 sequence comprising SEQ ID NO: 145. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 93, a CDR-L2 sequence comprising SEQ ID NO: 118, and a CDR-L3 sequence comprising SEQ ID NO: 146. In some embodiments, the antibody comprises a VL sequence comprising a CDR- L1 sequence comprising SEQ ID NO: 94, a CDR-L2 sequence comprising SEQ ID NO: 119, and a CDR-L3 sequence comprising SEQ ID NO: 147. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 95, a CDR-L2 sequence comprising SEQ ID NO: 120, and a CDR-L3 sequence comprising SEQ ID NO: 148. In some embodiments, theantibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 96, a CDR-L2 sequence comprising SEQ ID NO: 121, and a CDR-L3 sequence comprising SEQ ID NO: 149. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 97, a CDR-L2 sequence comprising SEQ ID NO: 122, and a CDR-L3 sequence comprising SEQ ID NO: 150. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 98, a CDR-L2 sequence comprising SEQ ID NO: 123, and a CDR-L3 sequence comprising SEQ ID NO: 151. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 99, a CDR-L2 sequence comprising SEQ ID NO: 124, and a CDR-L3 sequence comprising SEQ ID NO: 152. In some embodiments, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 100, a CDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence comprising SEQ ID NO: 153. 7.3.5.8 Variants of VLSequences Comprising Illustrative CDR-Ls

[0143] In some embodiments, the VLsequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and / or CDR-L1 sequence provided in this disclosure.

[0144] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0145] In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0146] In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in thisdisclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.6 VLSequences

[0147] In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 176-203. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 176. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 177. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 178. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 179. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 180. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 181. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 182. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 183. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 184. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 185. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 186. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 187. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 188. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 189. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 190. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 191. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 192. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 193. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 194. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 194. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 196. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 197. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 198. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 199. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 200. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 201. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 202. In some embodiments, the antibody comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 203. 7.3.6.1 Variants of VLSequences

[0148] In some embodiments, the VLsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VLsequence provided in this disclosure.

[0149] In some embodiments, the VLsequence comprises, consists of, or consists essentially of a variant of an illustrative VLsequence provided in this disclosure. In some embodiments, the VLsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VLsequences provided in this disclosure.

[0150] In some embodiments, the VLsequence comprises, consists of, or consists essentially of any of the illustrative VLsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.7 Pairs 7.3.7.1 CDR-H3 – CDR-L3 Pairs

[0151] In some embodiments, the antibody comprises a CDR-H3 sequence and a CDR-L3 sequence. In some embodiments, the CDR-H3 sequence is part of a VHand the CDR-L3 sequence is part of a VL.

[0152] In some embodiments, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 62-75 and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 129-153. 7.3.7.2 Variants of CDR-H3 – CDR-L3 Pairs

[0153] In some embodiments, the CDR-H3 – CDR-L3 pairs provided herein comprise a variant of anillustrative CDR-H3 and / or CDR-L1 sequence provided in this disclosure.

[0154] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0155] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.7.3 VH– VLPairs

[0156] In some embodiments, the antibody comprises a VHsequence and a VLsequence.

[0157] In some embodiments, the VHsequence is a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 157-172 and the VLsequence is a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 176-203.

[0158] In some embodiments, the VHsequence is SEQ ID NO: 157 and the VLsequence is selected from SEQ ID NOS: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VL sequence is SEQ ID NO: 177. In some embodiments, the VL sequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0159] In some embodiments, the VHsequence is SEQ ID NO: 158 and the VLsequence is selected from SEQ ID NOS: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0160] In some embodiments, the VHsequence is SEQ ID NO: 159 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VL sequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In someembodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0161] In some embodiments, the VHsequence is SEQ ID NO: 160 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0162] In some embodiments, the VHsequence is SEQ ID NO: 161 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VL sequence is SEQ ID NO: 182. In some embodiments, the VL sequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ IDNO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0163] In some embodiments, the VHsequence is SEQ ID NO: 162 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0164] In some embodiments, the VHsequence is SEQ ID NO: 163 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VL sequence is SEQ ID NO: 179. In some embodiments, the VL sequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VL sequence is SEQ ID NO: 202. In some embodiments, the VL sequence is SEQ ID NO: 203.

[0165] In some embodiments, the VHsequence is SEQ ID NO: 164 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0166] In some embodiments, the VHsequence is SEQ ID NO: 165 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VL sequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In someembodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VL sequence is SEQ ID NO: 199. In some embodiments, the VL sequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0167] In some embodiments, the VHsequence is SEQ ID NO: 166 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0168] In some embodiments, the VHsequence is SEQ ID NO: 167 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ IDNO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VL sequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0169] In some embodiments, the VHsequence is SEQ ID NO: 168 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0170] In some embodiments, the VHsequence is SEQ ID NO: 169 and the VLsequence is selectedfrom SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VL sequence is SEQ ID NO: 192. In some embodiments, the VL sequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0171] In some embodiments, the VHsequence is SEQ ID NO: 170 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ IDNO: 203.

[0172] In some embodiments, the VHsequence is SEQ ID NO: 171 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VLsequence is SEQ ID NO: 194. In some embodiments, the VLsequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203.

[0173] In some embodiments, the VHsequence is SEQ ID NO: 172 and the VLsequence is selected from SEQ ID NOs: 176-203. In some embodiments, the VLsequence is SEQ ID NO: 176. In some embodiments, the VLsequence is SEQ ID NO: 177. In some embodiments, the VLsequence is SEQ ID NO: 178. In some embodiments, the VLsequence is SEQ ID NO: 179. In some embodiments, the VLsequence is SEQ ID NO: 180. In some embodiments, the VLsequence is SEQ ID NO: 181. In some embodiments, the VLsequence is SEQ ID NO: 182. In some embodiments, the VLsequence is SEQ ID NO: 183. In some embodiments, the VLsequence is SEQ ID NO: 184. In some embodiments, the VLsequence is SEQ ID NO: 185. In some embodiments, the VLsequence is SEQ ID NO: 186. In some embodiments, the VLsequence is SEQ ID NO: 187. In some embodiments, the VLsequence is SEQ ID NO: 188. In some embodiments, the VLsequence is SEQ ID NO: 189. In some embodiments, the VLsequence is SEQ ID NO: 190. In some embodiments, the VLsequence is SEQ ID NO: 191. In some embodiments, the VLsequence is SEQ ID NO: 192. In some embodiments, the VLsequence is SEQ ID NO: 193. In some embodiments, the VL sequence is SEQ ID NO: 194. In some embodiments, the VL sequence is SEQ ID NO: 195. In some embodiments, the VLsequence is SEQ ID NO: 196. In some embodiments, the VLsequence is SEQ ID NO: 197. In some embodiments, the VLsequence is SEQ ID NO: 198. In some embodiments, the VLsequence is SEQ ID NO: 199. In some embodiments, the VLsequence is SEQ ID NO: 200. In some embodiments, the VLsequence is SEQ ID NO: 201. In some embodiments, the VLsequence is SEQ ID NO: 202. In some embodiments, the VLsequence is SEQ ID NO: 203. 7.3.7.4 CDR-H1 + CDR-H2 + CDR-H3 + CDR-L1 + CDR-L2 + CDR-L3

[0174] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR- L3 sequence SEQ ID NO: 129. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 130. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 131. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 132. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 32, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 63 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 80, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR-L3 sequence SEQ ID NO: 133. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 32, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 63 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 81, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR- L3 sequence SEQ ID NO: 133. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 33, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 64 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 82, a CDR-L2 sequence comprising SEQ ID NO: 106, and a CDR-L3 sequence SEQ ID NO: 134. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 83, a CDR-L2 sequence comprising SEQ ID NO: 107, and a CDR-L3 sequence SEQ ID NO: 135. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 35, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 66 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 84, a CDR-L2 sequence comprising SEQ ID NO: 108, and a CDR-L3 sequence SEQ ID NO: 136. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 85, a CDR-L2 sequence comprising SEQ ID NO: 109, and a CDR-L3 sequence SEQ ID NO: 137. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 32, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 63 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 80, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR- L3 sequence SEQ ID NO: 133. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 86, a CDR-L2 sequence comprising SEQ ID NO: 110, and a CDR-L3 sequence SEQ ID NO: 138. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 111, and a CDR-L3 sequence SEQ ID NO: 139. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 31, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 87, a CDR-L2 sequence comprising SEQ ID NO: 112, and a CDR-L3 sequence SEQ ID NO: 140. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 6, a Kabat CDR-H2 sequence comprising SEQ ID NO: 36, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 67 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 88, a CDR-L2 sequence comprising SEQ ID NO: 113, and a CDR-L3 sequence SEQ ID NO: 141. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 7, a Kabat CDR-H2 sequence comprising SEQ ID NO: 37, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 68 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 89, a CDR-L2 sequence comprising SEQ ID NO: 114, and a CDR- L3 sequence SEQ ID NO: 142. In some embodiments, the antibody comprises a VHsequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 90, a CDR-L2 sequence comprising SEQ ID NO: 115, and a CDR-L3 sequence SEQ ID NO: 143. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 91, a CDR-L2 sequence comprising SEQ ID NO: 116, and a CDR-L3 sequence SEQ ID NO: 144. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 92, a CDR-L2 sequence comprising SEQ ID NO: 117, and a CDR-L3 sequence SEQ ID NO: 145. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 93, a CDR-L2 sequence comprising SEQ ID NO: 118, and a CDR-L3 sequence SEQ ID NO: 146. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 8, a Kabat CDR-H2 sequence comprising SEQ ID NO: 38, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 94, a CDR-L2 sequence comprising SEQ ID NO: 119, and a CDR- L3 sequence SEQ ID NO: 147. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 9, a Kabat CDR-H2 sequence comprising SEQ ID NO: 34, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 70 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 94, a CDR-L2 sequence comprising SEQ ID NO: 120, and a CDR-L3 sequence SEQ ID NO: 148. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 10, a Kabat CDR-H2 sequence comprising SEQ ID NO: 39, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 71 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 96, a CDR-L2 sequence comprising SEQ ID NO: 121, and a CDR-L3 sequence SEQ ID NO: 149. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 11, a Kabat CDR-H2 sequence comprising SEQ ID NO: 40, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 72 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 97, a CDR-L2 sequence comprising SEQ ID NO: 122, and a CDR-L3 sequence SEQ ID NO: 150. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 12, a Kabat CDR-H2 sequence comprising SEQ ID NO: 41, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 73 and a VL sequence comprising a CDR-L1sequence comprising SEQ ID NO: 98, a CDR-L2 sequence comprising SEQ ID NO: 123, and a CDR- L3 sequence SEQ ID NO: 151. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 13, a Kabat CDR-H2 sequence comprising SEQ ID NO: 42, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 57 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 99, a CDR-L2 sequence comprising SEQ ID NO: 124, and a CDR-L3 sequence SEQ ID NO: 152. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 14, a Kabat CDR-H2 sequence comprising SEQ ID NO: 43, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 75 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 100, a CDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ ID NO: 153.

[0175] In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR- L3 sequence SEQ ID NO: 129. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 130. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 131. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 104, and a CDR-L3 sequence SEQ ID NO: 132. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 19, a Chothia CDR-H2 sequence comprising SEQ ID NO: 48, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 63 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 80, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR-L3 sequence SEQ ID NO: 133. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 19, a Chothia CDR-H2 sequence comprising SEQ ID NO: 48, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 63 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 81, a CDR-L2 sequence comprising SEQ ID NO: 105, and a CDR-L3 sequence SEQ ID NO: 133. In some embodiments, the antibodycomprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 20, a Chothia CDR-H2 sequence comprising SEQ ID NO: 49, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 64 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 82, a CDR-L2 sequence comprising SEQ ID NO: 106, and a CDR-L3 sequence SEQ ID NO: 134. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 83, a CDR-L2 sequence comprising SEQ ID NO: 107, and a CDR-L3 sequence SEQ ID NO: 135. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 22, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 66 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 84, a CDR-L2 sequence comprising SEQ ID NO: 108, and a CDR-L3 sequence SEQ ID NO: 136. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 85, a CDR-L2 sequence comprising SEQ ID NO: 109, and a CDR-L3 sequence SEQ ID NO: 137. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 65 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 86, a CDR-L2 sequence comprising SEQ ID NO: 110, and a CDR-L3 sequence SEQ ID NO: 138. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 79, a CDR-L2 sequence comprising SEQ ID NO: 111, and a CDR-L3 sequence SEQ ID NO: 139. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 62 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 87, a CDR-L2 sequence comprising SEQ ID NO: 112, and a CDR-L3 sequence SEQ ID NO: 140. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 29, a Chothia CDR-H2 sequence comprising SEQ ID NO: 49, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 67 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 88, a CDR-L2 sequence comprising SEQ ID NO: 113, and a CDR-L3 sequence SEQ ID NO: 141. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 23, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequence comprisingSEQ ID NO: 68 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 89, a CDR-L2 sequence comprising SEQ ID NO: 114, and a CDR-L3 sequence SEQ ID NO: 142. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 24, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 90, a CDR-L2 sequence comprising SEQ ID NO: 115, and a CDR-L3 sequence SEQ ID NO: 143. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 24, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 91, a CDR-L2 sequence comprising SEQ ID NO: 116, and a CDR-L3 sequence SEQ ID NO: 144. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 24, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 92, a CDR-L2 sequence comprising SEQ ID NO: 117, and a CDR-L3 sequence SEQ ID NO: 145. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 24, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 93, a CDR-L2 sequence comprising SEQ ID NO: 118, and a CDR-L3 sequence SEQ ID NO: 146. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 24, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 69 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 94, a CDR-L2 sequence comprising SEQ ID NO: 119, and a CDR-L3 sequence SEQ ID NO: 147. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 70 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 95, a CDR-L2 sequence comprising SEQ ID NO: 120, and a CDR-L3 sequence SEQ ID NO: 148. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2 sequence comprising SEQ ID NO: 54, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 71 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 96, a CDR-L2 sequence comprising SEQ ID NO: 121, and a CDR-L3 sequence SEQ ID NO: 149. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 25, a Chothia CDR-H2 sequence comprising SEQ ID NO: 55, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 72 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 97, a CDR-L2 sequence comprising SEQ ID NO: 122, and a CDR-L3 sequence SEQ ID NO: 150. In someembodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 28, a Chothia CDR-H2 sequence comprising SEQ ID NO: 56, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 73 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 98, a CDR-L2 sequence comprising SEQ ID NO: 123, and a CDR-L3 sequence SEQ ID NO: 151. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 26, a Chothia CDR-H2 sequence comprising SEQ ID NO: 57, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 74 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 99, a CDR-L2 sequence comprising SEQ ID NO: 124, and a CDR-L3 sequence SEQ ID NO: 152. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 27, a Chothia CDR-H2 sequence comprising SEQ ID NO: 58, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 75 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 100, a CDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ ID NO: 153. 7.3.7.5 Variants of VH– VLPairs

[0176] In some embodiments, the VH– VLpairs provided herein comprise a variant of an illustrative VHand / or VLsequence provided in this disclosure.

[0177] In some embodiments, the VHsequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VHsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.1% identity with any of the illustrative VHsequences provided in this disclosure.

[0178] In some embodiments, the VHsequence comprises, consists of, or consists essentially of any of the illustrative VHsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0179] In some embodiments, the VLsequence comprises, consists of, or consists essentially of a variant of an illustrative VLsequence provided in this disclosure. In some embodiments, the VLsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VLsequences provided in this disclosure.

[0180] In some embodiments, the VLsequence comprises, consists of, or consists essentially of any of the illustrative VLsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 orfewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.3.7.62.7.4 HC + LC

[0181] In some embodiments, the antibody comprises or consists of one or more heavy chains consisting of an HC sequence and one or more light chains consisting of an LC sequence. In some embodiments, the antibody comprises or consists of two identical heavy chains consisting of an HC sequence and two identical light chains consisting of an LC sequence.

[0182] In some embodiments, the HC sequence is an HC sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 207-222 and the LC sequence is an LC sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 226-253. In some embodiments, the HC sequence is an HC sequence consisting of a sequence selected from SEQ ID NOs: 207-222 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253.

[0183] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 207 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0184] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 208 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. Insome embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0185] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 209 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0186] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 210 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0187] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 211 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. Insome embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0188] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 212 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0189] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 213 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence isSEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0190] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 214 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0191] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 215 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments,the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0192] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0193] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 217 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. Insome embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0194] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 218 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0195] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 219 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence isSEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0196] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 220 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0197] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 221 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments,the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0198] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 222 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 226-253. In some embodiments, the LC sequence is SEQ ID NO: 226. In some embodiments, the LC sequence is SEQ ID NO: 227. In some embodiments, the LC sequence is SEQ ID NO: 228. In some embodiments, the LC sequence is SEQ ID NO: 229. In some embodiments, the LC sequence is SEQ ID NO: 230. In some embodiments, the LC sequence is SEQ ID NO: 231. In some embodiments, the LC sequence is SEQ ID NO: 232. In some embodiments, the LC sequence is SEQ ID NO: 233. In some embodiments, the LC sequence is SEQ ID NO: 234. In some embodiments, the LC sequence is SEQ ID NO: 235. In some embodiments, the LC sequence is SEQ ID NO: 236. In some embodiments, the LC sequence is SEQ ID NO: 237. In some embodiments, the LC sequence is SEQ ID NO: 238. In some embodiments, the LC sequence is SEQ ID NO: 239. In some embodiments, the LC sequence is SEQ ID NO: 240. In some embodiments, the LC sequence is SEQ ID NO: 241. In some embodiments, the LC sequence is SEQ ID NO: 242. In some embodiments, the LC sequence is SEQ ID NO: 243. In some embodiments, the LC sequence is SEQ ID NO: 244. In some embodiments, the LC sequence is SEQ ID NO: 245. In some embodiments, the LC sequence is SEQ ID NO: 246. In some embodiments, the LC sequence is SEQ ID NO: 247. In some embodiments, the LC sequence is SEQ ID NO: 248. In some embodiments, the LC sequence is SEQ ID NO: 249. In some embodiments, the LC sequence is SEQ ID NO: 250. In some embodiments, the LC sequence is SEQ ID NO: 251. In some embodiments, the LC sequence is SEQ ID NO: 252. In some embodiments, the LC sequence is SEQ ID NO: 253.

[0199] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 207 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 226. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 208 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 227. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 209 and the LC sequence is an LC sequence consisting of sequenceSEQ ID NO: 228. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 208 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 229. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 210 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 230. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 210 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 231. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 211 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 232. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 212 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 233. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 213 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 234. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 212 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 235. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 210 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 236. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 210 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 237. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 212 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 238. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 208 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 239. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 208 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 240. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 214 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 241. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 215 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 242. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 233. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 244. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 245. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 246. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 247. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 217 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 248. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 218 and the LC sequence is an LC sequence consisting of sequence SEQ IDNO: 249. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 219 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 250. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 220 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 251. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 221 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 252. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 222 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 253. 7.4 Epitopes

[0200] In some embodiments, the antibody binds to an epitope of IL-18BP. An epitope often consists of a number of contiguous amino acids such as, for example, without limitation, 5-6 amino acids. In some embodiments, the epitope comprises or consists of contiguous or non-contiguous amino acids. In some embodiments, the contiguous or non-contiguous amino acids are within a domain of IL-18BP.

[0201] In some embodiments, the antibody competes with any of the antibodies set forth herein. Competition could be, for example, without limitation, binding competition, inhibition competition, or any other form of competition. 7.5 Glycosylation Variants

[0202] In some embodiments, an antibody may be altered to increase, decrease, or eliminate the extent to which it is glycosylated. Glycosylation of polypeptides is typically either “N-linked” or “O-linked.”

[0203] “N-linked” glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site.

[0204] “O-linked” glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5- hydroxyproline or 5-hydroxylysine may also be used.

[0205] Addition or deletion of N-linked glycosylation sites to the antibody may be accomplished by altering the amino acid sequence such that one or more of the above-described tripeptide sequences is created or removed. Addition or deletion of O-linked glycosylation sites may be accomplished by addition, deletion, or substitution of one or more serine or threonine residues in or to (as the case may be) the sequence of an antibody.

[0206] In certain embodiments, the antibody is glycosylated. In certain embodiments, the antibody is deglycosylated. Carbohydrates may be removed by standard techniques. In certain embodiments, the antibody is aglycosylated, for instance by expression in a system that does not glycosylate.7.6 Fc Variants

[0207] In some embodiments, amino acid modifications may be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. In some embodiments, the Fc region variant possesses some, but not all, effector functions. Such antibodies may be useful, for example, in applications in which the half-life of the antibody in vivo is important yet certain effector functions are unnecessary or deleterious. Examples of effector functions include complement-dependent cytotoxicity (CDC) and antibody-directed complement-mediated cytotoxicity (ADCC). Numerous substitutions or substitutions or deletions with altered effector function are known in the art.

[0208] In some embodiments, the Fc is modified. In some embodiments, a hinge of an IgG1 or IgG4 antibody is modified. Modification of a hinge region stabilizes an antibody and prevents formation of unwanted bispecific antibodies. In some embodiments, an IgG Fc is engineered to modulate antibody effector function (See Wang et al., Protein Cell, 2018, Jan; 9(1): 63–73), which is incorporated by reference herein in its entirety, including any drawings).

[0209] Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are provided in U.S. Patent Nos.5,500,362 and 5,821,337; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1986, 83:7059-7063; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1985, 82:1499-1502; and Bruggemann et al., J. Exp. Med., 1987, 166:1351-1361. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, using an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. U.S.A., 1998, 95:652-656.

[0210] C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. Examples of C1q binding assays include those described in WO 2006 / 029879 and WO 2005 / 100402.

[0211] Complement activation assays include those described, for example, in Gazzano-Santoro et al., J. Immunol. Methods, 1996, 202:163-171; Cragg et al., Blood, 2003, 101:1045-1052; and Cragg and Glennie, Blood, 2004, 103:2738-2743.

[0212] FcRn binding and in vivo clearance (half-life determination) can also be measured, for example, using the methods described in Petkova et al., Intl. Immunol., 2006, 18:1759-1769. 7.7 Preparation of Antibodies 7.7.1 Antigen Preparation

[0213] The IL-18BP antigen to be used for production of antibodies may be intact IL-18BP or a fragment of IL-18BP. The intact IL-18BP, or fragment of IL-18BP, may be in the form of an isolated protein or expressed by a cell. Other forms of IL-18BP useful for generating antibodies will be apparent to those skilled in the art.7.7.2 Monoclonal Antibodies

[0214] Monoclonal antibodies may also be obtained, for example, using phage or yeast-based libraries. See e.g., U.S. Patent Nos.8,258,082 and 8,691,730.

[0215] Antibodies may also be obtained, for example, using the hybridoma method first described by Kohler et al., Nature, 1975, 256:495-497, and / or by recombinant DNA methods (see e.g., U.S. Patent No.4,816,567). In the hybridoma method, a mouse or other appropriate host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. See Goding J.W., Monoclonal Antibodies: Principles and Practice 3rded. (1986) Academic Press, San Diego, CA.

[0216] The hybridoma cells are seeded and grown in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0217] Useful myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive media conditions, such as the presence or absence of HAT medium. Among these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOP-21 and MC-11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA), and SP-2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. See e.g., Kozbor, J. Immunol., 1984, 133:3001.

[0218] After the identification of hybridoma cells that produce antibodies of the desired specificity, affinity, and / or biological activity, selected clones may be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0219] DNA encoding the monoclonal antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such asbacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies. 7.7.3 Humanized Antibodies

[0220] Humanized antibodies may be generated by replacing most, or all, of the structural portions of a monoclonal antibody with corresponding human antibody sequences. Consequently, a hybrid molecule is generated in which only the antigen-specific variable, or CDR, is composed of non-human sequence. Methods to obtain humanized antibodies include those described in, for example, Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. U.S.A., 1998, 95:8910- 8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Patent Nos.5,585,089, 5,693,761, 5,693,762, and 6,180,370. 7.7.4 Human Antibodies

[0221] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g., humanized mice). See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and U.S. Patent Nos.5,591,669, 5,589,369 and 5,545,807. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al., J. Mol. Biol., 1991, 227:381- 388; Marks et al., J. Mol. Biol., 1991, 222:581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905). Human antibodies may also be generated by in vitro activated B cells (see e.g., U.S. Patent. Nos. 5,567,610 and 5,229,275). Human antibodies may also be derived from yeast-based libraries (see e.g., U.S. Patent No.8,691,730). 7.7.5 Vectors, Host Cells, and Recombinant Methods

[0222] A second aspect provides isolated nucleic acids encoding anti-IL-18BP antibodies, vectors, and host cells comprising the nucleic acids and recombinant techniques for the production of the antibodies.

[0223] For recombinant production of the antibody, the nucleic acid encoding it may be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or expression. In some embodiments, the nucleic acid may be produced by homologous recombination, for example as described in U.S. Patent No.5,204,244.

[0224] Many different vectors are known in the art. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, for example as described in U.S. Patent No.5,534,615.

[0225] Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells. Suitable prokaryotes include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. One useful E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776, and E. coli W3110 are suitable.

[0226] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for anti-IL-18BP antibody-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is a commonly used lower eukaryotic host microorganism. However, a number of other genera, species, and strains are available and useful, such as Schizosaccharomyces pombe, Kluyveromyces (K. lactis, K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. drosophilarum, K. thermotolerans, and K. marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis), and filamentous fungi such as, for example Penicillium, Tolypocladium, and Aspergillus (A. nidulans and A. niger).

[0227] Useful mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse sertoli cells; African green monkey kidney cells (VERO- 76), and the like.

[0228] The host cells used to produce the anti-IL-18BP antibody of this invention may be cultured in a variety of media. Commercially available media such as, for example, Ham's F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco's Modified Eagle's Medium (DMEM) are suitable for culturing the host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and U.S. Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, and 5,122,469, or WO 90 / 03430 and WO 87 / 00195 may be used.

[0229] Any of these media may be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.

[0230] The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.

[0231] When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration. For example, Carter et al. (Bio / Technology, 1992, 10:163-167)describes a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 minutes. Cell debris can be removed by centrifugation.

[0232] In some embodiments, the antibody is produced in a cell-free system. In some embodiments, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225, incorporated by reference in its entirety. In some embodiments, the cell-free system utilizes a cell-free extract from a eukaryotic cell or from a prokaryotic cell. In some embodiments, the prokaryotic cell is E. coli. Cell-free expression of the antibody may be useful, for example, where the antibody accumulates in a cell as an insoluble aggregate, or where yields from periplasmic expression are low.

[0233] Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon®or Millipore®Pellcon®ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.

[0234] The antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly useful purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human γ1, γ2, or γ4 heavy chains (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13). Protein G is useful for all mouse isotypes and for human γ3 (Guss et al., EMBO J., 1986, 5:1567-1575).

[0235] The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a CH3domain, the BakerBond ABX®resin is useful for purification.

[0236] Other techniques for protein purification, such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin Sepharose®, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available, and can be applied by one of skill in the art.

[0237] Following any preliminary purification step(s), the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5 to about 4.5, generally performed at low salt concentrations (e.g., from about 0 to about 0.25 M salt).7.8 Therapeutic Applications

[0238] A third aspect provides a method of treating an individual having a disease or condition comprising administering any of the antibodies set forth herein to an individual in need thereof. For therapeutic applications, the antibodies of the invention are administered to a mammal, generally a human, in a pharmaceutically acceptable dosage form such as those known in the art and those discussed above. Alternatively, the antibodies of the invention may be administered to a human intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra- cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, intravesicle, or intratumoral routes. The antibodies also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. The intraperitoneal route may be particularly useful, for example, in the treatment of ovarian tumors.

[0239] In some embodiments, one or more antibodies is capable of binding to human IL-18BP (hIL- 18BP). In some embodiments, the one or more antibodies is an isolated antibody. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18- 29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47- 58; and a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58; and a VHCDR3 having the sequence set forth in SEQ ID NOS: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153.

[0240] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and / or a light chain variable region (VL), the VH comprising at least one sequence set forth in any one of SEQ ID NOs: 157-172 and the VL comprising at least one sequence set forth in any one of SEQ ID NOs: 176-203. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and a VHCDR3 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the sequence set forth in any one of SEQ ID Nos: 129-153.

[0241] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more VH molecules having a sequence consisting of one of SEQ ID NOs: 157-172 and the light chain comprising one or more VL molecules having a sequence consisting of one of SEQ ID NOs: 176-203.

[0242] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more HC molecules having a sequence consisting of one of SEQ ID NOs: 207-222 and the light chain comprising one or more LC molecules having a sequence consisting of one of SEQ ID NOs: 226-253.

[0243] In some embodiments, the subject is a human subject. In some embodiments, treatment achieves one or more of the following: a) restoration of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; f) increasing frequency of tumor specific CD8 T cells; g) increasing CD11c activated tumor specific CD8 T cells; h) decreasing tumor CD4 Tregs; i) inhibiting poxvirus, chikungunya, and / or hepatitis C; j) activating local and / or tumor infiltrating T cells and NK cells to produce IFNγ and / or IL-22.k) promoting barrier functions; l) promoting antigen presentation; m) enhancing response to parasites and bacterial infection; and / or n) promoting neutrophil activation and effector function.

[0244] In some embodiments, treatment using the anti-IL-18BP antibody is capable of providing in- vivo enhancement, such as restoration, of IL-18 responses. In some embodiments, treatment using the anti-IL-18BP antibody is capable of blocking and / or inhibiting binding of IL-18BP to IL-18. In some embodiments, treatment using the anti-IL-18BP antibody is capable of reversing suppression of IFNγ. In some embodiments, treatment using the anti-IL-18BP antibody is capable of enhancing tumor specific T-cell function. In some embodiments, treatment using the anti-IL-18BP antibody is capable of restimulating tumor specific T cells. In some embodiments, treatment using the anti-IL-18BP antibody is capable of activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells. In some embodiments, treatment using the anti-IL-18BP antibody is capable of providing / inducing an increase in frequency of CD8 T cells in the tumor. In some embodiments, treatment using the anti-IL- 18BP antibody is capable of providing / inducing an increase in CD11c activated T cells in the tumor. In some embodiments, treatment using the anti-IL-18BP antibody is capable of providing / inducing a decrease in CD4 Tregs in the tumor. In some embodiments, treatment using the anti-IL-18BP antibody is capable of providing / inducing an increase in Granzyme B staining in tumor specific CD8 T cells. In some embodiments, treatment using the anti-IL-18BP antibody is capable of inhibiting poxvirus, chikungunya, and / or hepatitis C. In some embodiments, treatment using the anti-IL-18BP antibody is capable of activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22. In some embodiments, treatment using the anti-IL-18BP antibody is capable of promoting barrier functions. In some embodiments, treatment using the anti-IL-18BP antibody is capable of promoting antigen presentation. In some embodiments, treatment using the anti-IL-18BP antibody is capable of enhancing response to parasites and bacterial infection. In some embodiments, treatment using the anti- IL-18BP antibody is capable of promoting neutrophil activation and effector function.

[0245] The antibodies provided herein may be useful for the treatment of any disease or condition, such as cancer, autoimmune disease, and infection. Any suitable cancer may be treated with the antibodies provided herein. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is a hematological cancer.

[0246] Illustrative examples of other suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenousleukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor. In some embodiments, the cancer is selected from breast, lung, CRC, gastric, esophageal, neuroblastoma, cervical, and hematological cancers.

[0247] Any suitable autoimmune disease may be treated with the antibodies provided herein. Illustrative suitable autoimmune diseases, or diseases with an autoimmune component, include, for example, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticarial, axonal & neuronal neuropathies, Balo disease, Behcet’s disease, bullous pemphigoid, cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal ostomyelitis (CRMO), Churg- Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, cold agglutinin disease, colitis, congenital heart block, coxsackie myocarditis, CRESTdisease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressler’s syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener’s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease. interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease (chronic), Meniere’s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic’s), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, II, & III autoimmune polyglandular syndromes, polymyalgia rheumatic, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter’s syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren’s syndrome, sperm & testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia, Takayasu’s arteritis, temporal arteritis / giant cell arteritis, thrombotic disease, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, and Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA).

[0248] Any suitable infection may be treated with the antibodies provided herein. Illustrative suitable infections include, for example, hepatitis A virus, hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus (HIV), and other viral infections.

[0249] In some embodiments, the subject is a human subject. Other potential subjects include, but arenot limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In some embodiments, the subject is suspected to have cancer, an autoimmune disease or condition, and / or an acute infection and chronic infection.

[0250] In some embodiments, treatment achieves restoration of IL-18 responses. Interleukin-18 (IL- 18) is a member of the IL-1 family that was identified based on its ability to induce natural killer (NK) and T cell production of interferon (IFN)-g and promote Th1 immunity. IL-18 acts synergistically with IL-12 to optimize production of IFN-g and tumor necrosis factor (TNF)-a by innate lymphoid cells (ILCs) and T cells. Endogenous IL-18 contributes to optimal resistance to diverse intracellular pathogens that include Mycobacterium tuberculosis, Salmonella tymphimurium, Cryptosporidium parvum, and Leishmania major.

[0251] Interleukin 18 (IL-18) is a pro-inflammatory cytokine that can stimulate T cells, NK cells, and myeloid cells. IL-18 has been proposed as an immunotherapeutic agent for the treatment of cancer, given its ability to stimulate anti-tumor immune cells.

[0252] In some embodiments, treatment blocks and / or inhibits binding of IL-18BP to IL-18. IL-18 is negatively regulated by IL-18BP, a secreted antagonist that binds IL-18 with extremely high affinity (KD < 1 nM). IL 18-BP binds IL-18, prevents the binding of IL-18 to its receptor and thus functions as an inhibitor of IL-18. IL18-BP inhibits IL-18 induced T and NK cell activation and proliferation and pro-inflammatory cytokine production, resulting in reduced T and NK cell activity and T-helper type 1 immune responses. IL-18BP is frequently upregulated in diverse human and mouse tumours and limits the anti-tumor activity of IL-18 in mice.

[0253] In some embodiments, treatment reverses suppression of IFNγ. IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity. IFN-γ is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. For example, IFN-γ is produced predominantly by natural killer cells (NK) and natural killer T cells (NKT) as part of the innate immune response and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops as part of the adaptive immune response.

[0254] The primary cells that secrete type II IFN are CD4+T helper 1 (Th1) cells, natural killer (NK) cells, and CD8+cytoxic T cells. It can also be secreted by antigen presenting cells such as dendritic cells, macrophages, and B cells to a lesser degree.

[0255] In some embodiments, treatment enhances tumor specific T-cell function. In some embodiments, treatments activates NK cells, macrophages, gamma delta T cells, and / or dendritic cells.

[0256] In some embodiments, treatment increases the frequency of tumor specific CD8 T cells. CD8T cells are the most powerful effectors in the anticancer immune response and constitute the backbone of cancer immunotherapy. CD8 T cells are major killers of pathogens and neoplastic cells, with CD4 T cells playing important roles in the maintenance of the CD8 response and prevention of exhaustion.

[0257] In some embodiments, treatment increase CD11c activated tumor specific CD8 T cells. CD11c is highly expressed in dendritic cells, some B lymphocytes, CD8+ T cell subsets, and natural killer cells. CD11c plays an important role in the proliferation and function of CD4+ and CD8+ T cells.

[0258] In some embodiments, treatment decrease tumor CD4 Tregs. CD4 Tregs are CD4+ cells that are key players in immune tolerance. They are often powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation, such as T cell.

[0259] In some embodiments, treatments inhibits poxvirus, chikungunya, and / or hepatitis C. In some embodiments, treatment activates local and / or tumor infiltrating T cells and NK cells to produce IFNγ and / or IL-22.

[0260] In some embodiments, treatment promotes barrier functions. In some embodiments, treatment promotes antigen presentation. In some embodiments, treatment enhances response to parasites and bacterial infection. In some embodiments, treatment promotes neutrophil activation and effector function.

[0261] In some embodiments, the method further comprises administering one or more additional compounds or more additional cell therapies. In some embodiments, the one or more additional compounds comprise or consist of one or more of IL-12, IL-2, IL-15, IL-1β, IFNα, IFNγ, IL-18, IL-21, IL-22, IL-3, IL-4, IL-13, IL-9, and / or IL-5.

[0262] In some embodiments, the one or more additional cell therapies comprise or consist of CAR- T. CARs are engineered synthetic receptors that function to redirect lymphocytes, most commonly T cells, to recognize and eliminate cells expressing a specific target antigen. CARs are modular synthetic receptors that consist of four main components: (1) an extracellular target antigen-binding domain, (2) a hinge region, (3) a transmembrane domain, and (4) one or more intracellular signaling domains. CAR binding to target antigens expressed on the cell surface is independent from the MHC receptor and that can result in vigorous T cell activation and powerful anti-tumor responses. In some embodiments, the one or more additional cell therapies comprise or consist of NK cell therapies.

[0263] In some embodiments, the one or more additional compounds comprises or consist of an effective amount of a PD-1 and / or an anti-PD-L1 antibody. Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape. Manyanti-PD-1 / PD-L1 antibodies have shown effectiveness in cancer immunotherapy.

[0264] In some embodiments, the one or more additional compounds comprises or consist of an effective amount of anti-CTLA4 and / or an LAG-3 antibody. Blocking CTLA4 improves the activity of anti-tumor T cells by increasing the activation and proliferation of T cells as well as an increase in memory cells, causing more T cells to bind tumor antigens. Likewise, an anti-LAG-3 antibody can affect T cell function and enhance antitumor immune function.

[0265] Some embodiments provide a method for modulating immune system function in a subject in need thereof, comprising the step of contacting a population of immune cells of the subject with a pharmaceutical composition comprising an effective amount of the antibody as set forth herein, under conditions such that the immune system is modulated. Some embodiments provide a method for modulating immune system function in a subject in need thereof, comprising the step of contacting a population of immune cells of the subject with an effective amount of any of the antibodies set forth herein in combination with an effective amount of another antibody set forth herein. In some embodiments, the antibody comprises a bispecific antibody or a complexing antibody. 7.9 Pharmaceutical Compositions, and Methods of Administration

[0266] A fourth aspect provides a pharmaceutical composition comprising one or more of the antibodies set forth herein.

[0267] In some embodiments, the one or more antibodies is capable of one or more of the following: a) in-vivo enhancement, such as restoration, of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) restimulation of tumor specific T cells; f) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; g) an increase in frequency of CD8 T cells in the tumor; h) an increase in CD11c activated T cells in the tumor; i) a decrease in CD4 Tregs in the tumor; j) an increase in Granzyme B staining in tumor specific CD8 T cells; k) inhibiting poxvirus, chikungunya, and / or hepatitis C; l) activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL- 22; m) promoting barrier functions; n) promoting antigen presentation; o) enhancing response to parasites and bacterial infection; and / orp) promoting neutrophil activation and effector function.

[0268] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58; and a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29; a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58; and a VHCDR3 having the sequence set forth in SEQ ID NOS: 62-75; a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100; a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153. In some embodiments, the one or more antibodies is capable of specifically binding to human IL-18BP.

[0269] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and / or a light chain variable region (VL), the VH comprising at least one sequence set forth in any one of SEQ ID NOs: 157-172 and the VL comprising at least one sequence set forth in any one of SEQ ID NOs: 176-203. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID Nos: 129-153. In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising 1, 2, or 3 of: a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or 18-29, a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and aVHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 79-100, a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 104-125, and a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID Nos: 129-153.

[0270] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more VH molecules having a sequence consisting of one of SEQ ID NOs: 157-172 and the light chain comprising one or more VL molecules having a sequence consisting of one of SEQ ID NOs: 176-203.

[0271] In some embodiments, the one or more antibodies comprise, consist of, or consist essentially of a heavy chain and a light chain, the heavy chain comprising one or more HC molecules having a sequence consisting of one of SEQ ID NOs: 207-222 and the light chain comprising one or more LC molecules having a sequence consisting of one of SEQ ID NOs: 226-253.

[0272] Any of the antibodies provided herein can be provided in any appropriate pharmaceutical composition and be administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, the inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, intravesicle, and subcutaneous routes.

[0273] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

[0274] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some embodiments, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some embodiments, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0275] In some embodiments, the pharmaceutical composition comprises a cosolvent. Illustrative examples of cosolvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0276] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0277] In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0278] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.

[0279] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.

[0280] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference in its entirety.

[0281] In some embodiments, the pharmaceutical composition comprises a solvent. In some embodiments, the solvent is saline solution, such as a sterile isotonic saline solution or dextrose solution. In some embodiments, the solvent is water for injection.

[0282] In some embodiments, the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle. Microparticles and nanoparticles may be formed from any suitable material, such as a polymer or a lipid. In some embodiments, the microparticles or nanoparticles are micelles, liposomes, or polymersomes. In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.

[0283] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising an antibody, since water can facilitate the degradation of some antibodies.

[0284] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0285] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. 7.9.1 Parenteral Dosage Forms

[0286] In some embodiments parenteral dosage forms are provided. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0287] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0288] Excipients that increase the solubility of one or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage forms. 7.9.2 Dosage and Unit Dosage Forms

[0289] In human therapeutics, the doctor will determine the dosology which she considers most appropriate according to a preventive or curative treatment and according to the age, weight, condition and other factors specific to the subject to be treated.

[0290] The amount of the antibody or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of thedisease or condition, and the route by which the antibody is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0291] In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the antibody per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). In some embodiments, the dosage of the antibody provided herein, based on weight of the antibody, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of a subject’s body weight. In some embodiments, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0292] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or for times weekly. It may be necessary to use dosages of the antibody outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0293] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibodies provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0294] In some embodiments, treatment or prevention can be initiated with one or more loading doses of an antibody or composition provided herein followed by one or more maintenance doses.

[0295] In some embodiments, a dose of an antibody or composition provided herein can be administered to achieve a steady-state concentration of the antibody in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.

[0296] In some embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In some embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. 8. KITS

[0297] In some embodiments, an anti-IL-18BP antibody provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure. In some embodiments, the procedure is a diagnostic assay. In other embodiments, the procedure is a therapeutic procedure.

[0298] In some embodiments, the kit further comprises a solvent for the reconstitution of the anti- aCKR antibody. In some embodiments, the anti-IL-18BP antibody is provided in the form of a pharmaceutical composition. 9. EXAMPLES 9.1 Example 1: Discovery of anti-IL18BP Antibodies

[0299] IL-18BP antibodies were discovered by using naïve scFv and Fab phage display libraries. Soluble panning was performed by using biotinylated recombinant human and mouse IL-18BP proteins captured by streptavidin-coated magnetic beads. Two panning strategies were performed in parallel to increase diversity and mitigate risks of discovering a cross-reactive antibody. In the first strategy, four rounds of selection were performed against human IL-18BP. In the second strategy, the phage output from round 1 was twice panned against murine IL-18BP followed by a fourth round against human IL- 18BP. Selection pressure was applied round-to-round by the addition of wash cycles and the reduction of the concentration of IL-18BP antigen. To limit the enrichment of non-specific phage clones, each round of panning included a deselection step against a panel of polyreactive reagents that were pooled and biotinylated as a mixture. The antigens in the polyreactive reagents pool were myoglobin, insulin, sclerostin, histone H3, human serum albumin, and single- and double-stranded DNA.

[0300] Periplasmic extract (PPE) from round 4 panning outputs were used for screening. PPEs were evaluated for binding to human and mouse IL-18BP by ELISA. Clones that showed 3-5× binding to human and mouse IL-18BP were selected and sequenced to identify unique clones which were later reformatted as IgGs. The sequences of these antibodies are provided in Table S. 9.1.1 Transfection and plasmids

[0301] Il-18BP were expressed and purified from Expi293 cells using transient transfection with ExpiFectamine (Thermo Fisher Scientific). Enhancers were added 20 h after transfection. Cells were incubated for 5 days at 37 °C and 8% CO2.

[0302] For IL-18BP IgGs, medium was collected by centrifugation at 4,000g for 20 min. IL-18BP IgGs were purified by Protein A affinity chromatography using MabSelect SuRe 5-ml column (Cytiva) and buffer exchanged into 1X PBS, pH 7.4 by dialysis. 9.2 Example 2: Biophysical Characterization of Anti-IL18-BP antibodies by biolayer interferometry (BLI)

[0303] Binding kinetics were measured using the Octet RED96 system (ForteBio) at 30° C in 1 × Kinetics Buffer (KB). 1 µg / ml of IL-18BP antibody or control was immobilized onto anti-human Fc (AHC) biosensor to a binding response of approximately 0.5 nm. After a short baseline step in 1× KB, the sensors were exposed to 1 to 2 µg / ml recombinant human, mouse, or cynomolgus IL-18BP for the association step. Dissociation of the complex was monitored upon exposure of the sensors to 1× KB for up to 10 min. Data was processed using ForteBio Octet software (v10) with negative control IgG subtraction, global fit, and 1:1 binding model to obtain association (kon) and dissociation (koff) rates. Equilibrium dissociation constant (KD) was calculated from the ratio of koffto kon.

[0304] FIG. 1 shows representative raw curves of binding by time and a summary table showing recombinant IL-18BP binding by IL-18BP antibodies and demonstrating characterization of antibody / IL-18BP binding affinities and cross reactivity. FIG.1A shows antibody binding to human, murine, and cynomolgus IL-18BP by biolayer interferometry. A summary table is inserted into FIG. 1A. FIG.1B shows human IL-18BP binding with a summary table inserted; FIG.1C shows murine IL- 18BP binding; FIG. 1D shows cyno IL-18BP binding. The majority of the anti-IL-18BP antibodies were capable of binding to human, mouse, and cynomolgus IL-18BP.

[0305] An affinity and blockade summary table is set forth below in Table A. Human blocking Clone ID Mouse (nM) Cyno (nM) (nM) ELISA(IC50)10ng TZ-02349 0.404 0.78 2.85 0.24 (2.5 rep)TZ-02352 0.424 0.12 13 2.1 TZ-02354 0.608 1.1 18 2.3 TZ-02355 0.418 0.6 17 2.4 TZ-02357 0.832 1.6 22 3.1 TZ-02358 0.592 1.2 2.5 2.5 TZ-02362 0.597 6.5 ? No blocking TZ-02365 0.15 0.575 175 2.1 TZ-02366 0.54 1 19 2 TZ-02367 0.22 0.523 1.5 2.7 TZ-02368 No binding 7 No binding 1.6 TZ-02369 0.18 Very weak No binding 0.75 TZ-02370 0.32 0.781 12 2.5 TZ-02379 93 ND No binding ND TZ-02380 21 ND No binding ND TZ-02381 311 ND No binding ND TZ-02382 2.7 ND No binding ND TZ-02383 No binding ND No binding ND 9.3 Example 3: Developability Assessment of Anti-IL-18BP Antibodies

[0306] The specificity of anti-IL-18BP antibodies was assessed by the multiantigen ELISA as previously described (Jain, T., et al, PNAS 2017, which is incorporated by reference herein in its entirety, including any drawings). Briefly, 100 nM of each antibody was incubated for 1 hour to wells precoated with various antigens. Following washing, any bound antibody was detected using an anti- huIgG HRP secondary antibody.

[0307] FIG. 2 shows that anti-IL-18BP antibodies TZ-2349 and TZ-2367 perform similarly to the negative control and have minimal binding to the multiantigen panel. This suggests a favorable developability profile.9.4 Example 4: Biophysical Characterization of Anti-IL-18BP Antibodies by IL- 18BP-IL-18 Blocking ELISA

[0308] The ability of the IL18BP antibodies to block IL-18BP binding was assessed through Enzyme Linked ImmunoSorbant Assay (ELISA). Human IL-18BP was coated onto 96-well microplates at 1µg / mL. After overnight incubation at 4°C, the wells were washed multiple times with 1x PBS with 0.05% Tween 20.

[0309] A fixed concentration of anti-IL-18 was added onto the well at 2x the final concentration and allowed to incubate for one hour at room temperature. Without removal of the antibody, 2ng / mL of biotinylated recombinant human IL-18 was added to the wells and allowed to incubate for 30 minutes at room temperature. After incubation, the plate was again washed multiple times with 1x PBS with 0.05% Tween 20.

[0310] Any biotinylated IL18 that was able to bind the coated IL-18BP was detected with Streptavidin conjugated horseradish peroxidase (HRP) diluted 5000-fold. Color development was achieved with TMB substrate solution. Once sufficient color was achieved, the reaction was quenched with 2N sulfuric acid. Signal was then read at 450nm on an optical plate reader.

[0311] Isotype control antibody had minimal effect on the binding of IL-18BP to immobilized IL-18. In contrast, all anti-IL18BP clones were capable of blocking IL-18BP binding to immobilized IL-18 at nanomolar and subnanomolar IC50s. These results indicate that the IL-18BP antibodies are capable of inhibiting the binding of IL-18BP to IL-18. The results can be seen in FIG.3. 9.5 Example 5: Functional assessment of IL-18BP blocking antibodies by HEK-IL-18 Receptor Reporter assay

[0312] The HEK-Blue™ IL-18 cell line (Invitrogen) was used to evaluate the function of anti-IL-18BP antibodies. This cell line has molecular modifications including ectopic IL-18R expression and mutations in signaling molecules to restrict the NFKB promoter driven production of secreted alkaline phosphatase (SEAP) to IL-18 cytokine binding signaling. The anti-IL18BP antibodies were tested for function.

[0313] To do so, cells were lifted, plated, and tested the same day as the stimulations were given. Antibodies at the indicated concentrations were added to wells, followed by 1 ng / mL IL-18BP and then 30 pg / mL. No deliberate pre-complexing incubations were performed. Cells were then cultured overnight, then supernatants were collected and sometimes frozen and developed according to the manufacturer’s protocol.

[0314] FIG.4 shows the results of testing anti-IL18BP antibodies in a suppression assay using an IL- 18 reporter cell line, HEK-Blue™ IL-18. Cells were stimulated with IL-18 (x ug / ml) in the presence of an inhibitory concentration of IL-18BP (x ug / ml) and a dose titration of anti-IL-18BP antibodyclones. Cells were stimulated overnight and SEAP activity in supernatants was tested.

[0315] The results of the assay where isotype-matched antibody was unable to restore reporter function; activity with anti-IL-18BP antibodies all showed restoration of IL-18 function. This shows that the anti-IL-18BP antibody clones tested were effective at blocking the suppression of IL-18 signaling via IL-18BP. 9.6 Example 6: IL-18BP antibodies enhance response to systemically administered IL-18

[0316] To evaluate the efficacy of anti-IL18-BP antibodies in vivo and the cross reactivity of anti- human IL-18BP antibodies to mouse IL-18BP, eight week old female BALB / c mice were intravenously injected with 100ug of isotype control and anti-IL-18BP antibodies, followed by intraperitoneal injection of 30ng recombinant mouse IL-18 (R&D Systems cat# 9139-IL) two hours later. Serum was collected two hours after IL-18 administration for analysis. Samples from two or three mice were then tested for IFN-gamma by ELISA.

[0317] FIG.5 shows the results of testing anti-IL18BP antibodies in a suppression assay with in-vivo enhancement of IL-18 responses by anti-IL-18BP antibodies. As shown in FIG.5, the IL18BP antibody clones were able to reverse suppression of IFN-gamma production by IL-18BP demonstrating that clones against IL-18BP were active in vivo. Mice were injected with anti-IL18BP antibodies clones and recombinant mouse IL-18 as depicted. Serum was collected and tested for IFN-gamma levels by ELISA. This demonstrates that the IL-18BP antibodies were functional in vivo and are cross reactive to mouse IL-18BP in an in vivo experiment. 9.7 Example 7: IL-18BP antibodies productively alter the tumor microenvironment in a syngeneic mouse tumor model

[0318] A syngeneic, ectopic tumor study was conducted to evaluate the effects of anti-IL18BP TZ- 2349 in combination with anti-PD1. 1x105CT26m colon carcinoma tumor cells were injected subcutaneously into the flank in 100 uL of PBS. Sizes were measured using a digital caliper and tumor volumes calculated with the formula (length x width2) / 2.

[0319] Following tumor implantation, at day 9 mice were randomized into treatment groups and treated by IP injection on days 9, 13, 16, and 20 of the indicated antibodies at 175ug / mouse for anti-IL18BP and 200ug / mouse for anti-PD1. Isotype controls were combined and injected to deliver matched doses. Clones of antibodies were as follows: an anti-HA antibody was the isotype control for the anti-IL18BP antibodies, and anti-Trinitrophenol clone 2A3 (BioXcell) for anti-PD1, anti-PD1 was clone RMP1-14, BioXcell.

[0320] Seven days after the first injection of antibodies mice were sacrificed and tumors and spleens were collected for analysis of tumor-specific T cells. Spleens were mashed and filtered while tumorswere disintegrated to single cell suspension by mincing with scissors, then via gentleMACS Octo Dissociator (Miltenyi) digested in media containing 2% Collagenase IV (Worthington), and ultrapure Benzonase (Sigma). TILs and splenocytes were either stained for surface markers, transcription factor and AH1-tetramer (SPSYVYHQF, gp70423-431) for tumor specificity determination or stimulated with 1 ug / ml with AH1 peptide (SPSYVYHQF, gp70423-431) with GolgiPLug (BD)and incubated for 5 hours at 37C with 5% CO2 and then processed for flow cytometry and stained for intracellular cytokines.

[0321] FIG.6 depicts the enhancement of tumor specific T-cell function following treatment with anti- IL-18BP antibody TZ-2349 in combination with anti-PD1. Tumor bearing mice were treated with isotype controls, anti-PD-1, or the combination of anti-PD-1 anti-IL-18BP. Tumor and spleen cells were stimulated with media or the immunodominant epitope AH1. Shown are the FACS plots for Interferon gamma and CCL5 of tumor lymphocytes stimulated with AH1 peptide (A) and the frequencies of Interferon gamma and CCL5 positive cells in the spleen and tumors from treated mice (B). Data were analyzed by one-way ANOVA with Tukey’s multiple comparisons test.∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.

[0322] As cells from tumor and spleen were stimulated with AH1 peptide and stained for cytokines, upon restimulation with AH1 peptide, treatment with isotype-matched antibodies or anti-PD-1 antibody failed to elicit responses above stimulation with media alone. In comparison, the splenocytes and TILs from mice treated with the combination of anti-PD1 and anti-IL18BP 2349 had significantly more T cells that stained for interferon gamma or Ccl5 following AH1-peptide stimulation compared to the media control and, importantly, significantly more cytokine positive cells compared to AH1- stimulations of cells from isotype or anti-PD1 treated mice.

[0323] Further analysis of TME was conducted by ex vivo staining of lymphocytes for AH1-tetramer. FIG. 7 shows that the combination of anti-PD1 and anti-IL18BP clone 2349 resulted in an increased frequency of tumor-specific AH1-tetramer staining CD8 T cells, a decrease in the frequency of CD4 Tregs (FOXP3+) amongst the CD45-staining lymphocytes in the tumor when compared to isotype antibody treatment or anti-PD1 alone. Peripheral blood mononuclear cells were stimulated over night with IL-18, IL-12, IL-18BP and anti-IL18BP antibodies. Supernatants were collected and tested for concentrations of Interferon gamma Data were analyzed by one-way ANOVA with Tukey’s multiple comparisons test.∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.

[0324] Accordingly, the ratio of tumor-specific T cells to Tregs was increased in the tumors from mice treated with the combination of anti-PD1 and anti-IL18BP clone 2349. Further, analysis of the tumor specific CD8 T cells in the spleen showed that such cells from mice treated with the combination of anti-PD1 and anti-IL18BP stained for more CD11c (an activation marker for recently activated CD8 T cells) and Granzyme B. CD4 T cells (non-Treg, FoxP3-, CD4+) from mice treated with the combinationof anti-PD1 and anti-IL18BP 2349 had increased Granzyme B staining compared to isotype or anti- PD1 treatment.

[0325] The results demonstrate that the combination of anti-PD1 and anti-IL18BP clone 2349 alter the tumor microenvironment in a productive manner including activation of tumor-specific CD8 T cells and non-Treg CD4 T cells. These results demonstrate that anti-IL18BP clones are functional in the tumor microenvironment and are cross reactive to mouse IL-18BP. 9.8 Example 8: IL-18BP antibodies reverse suppression of IL-18BP in a human peripheral blood mononuclear cell assay

[0326] To further test the function of anti-IL18BP antibodies in human cells, a primary cell assay was developed using peripheral blood mononuclear cells. Optimized concentrations of IL-18 and IL-12 to induce interferon gamma and suppression by IL-18BP were determined in an overnight culture with interferon gamma concentration as a readout for the response. The efficacy of the IL-18BP antibodies were then tested in these conditions.

[0327] Shown in FIG.8 are the concentrations of interferon gamma following stimulation in the presence of the anti-IL-18BP antibodies. Controls, no IL-18, and no IL-18BP are the minimal and maximal signal for the assay respectively. All clones tested showed partial or complete restoration of signal compared to the stimulation in the absence of IL-18BP. The results further support the functional activity of the anti-IL-18BP antibodies. Example S: Sequences

[0328] Table S provides sequences referred to herein. Table S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 1 CDR-H1 Kabat, 2352, 2353, 2354, 2355, 2366, 2367NYVMH2 CDR-H1 Kabat, 2349, 2356, 2358, 2360, 2361ELSMH3 CDR-H1 Kabat, 2365NYAIN4 CDR-H1 Kabat, 2357, 2359, 2362SYGMH56 CDR-H1 Kabat, 2368SYAIS7CDR-H1Kabat, 2369KLSMHTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 8 CDR-H1 Kabat, 2371, 2372, 2373, 2374, 2378NYAIS9 CDR-H1Kabat, 2379SYAMH10 CDR-H1Kabat, 2380SYAMS11 CDR-H1Kabat, 2381SKYMS12 CDR-H1Kabat, 2382SYWIS13 CDR-H1Kabat, 2383HYGMH14 CDR-H1Kabat, 2375NYAMH15161718 CDR-H1 Chothia, 2352, 2353, 2354, 2355, 2366, 2367 GFVFNNY 19 CDR-H1 Chothia, 2349, 2356, 2360, 2361GYTLTEL20 CDR-H1Chothia, 2365GGTFNNY21 CDR-H1 Chothia, 2357, 2359, 2362, 2379, 2380 GFTFSSY 22 CDR-H1Chothia, 2358GYTVTEL23 CDR-H1 Chothia, 2369GYTLTKL24 CDR-H1 Chothia, 2371, 2372, 2373, 2374, 2378GGTFINY25 CDR-H1 Chothia, 2381 GFTVSSK 26 CDR-H1 Chothia, 2383GFTFNHY27 CDR-H1 Chothia, 2375GYTFINY28 CDR-H1 Chothia, 2382GYDFSSY29 CDR-H1 Chothia, 2368GGTFSSY30Table S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 31 CDR-H2 Kabat, 2352, 2353, 2354, 2355, 2366, 2367 VVSYEGNGRYYADSVRG 32 CDR-H2 Kabat, 2349, 2356, 2360, 2361GFDPEDGETIYAQKFQG33 CDR-H2 Kabat, 2365RIIPIFGTAFSPQRFQG34 CDR-H2 Kabat, 2357, 2359, 2362, 2379VISYDGSNKYYADSVKG35 CDR-H2 Kabat, 2358FFHPEDGEAINAQNFQG36 CDR-H2 Kabat, 2368GIIPIFGTANYAQKFQG37 CDR-H2 Kabat, 2369GFDPEDGKTIYAQKFQG38 CDR-H2 Kabat, 2371, 2372, 2373, 2374, 2378GVIPISGTINYAQKFRD39 CDR-H2 Kabat, 2380AISGSGGSTYYADSVKG40 CDR-H2 Kabat, 2381GIYSGGSTYYADSVKG41 CDR-H2 Kabat, 2382RIDPSDSYSHYSPSFQG42 CDR-H2 Kabat, 2383IISDDGENKYYADSVKG43 CDR-H2 Kabat, 2375 WISPGSGNTKYSQKFQG 44454647 CDR-H2 Chothia, 2352, 2353, 2354, 2355, 2366, 2367 SYEGNG 48 CDR-H2 Chothia, 2349, 2356, 2360, 2361DPEDGE49 CDR-H2 Chothia, 2365, 2368IPIFGT50 CDR-H2 Chothia, 2357, 2359, 2362, 2379 SYDGSN 51 CDR-H2 Chothia, 2358HPEDGE52 CDR-H2 Chothia, 2369DPEDGKTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 53 CDR-H2 Chothia, 2371, 2372, 2373, 2374, 2378IPISGT54 CDR-H2 Chothia, 2380SGSGGS55 CDR-H2 Chothia, 2381YSGGS56 CDR-H2 Chothia, 2382DPSDSY57 CDR-H2 Chothia, 2383SDDGEN58 CDR-H2 Chothia, 2375 SPGSGN 59606162 CDR-H3 2352, 2353, 2354, 2355, 2366, 2367 AFWEHLAFFDV 63 CDR-H3 2349, 2356, 2360, 2361GRVVPPYYYYGMDV64 CDR-H3 2365DPTIEWEVIDAFDI65 CDR-H3 2357, 2359, 2362DKFPAAMRGYYYGMDV66 CDR-H3 2358 DLRFPLDY 67 CDR-H3 2368LPEGIAVAGTPKSYYFDY68 CDR-H3 2369ESWFWSGYPAFDY69 CDR-H3 2371, 2372, 2373, 2374, 2378DSGE70 CDR-H3 2379 SDQDSSSFDY 71 CDR-H3 2380DHRFHDTYHGAFDI72 CDR-H3 2381DRGDGYNSVGAFDI73 CDR-H3 2382EYSRSLIAFDI74 CDR-H3 2383IPFDFWSGYSKYNYGRDV75 CDR-H3 2375GRHYYYSMDV767778Table S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 79 CDR-L1 2352, 2353, 2354, 2355, 2366RASQSVSSYLA80 CDR-L1 2349, 2360, 2361TLRSGINIGSYRIF81 CDR-L1 2356TLRSGINVGTYRIF82 CDR-L1 2365TGSSSNIGAGFPVH83 CDR-L1 2357TGSSSNIGAGYDVH84 CDR-L1 2358 TGTSSDIGGYNYVS 85 CDR-L1 2359TGNSSNLGAGYDVH86 CDR-L1 2362TGSTSNIGAAYDVH87 CDR-L1 2367RASQSVTSYLA88 CDR-L1 2368RSSQSLVKSDGITYLM89 CDR-L1 2369TLRSGINLGSYRIF90 CDR-L1 2371RASQGINSALA91 CDR-L1 2372RASQSVSNNYVA92 CDR-L1 2373RASQGINRALA93 CDR-L1 2374 RASQSVSTNYLA 94 CDR-L1 2378QASQDISNYLN95 CDR-L1 2379RASQAISSYLA96 CDR-L1 2380RSSQSLLYSNGYNYVD97 CDR-L1 2381 TGNTSNIGAGFDVH 98 CDR-L1 2382TGTSSDVGGYNYVS99 CDR-L1 2383GSSTGAVTSGHYPY100 CDR-L1 2375TGSSSNIGTGYDVH101102 103104 CDR-L2 2352, 2353, 2354, 2355DASNRATTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 105 CDR-L2 2349, 2356, 2360, 2361YFSDSYNHQGS106 CDR-L2 2365QNDNRAS107 CDR-L2 2357GNSNRPS108 CDR-L2 2358AVNKRPS109 CDR-L2 2359GNTNRPS110 CDR-L2 2362 ANSNRPS 111 CDR-L2 2366DASKRAT112 CDR-L2 2367DTSNRAT113 CDR-L2 2368HVSGRDS114 CDR-L2 2369YYSDSSKHQGS115 CDR-L2 2371SASTLEG116 CDR-L2 2372SASSRAT117 CDR-L2 2373DASTLES118 CDR-L2 2374GASNRAT119 CDR-L2 2378 AASILQS 120 CDR-L2 2379AASTLQS121 CDR-L2 2380LTSNRAS122 CDR-L2 2381GNNNRPS123 CDR-L2 2382 EVSNRPS 124 CDR-L2 2383HTSNKYS125 CDR-L2 2375GDNNRPS126127128 129 CDR-L3 2352QQRSNWPPEIT130 CDR-L3 2353QQRVSWPPSIT131 CDR-L3 2354QQRSNWPSLTTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 132 CDR-L3 2355QQRSNWPQLT133 CDR-L3 2349, 2356, 2360, 2361MIWHNSASS134 CDR-L3 2365QSFDSGLQAWV135 CDR-L3 2357HSYDSSLSAWV136 CDR-L3 2358SSYAGMNNPYV137 CDR-L3 2359 QSYDSSLSGWV 138 CDR-L3 2362QSYDSSLTGWV139 CDR-L3 2366QQRTNWPPALT140 CDR-L3 2367QQRSNWPPMYS141 CDR-L3 2368MQNRHWPHT142 CDR-L3 2369FGGGTQLTVLG143 CDR-L3 2371QHFNGYPL144 CDR-L3 2372QQYGSSPWT145 CDR-L3 2373QQFNSYPPIT146 CDR-L3 2374 QQYDTSPRT 147 CDR-L3 2378QKYNSAPPT148 CDR-L3 2379QQLNS149 CDR-L3 2380MQPLRTPWT150 CDR-L3 2381 QSHDSSLRGV 151 CDR-L3 2382SSYTSSSNVV152 CDR-L3 2383LLSYSGAEV153 CDR-L3 2375QSFDSSLSAVV154155 156157 VH QVQLVESGGGVVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA 2352 FWEHLAFDVWGQGTLVTVSSTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 158 VH EVQLVESGGGLVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG 2353, 2355, 2366, RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA 2367 FWEHLAFFDVWGQGTLVTVSS 159 VH QVQLVESGGGLVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA 2354 FWEHLAFFDVWGQGTLVTVSS 160 VH EVQLVQSGAEVKKPGASVKVSCKVSGYTLTELS MHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQG 2349, 2356, 2360, RVTMTEDTSTDTAYMELSSLRSEDTAVYYCATG 2361 RVVPPYYYYGMDVWGQGTTVTVSS 161 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFNNYA INWVRQAPGQGLEWMGRIIPIFGTAFSPQRFQG RVTITADRSTATAYMELNSLRSDDTAVYYCARD 2365 PTIEWEVIDAFDIWGQGTMVTVSS 162 VH EVQLVESGGGLVQPGRSLRLSCAASGFTFSSYG MHWVRQAPGKGLEWVAVISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD 2357, 2359, 2362 KFPAAMRGYYYGMDVWGQGTTVTVSS 163 VH QVQLVQSGAEVKKPGASVKVSCKVSGYTVTELS MHWVRQAPGKGLEWMGFFHPEDGEAINAQNFQG RITMTEDTSTDTAYMELRSLTSEDAAVYYCATD 2358 LRFPLDYWGQGTLVTVSS 164 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAIL 2368 PEGIAVAGTPKSYYFDYWGQGTLVTVSS 165 VH EVQLVQSGAEVKKPGASVKVSCKVSGYTLTKLS MHWVRQAPGKGLEWMGGFDPEDGKTIYAQKFQG RVTMTEDTSTDTAYMELSSLRSEDTAVYYCATE 2369 SWFWSGYPAFDYWGQGTLVTVSS 166 VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFINYA ISWLRQAPGQGLEWMGGVIPISGTINYAQKFRD 2371, 2372, 2373, RLTITADASTSTAYMELSSLRSDDTAVYYCARD 2374, 2378 SGEIGGGTLVTVSS 167 VH EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYA MHWVRQAPGKGLEWVAVISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARS 2379 DQDSSSFDYWGQGTLVTVSS 168 VH 2380EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD HRFHDTYHGAFDIWGQGTMVTVSS 169 VH EVQLVESGGGLVQPGGSLRLSCAASGFTVSSKY MSWVRQAPGKGLEWVSGIYSGGSTYYADSVKGR 2381 FTISRDNSKNTLYLQMNSLRAEDTAVYYCARDR GDGYNSVGAFDIWGQGTMVTVSS170 VH EVQLVQSGAEVKKPGESLRISCKGSGYDFSSYW ISWVRQMPGKGLEWMGRIDPSDSYSHYSPSFQG HVTISADKSISTAYLQWSSLEASDTAMYYCARE 2382 YSRSLIAFDIWGQGTMVTVSS 171 VH EVQLVESGGGVVQPGRSLRLSCAASGFTFNHYG MHWVRQAPGKGLEWVAIISDDGENKYYADSVKG RFTISRDNSENTVYLQMDSLRVEDTAVYYCAKI 2383 PFDFWSGYSKYNYGRDVWGQGTTVTVSS 172 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFINYA MHWVRQAPGQRLEWMGWISPGSGNTKYSQKFQG RVTITSDKSASTGYMELSSLTSEDTAVYYCTTG 2375 RHYYYSMDVWGQGTTVTVSS 173 174 175 176 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPPEIT 2352 FGQGTRLEIK 177 VL IVLTQSPATLSLSPGERATLSCRASQSVSSYLA WYQQKPGQAPRLLIYDASNRATGIPARFSGSGS GTDFTLTISSLEPEDFAVYYCQQRVSWPPSITF 2353 GQGTRLEIK 178 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPSLTF 2354 GGGTKLEIK 179 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPQLTF 2355 GGGTKLEIK 180 VL QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW 2349 HNSASSFGGGTKLTVLGTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 181 VL QAVLTQPASLSASPGASASLTCTLRSGINVGTY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW 2356 HNSASSFGGGTKVTVLG 182 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGF PVHWYRQLPGAAPKLLIFQNDNRASGVPERFSG SRSATSASLAITGLQTEDESDYFCQSFDSGLQA 2365 WVFGGGTQLTVLG 183 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGY DVHWYQQLPGTAPKFLIYGNSNRPSGVPDRFSG SKSGTSASLAITGLQAEDEADYYCHSYDSSLSA 2357 WVFGGGTKVTVLG 184 VL QSALTQPRSASGSPGQSVTISCTGTSSDIGGYN YVSWYQQHPGKAPKLMIFAVNKRPSGVPDRFSG SKSGNTASLTVSGLQAADEADYYCSSYAGMNNP 2358 YVFGTGTKLTVLG 185 VL QSVLTQPPSVSGAPGQRVILSCTGNSSNLGAGY DVHWYLQLPGAAPKLLIYGNTNRPSGVPDRFSG SKSGTSASLAITGLQAQDEADYYCQSYDSSLSG 2359 WVFGGGTKLTVLG 186 VL QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW 2360 HNSASSFGGGTQLTVLG 187 VL QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW HNSASSFGGGTKVTVLG 2361 188 VL QSVLTQPPSVSGAPGQRVTISCTGSTSNIGAAY DVHWYQQVPGTAPKLLIYANSNRPSGVPDRFSG SKSGTSASLAITGLQAEDEADYYCQSYDSSLTG 2362 WVFGGGTKLTVLG 189 VL EIVMTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASKRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRTNWPPALT 2366 FGGGTKVEIK 190 VL EIVLTQSPATLSLFPGERATLSCRASQSVTSYL AWYQQKPGQPPRLLIYDTSNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPPMYS 2367 FGQGTKLEIK 191 VL 2368DVVMTQSPLSLPVTLGQPASISCRSSQSLVKSDGITYLMWFHQRPGQSPRRLIDHVSGRDSGVPDRTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: FSGSGSGTDFTLEISRVEAEDVGVYYCMQNRHW PHTFGQGTKLEIK 192 VL QAVLTQPASLSASPGASARLTCTLRSGINLGSY RIFWYQQKPESPPRYLLSYYSDSSKHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW 2369 HSSASKVFGGGTQLTVLG 193 VL DIQLTQSPSSLSASVGDRVSITCRASQGINSAL AWYQQTPGKPPKLLIYSASTLEGGVPPRFSGSG SGTDFTLTISSLQPEDFATYYCQHFNGYPLFGQ 2371 GTRLEIK 194 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSNNY VAWYQQKSGQAPRLLIYSASSRATGIPDRFSGS GSGTDFTLTISRLEPEDFAVYHCQQYGSSPWTF GQGTKVEIK 2372 195 VL DIQLTQSPSSLSASVGDEVTITCRASQGINRAL AWYQQHPGKAPKLLIFDASTLESGVPARFSGSG SGTDFTLTISSLQPEDFATYYCQQFNSYPPITF 2373 GQGTRLEIK 196 VL EIVLMQSPGTLSLSPGERVTLSCRASQSVSTNY LAWYQQKPGQAPRLLIYGASNRATGIPDRFSGR GSGTDFTLTISRLEPEDFALYYCQQYDTSPRTF 2374 GQGTKLEIK 197 VL AIQMTQSPSSLSASVGDRVTITCQASQDISNYL NWYQQKPGKAPKLLIYAASILQSGVPSRFSGSG SGTDFTLTISSLQPEDVATYYCQKYNSAPPTFG 2378 QGTKVEIK 198 VL AIQLTQSPSFMSASVGDRVTITCRASQAISSYL AWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSG SGTEFTLTISSLQPEDFATYYCQQLNSFGPGTK 2379 VEIK 199 VL DVVMTQSPLSLPVTPGEPASISCRSSQSLLYSN GYNYVDWYLQKPGQSPQLLIYLTSNRASGVPDR FSGSGSGTDFTLKISRVEAEDVGTYYCMQPLRT 2380 PWTFGQGTKVEIK 200 VL QSVLTQPPSVSGAPGQRVTISCTGNTSNIGAGF DVHWYQQVPGTAPKLLIYGNNNRPSGVPDRFSG SKSGTSASLAITGLQTEDEADYYCQSHDSSLRG 2381 VFGGGTKVTVLG 201 VL QSALTQPASVSGSPGQSITISCTGTSSDVGGYN YVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSG SKSGNTASLTISGLQAEDEADYYCSSYTSSSNV 2382 VFGGGTKVTVLGTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 202 VL QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGH YPYWFQQKPGQAPRTLIYHTSNKYSWTPARFSG SLLGGKAALTLSGAQPEDEADYYCLLSYSGAEV 2383 FGGGTKLTVLG 203 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGY DVHWYQQLPRTAPKLLMYGDNNRPSGVPDRFSA SKSGTSASLAITGLQAEDEADYYCQSFDSSLSA 2375 VVFGGGTKLTVLG 204 205 206 207 HC QVQLVESGGGVVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA FWEHLAFFDVWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS 2352 VMHEALHNHYTQKSLSLSPGK 208 HC EVQLVESGGGLVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA FWEHLAFFDVWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 2353, 2355, 2366, TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS 2367 VMHEALHNHYTQKSLSLSPGK 209 HC QVQLVESGGGLVQPGRSLRLSCEASGFVFNNYV MHWVRQAPGKGPEWIAVVSYEGNGRYYADSVRG RFTISRDNSKNTLYLQMDSLRREDTAVYFCAKA FWEHLAFFDVWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 2354 CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREETable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK 210 HC EVQLVQSGAEVKKPGASVKVSCKVSGYTLTELS MHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQG RVTMTEDTSTDTAYMELSSLRSEDTAVYYCATG RVVPPYYYYGMDVWGQGTTVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 2349, 2356, 2360, YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 2361 SCSVMHEALHNHYTQKSLSLSPGK 211 HC QVQLVQSGAEVKKPGSSVKVSCKASGGTFNNYA INWVRQAPGQGLEWMGRIIPIFGTAFSPQRFQG RVTITADRSTATAYMELNSLRSDDTAVYYCARD PTIEWEVIDAFDIWGQGTMVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 2365 SCSVMHEALHNHYTQKSLSLSPGK 212 HC EVQLVESGGGLVQPGRSLRLSCAASGFTFSSYG MHWVRQAPGKGLEWVAVISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD KFPAAMRGYYYGMDVWGQGTTVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 2357, 2359, 2362 VFSCSVMHEALHNHYTQKSLSLSPGKTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 213 HC QVQLVQSGAEVKKPGASVKVSCKVSGYTVTELS MHWVRQAPGKGLEWMGFFHPEDGEAINAQNFQG RITMTEDTSTDTAYMELRSLTSEDAAVYYCATD LRFPLDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH 2358 EALHNHYTQKSLSLSPGK 214 HC QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAIL PEGIAVAGTPKSYYFDYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 2368 GNVFSCSVMHEALHNHYTQKSLSLSPGK 215 HC EVQLVQSGAEVKKPGASVKVSCKVSGYTLTKLS MHWVRQAPGKGLEWMGGFDPEDGKTIYAQKFQG RVTMTEDTSTDTAYMELSSLRSEDTAVYYCATE SWFWSGYPAFDYWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS 2369 CSVMHEALHNHYTQKSLSLSPGK 216 HC EVQLVQSGAEVKKPGSSVKVSCKASGGTFINYA ISWLRQAPGQGLEWMGGVIPISGTINYAQKFRD RLTITADASTSTAYMELSSLRSDDTAVYYCARD SGEIGGGTLVTVSSASTKGPSVFPLAPSSKSTS 2371, 2372, 2373, GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 2374, 2378 FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAATable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: GAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK 217 HC EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYA MHWVRQAPGKGLEWVAVISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARS DQDSSSFDYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV 2379 MHEALHNHYTQKSLSLSPGK 218 HC EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYA MSWVRQAPGKGLEWVSAISGSGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD HRFHDTYHGAFDIWGQGTMVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 2380 SCSVMHEALHNHYTQKSLSLSPGK 219 HC EVQLVESGGGLVQPGGSLRLSCAASGFTVSSKY MSWVRQAPGKGLEWVSGIYSGGSTYYADSVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCARDR GDGYNSVGAFDIWGQGTMVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS 2381 CSVMHEALHNHYTQKSLSLSPGKTable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 220 HC EVQLVQSGAEVKKPGESLRISCKGSGYDFSSYW ISWVRQMPGKGLEWMGRIDPSDSYSHYSPSFQG HVTISADKSISTAYLQWSSLEASDTAMYYCARE YSRSLIAFDIWGQGTMVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS 2382 VMHEALHNHYTQKSLSLSPGK 221 EVQLVESGGGVVQPGRSLRLSCAASGFTFNHYG MHWVRQAPGKGLEWVAIISDDGENKYYADSVKG RFTISRDNSENTVYLQMDSLRVEDTAVYYCAKI PFDFWSGYSKYNYGRDVWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ HC 2383 GNVFSCSVMHEALHNHYTQKSLSLSPGK 222 QVQLVQSGAEVKKPGASVKVSCKASGYTFINYA MHWVRQAPGQRLEWMGWISPGSGNTKYSQKFQG RVTITSDKSASTGYMELSSLTSEDTAVYYCTTG RHYYYSMDVWGQGTTVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV HC 2375 MHEALHNHYTQKSLSLSPGK 223224225Table S Sequences. SEQ ID Region Scheme / Clone Sequence NO: 226 EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPPEIT FGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV LC, hKappa 2352 THQGLSSPVTKSFNRGEC 227 EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRVSWPPSIT FGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV LC, hKappa 2353 THQGLSSPVTKSFNRGEC 228 EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPSLTF GGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT LC, hKappa 2354 HQGLSSPVTKSFNRGEC 229 EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPQLTF GGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT LC, hKappa 2355 HQGLSSPVTKSFNRGEC 230 QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW HNSASSFGGGTKLTVLGQPKAAPSVTLFPPSSE ELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR LC, hLambda 2349 SYSCQVTHEGSTVEKTVAPTECS 231 QAVLTQPASLSASPGASASLTCTLRSGINVGTY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW HNSASSFGGGTKVTVLGQPKAAPSVTLFPPSSE ELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR LC, hLambda 2356 SYSCQVTHEGSTVEKTVAPTECS 232 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGF PVHWYRQLPGAAPKLLIFQNDNRASGVPERFSG SRSATSASLAITGLQTEDESDYFCQSFDSGLQA LC, hLambda 2365 WVFGGGTQLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGVETable S Sequences. SEQ ID Region Scheme / Clone Sequence NO: TTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC QVTHEGSTVEKTVAPTECS 233 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGY DVHWYQQLPGTAPKFLIYGNSNRPSGVPDRFSG SKSGTSASLAITGLQAEDEADYYCHSYDSSLSA WVFGGGTKVTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGVE TTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC LC, hLambda 2357 QVTHEGSTVEKTVAPTECS 234 QSALTQPRSASGSPGQSVTISCTGTSSDIGGYN YVSWYQQHPGKAPKLMIFAVNKRPSGVPDRFSG SKSGNTASLTVSGLQAADEADYYCSSYAGMNNP YVFGTGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGVE TTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC LC, hLambda 2358 QVTHEGSTVEKTVAPTECS 235 QSVLTQPPSVSGAPGQRVILSCTGNSSNLGAGY DVHWYLQLPGAAPKLLIYGNTNRPSGVPDRFSG SKSGTSASLAITGLQAQDEADYYCQSYDSSLSG WVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGVE TTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC LC, hLambda 2359 QVTHEGSTVEKTVAPTECS 236 QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW HNSASSFGGGTQLTVLGQPKAAPSVTLFPPSSE ELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR LC, hLambda 2360 SYSCQVTHEGSTVEKTVAPTECS 237 QAVLTQPASLSASPGASARLTCTLRSGINIGSY RIFWYQQKPESPPRYLLSYFSDSYNHQGSGVPS RFSGSKDASSNAGILVISGLQSEDEADYYCMIW HNSASSFGGGTKVTVLGQPKAAPSVTLFPPSSE ELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR LC, hLambda 2361 SYSCQVTHEGSTVEKTVAPTECS 238 QSVLTQPPSVSGAP...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. An antibody that binds IL18BP (IL-18BP) and is capable of one or more of the following: a) in-vivo enhancement, such as restoration, of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) restimulation of tumor specific T cells; f) activating NK cells, macrophages, gamma delta T cells, g) and / or dendritic cells; h) an increase in frequency of CD8 T cells in the tumor; i) an increase in CD11c activated T cells in the tumor; j) a decrease in CD4 Tregs in the tumor; k) an increase in Granzyme B staining in tumor specific CD8 T cells; l) inhibiting poxvirus, chikungunya, and / or hepatitis C; m) activating local and / or infiltrating T cells and NK cells to produce IFNγ and / or IL-22; n) promoting barrier functions; o) promoting antigen presentation; p) enhancing response to parasites and bacterial infection; and / or q) promoting neutrophil activation and effector function.

2. The antibody according to claim 1, wherein the antibody binds specifically to human, murine, or cynomolgus IL-18BP.

3. The antibody of claim 1 or claim 2, wherein the antibody has any of the following characteristics: a) is a monoclonal antibody; b) is a human antibody, a humanized antibody, or a chimeric antibody; c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody; d) is of the IgA, IgD, IgG1, IgG2, IgG3, IgG4, or IgM type; e) is an antigen-binding antibody fragment; f) is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or an Fv fragment; and / or g) is a single chain antibody, a single domain antibody, or a nanobody.

4. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, c) a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75, d) a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100, e) a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and f) a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153.

5. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-48, c) a VHCDR3 having the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising: a) a VLCDR1 having the sequence set forth in any one of SEQ ID NOs: 79-100, b) a VLCDR2 having the sequence set forth in any one of SEQ ID NOs: 104-125, and c) a VLCDR3 having the sequence set forth in any one of SEQ ID NOs: 129-153.

6. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain variable region (VH) and / or a light chain variable region (VL), the VH comprising at least one sequence set forth in any one of SEQ ID NOs: 157-172 and the VL comprising at least one sequence set forth in any one of SEQ ID NOs: 176-203.

7. An isolated nucleic acid encoding an antibody according to claim 4, claim 5, or claim 6.

8. An expression vector comprising the nucleic acid according to claim 7.

9. A prokaryotic or eukaryotic host cell comprising the vector of claim 8.

10. An oncolytic virus encoding the nucleic acid of any one of claims 7-9.

11. A method for the production of a recombinant protein comprising the steps of expressing a nucleic acid according to claim 7 or claim 8 in a prokaryotic or eukaryotic host cell and recovering the protein from the cell or the cell culture supernatant.

12. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising 1, 2, or 3 of: a) a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29, b) a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 31-43 or SEQ ID NOs: 47-58, and c) a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a) a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 79-100, b) a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 104-125, and c) a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in any one of SEQ ID NOs: 129-153.

13. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising 1, 2, or 3 of: a) a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 1-4 or 6-14 or SEQ ID NOs: 18-29, b) a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in S any one of EQ ID NOs: 31-43 or SEQ ID NOs: 47-58, andc) a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 62-75; and the VL comprising 1, 2, or 3 of: a) a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 79-100, b) a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 104-125, and c) a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in any one of SEQ ID NOs: 129-153.

14. An isolated antibody molecule capable of binding to human IL18BP (IL-18 BP), comprising a heavy chain (HC) and a light chain (LC), a) the heavy chain (HC) comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NOs: 207-222 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NOs: 226-253.

15. An isolated nucleic acid encoding an antibody according to any one of claims 12-14.

16. A method of treating a subject in need with a disease by administering any one of the antibodies of claims 1-6 or 12-15.

17. The method according to claim 16, wherein the disease is cancer.

18. The method according to claim 16 or claim 17, further comprising administering one or more additional compounds or one or more additional cell therapies.

19. The method according to claim 18, wherein the one or more additional compounds comprise or consist of one or more of IL-12, IL-2, IL-15, IL-1β, IFNα, IFNγ, IL-18, IL-21 IL-22, IL-3, IL-4, IL-13, IL-9, and / or IL-5.

20. The method according to any one of claims 16-19, wherein the one or more additional cell therapies comprise or consist of CAR-T or NK cell therapies.

21. The method according to claim 20, wherein the one or more additional compounds comprise or consist of an effective amount of an anti-PD-1, an anti-PD-L1, anti-CTLA4, and / or anti- LAG3 antibody.

22. The method according to any one of claims 17-21, wherein the cancer is a solid cancer.

23. The method according to claim 22, wherein the solid cancer is colon cancer.

24. The method according to any one of claims 17-21, wherein the cancer is a hematological cancer.

25. The method according to any one of claims 16-24, wherein the subject is a human subject.

26. The method according to any one of claims 16-25, wherein the treatment achieves one or more of the following: a) restoration of IL-18 responses; b) blocking and / or inhibiting binding of IL-18BP to IL-18; c) reversing suppression of IFNγ; d) enhancing tumor specific T-cell function; e) activating NK cells, macrophages, gamma delta T cells, and / or dendritic cells; f) increasing frequency of tumor specific CD8 T cells; g) increasing CD11c activated tumor specific CD8 T cells; h) decreasing tumor CD4 Tregs; i) inhibiting poxvirus, chikungunya, and / or hepatitis C; j) activating local and / or tumor infiltrating T cells and NK cells to produce IFNγ and / or IL-22. k) promoting barrier functions; l) promoting antigen presentation; m) enhancing response to parasites and bacterial infection; and / or n) promoting neutrophil activation and effector function.

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