EA045983B1 - ANTI-HLA-G ANTIBODIES, COMPOSITIONS CONTAINING ANTI-HLA-G ANTIBODIES, AND METHODS OF USE OF ANTI-HLA-G ANTIBODIES - Google Patents

Description

Related applications

This application claims priority to U.S. Provisional Patent Application No. 62/737666, filed September 27, 2018, which is incorporated by reference herein in its entirety.

Technical field

The present invention provides antibodies having binding specificity for HLA-G and compositions containing said antibodies, including pharmaceutical compositions, diagnostic compositions and kits. Methods of using antibodies against HLA-G for therapeutic and diagnostic purposes are also proposed.

State of the art

Class I histocompatibility antigen G, HLA-G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans encodes the HLA-G gene. HLA-G belongs to the non-classical heavy chain paralogues of HLA class I. HLA-G is a heterodimer consisting of a heavy chain and a light chain (beta-2-microglobulin). There are membrane-bound and soluble forms of HLA-G.

HLA-G is normally expressed at the transplacental barrier and other immunologically privileged sites. HLA-G may play a role in immunotolerance in pregnancy because it is expressed in the placenta by extravillous trophoblast cells, whereas the classical MHC class I genes (HLA-A and HLA-B) are not expressed. Since HLA-G was first identified in placental samples, many studies have assessed its role in pregnancy disorders such as preeclampsia and recurrent miscarriage. See source: Michita, Rafael Tomoya et al., Human Immunology. 2016, 77 (10): 892-897, which is incorporated by reference herein in its entirety with all drawings.

HLA-G has been shown to be immunosuppressive. By binding to receptors expressed on various myeloid and lymphoid cells, HLA-G can directly inhibit the functions of NK cells, cytotoxic T lymphocytes, B cells, neutrophils, monocytes, macrophages and dendritic cells. HLA-G also inhibits T and NK cell proliferation and cytolytic activity. HLA-G inhibits phagocytosis and induces the formation or expansion of regulatory T cells.

HLA-G mediates immune function through at least three PTM-containing inhibitory receptors, ILT2, ILT4, and KIR2DL4. On lymphoid and myeloid cells, for example, HLA-G mediates function through ILT2. On myeloid cells, HLA-G mediates function through ILT4. On decidual NK cells, HLA-G mediates immune function through KIR2DL4 and ILT2.

HLA-G is an immune checkpoint target. HLA-G can directly suppress immune cell function through receptor binding and/or trogocytosis and disruption of chemotaxis. HLA-G can enhance the invasive and metastatic potential of tumor cells. HLA-G promotes tumor evasion from immunological surveillance, enhances metastasis and progression of malignant neoplasms. During tumor progression, HLA-G has other effects such as inhibition of immune cell cytolysis, induction of immune cell apoptosis, and/or acquisition of regulatory cells through receptor binding and/or trogocytosis.

Upregulation of HLA-G expression occurs in a variety of tumors and is associated with poor prognosis and disease progression. Serum HLA-G levels are elevated in breast, lung, colorectal (CRC), gastric, esophageal, neuroblastoma, cervical, and hematologic cancers. HLAG has also been found to correlate with clinical indicators in advanced stage diseases, such as tumor metastasis, poor prognosis, immunosurveillance evasion, and tumor invasiveness.

HLA-G is a promising target in diseases such as cancer.

Brief description of the invention

The present invention provides antibodies that selectively bind HLA-G. In some embodiments, the antibodies bind human HLA-G. In some embodiments, the antibodies comprise at least one CDR sequence defined by a consensus sequence set forth herein. In some embodiments, the antibodies comprise one or more of the exemplary CDR, VH, or _VL sequences described herein, or variants thereof. In some aspects, the variant is a variant with one or more conservative amino acid substitutions.

Compositions and kits containing the said antibodies are also proposed.

In some embodiments, the compositions are pharmaceutical compositions. Any suitable pharmaceutical composition may be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration.

Also described herein are methods of using the anti-HLA-G antibodies of the present invention. According to some embodiments, the method provides

- 1 045983 fight method of treatment. In some embodiments, the method is an analytical method. In some embodiments, the method is a method for purifying and/or quantifying HLA-G.

In some embodiments, the method is a diagnostic method. In some embodiments, the diagnostic method includes or consists of detecting tumor-expressed HLA-G. In some embodiments, the diagnostic method includes or consists of detecting soluble HLA-G. In some embodiments, the detection method includes or consists of detecting HLA-G expression on immune cells.

In some embodiments, the antibodies are used to treat a disease or condition. In some aspects, said disease or condition is selected from cancer, autoimmune disease, and infection. In some aspects, the use of any of the antibodies or pharmaceutical compositions of the present invention is provided for the treatment of a disease or condition selected from cancer, autoimmune disease, and infection.

Brief description of drawings

In fig. Figure 1 shows a table with the avidity and monomer affinity values of anti-HLA-G antibodies for the recombinant HLA-G protein.

In fig. 2A and 2B show biolayer interferometry sensograms for anti-HLA-G antibodies that bind to HLA-G and can be divided into three biochemical groups based on their ability to cross-block in pairwise binding testing.

In fig. Figure 3 shows sensograms obtained by biolayer interferometry for antibodies that bind and block the interaction of HLA-G with ILT2 and ILT4 at different levels of effectiveness.

In fig. 4 shows an assessment of the binding of anti-HLA-G antibodies to naturally expressed HLA-G found on JEG-3 tumor cells.

In fig. 5A-5D show data for Fab and anti-HLA-G antibodies that restore NKL killing activity by blocking suppression mediated by the interaction of HLA-G with ILT2 or ILT4.

In fig. 6 shows an assessment of anti-HLA-G antibody reversal of HLA-G-mediated suppression of primary human cells. In fig. 6A and 6B present an assessment of phagocytosis in a human macrophage assay. In fig. Figure 6C shows an assessment of the cytotoxic activity of primary human NK cells. In fig. 6D shows an assessment of the function of primary human CD8' T cells.

In fig. 7A and 7B show results corresponding to values for binding of anti-HLA-G antibodies to individual recombinant HLA class Ia antigens immobilized on beads.

In fig. 8 shows an assessment of the binding of anti-HLA-G antibodies to a panel of B-lymphoblastoid cells (B-LCL) of 28 HLA-typed lines.

In fig. 9A and 9B show an assessment of the binding of anti-HLA-G antibodies to various forms of HLA-G after site-directed mutagenesis.

In fig. 10 shows data confirming the inhibition of tumor growth by an anti-HLA-G antibody with Fc effector function in a tumor xenograft mouse model using 721.221 cells expressing HLA-G.

Detailed Description of the Invention

1. Definitions.

Unless otherwise indicated, all terms, symbols and other scientific terms used herein are intended to have meanings well known to those skilled in the art to which this invention relates. In some cases, terms with commonly known meanings are defined herein for clarity of understanding and/or ease of reference; the inclusion of such definitions herein does not necessarily imply any difference from the meanings customary in the art. The techniques and procedures described or referred to herein are generally well known and are often used using standard techniques by those skilled in the art, such as the widely used molecular cloning methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual, ^2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. If necessary, procedures involving the use of commercially available kits and reagents are performed, generally in accordance with manufacturer-provided protocols and/or parameters unless otherwise specified.

As used herein, terms used in the singular include their plural equivalents unless the context clearly indicates otherwise.

The term approximates a given value and covers a given value as well as a range of smaller and larger values relative to it. According to some embodiments

- 2 045983 the term approximately indicates the specified value of ±10%, ±5% or ±1%. In some embodiments, the term approximately indicates the indicated value ± standard deviation of the indicated value.

The term combination includes all possible combinations of elements to which the given term refers.

The term immunoglobulin refers to a class of structurally related proteins typically containing two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In intact immunoglobulin, all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been described in detail. See, for example, Paul, Fundamental Immunology ^7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically contains a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically contains three domains, _CH1 , _CH2 and _CH3 . Each light chain typically contains a light chain variable region (V _L ) and a light chain constant region. The light chain constant region typically contains one domain, abbreviated CL.

The term antibody describes a type of immunoglobulin molecule and is used herein in its broadest sense. Antibody specifically includes intact antibodies (eg, intact immunoglobulins), as well as antibody fragments and antigen-binding proteins. Antibodies contain at least one antigen binding domain. One example of an antigen binding domain is the antigen binding domain formed by the VH-VL dimer. An anti-HLA-G antibody, an anti-HLA-G antibody, an HLA-G-Ab, an HLA-G-specific antibody, or an anti-HLA-G Ab is an antibody as described herein that specifically binds to an HLA-G antigen.

The V _H and V _L regions can be further subdivided into hypervariable regions (hypervariable regions (HVRs); also called complementarity determining regions (CDRs)) interspersed with more conserved regions. These more conserved regions are called framework regions (FR). Each of the VH and VL regions typically contains three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 FR3 - CDR3 - FR4. These CDRs are involved in antigen binding and impart antigen specificity and binding affinity to the antibody. See source: Kabat et al., Sequences of Proteins of Immunological Interest ^5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated herein by reference in its entirety.

The light chain of any vertebrate species can be classified into one of two types, called kappa and lambda, based on the sequence of the constant domain.

The heavy chain of any vertebrate species can be classified into one of five distinct classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also called α, δ, ε, γ and μ, respectively. The IgG and IgA classes are further divided into subclasses based on differences in sequence and function. In humans, the following subclasses are expressed: IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.

CDR amino acid sequence boundaries can be determined by one skilled in the art using any of a number of known numbering schemes, including those described in Kabat et al., supra (Kabat numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol, 273:927948 (Chothia numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (contact numbering scheme); Lefranc et al., Dev. Sotr. Immunol 2003, 27:55-77 (IMGT numbering scheme); and Honegge and Pluckthun, J. Mol. Biol, 2001, 309:657-70 (ANO numbering scheme), each of which is incorporated herein by reference in its entirety.

In table Figure 1 shows the positions included in CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3, identified according to the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both Kabat and Chothia numbering schemes.

Unless otherwise noted, the Kabat/Chothia numbering scheme is used to identify a specific CDR in this document. In cases where the residues defined by the two numbering schemes are different, it is specified which numbering scheme is used, Kabat or Chothia.

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Table 1

Remnants of the CDR according to the Kabat and Chothia numbering schemes

CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat numbering) Н31-Н35В H26-H32 or H34* Hl (Chothia numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 NZ N95-N102 N95-N102

*The C-terminus of CDR-H1 when numbered using the Kabat numbering system varies, corresponding to residue H32 or H34, depending on the length of the CDR.

The EU numbering scheme is typically used when describing the constant region residues of an antibody heavy chain (eg, as described by Kabat et al., supra). Unless otherwise noted, the EU numbering scheme is used to describe the heavy chain constant region residues of the antibodies described herein.

An antibody fragment contains 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') ₂ fragments, Fab fragments, scFv-(sFv) fragments and scFv-Fc fragments.

Fv'' fragments contain a non-covalently linked dimer containing one heavy chain variable domain and one light chain variable domain.

Fab'' fragments contain, along with heavy and light chain variable domains, a light chain constant domain and a first heavy chain constant domain ( _CH1 ). Fab fragments can be obtained, for example, by digesting the full-length antibody with papain.

F(ab')2 fragments contain two Fab' fragments connected near the hinge region by disulfide bonds. F(ab')2 fragments can be obtained, for example, by digestion of the intact antibody with pepsin. F(ab') fragments can be dissociated, for example, by treatment with βmercaptoethanol.

Single-chain Fv, or sFv, or scFv'' antibody fragments contain a VH domain and a VL domain in the same polypeptide chain. VH and VL are usually connected by a peptide linker. See Pluckthun 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, which is incorporated herein by reference in its entirety. scFv-Fc'' fragments contain scFv attached to an Fc domain. For example, the Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow VH or VL, depending on the orientation of the variable domains in scFv (ie, VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein can be used.

The term monoclonal antibody refers to an antibody from a population of essentially homogeneous antibodies. A population of substantially homogeneous antibodies contains antibodies that are substantially similar and bind the same epitope(s), excluding variations that may normally occur when a monoclonal antibody is produced. Such variants are usually present in small quantities. A monoclonal antibody is typically produced by a process that involves selecting a single antibody from a plurality of antibodies. For example, the selection method may be selecting 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 may be further modified, 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 immunogenicity in a subject.

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 and the remainder of the heavy and/or light chain is derived from another source or species.

Humanized forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from a non-human antibody. A humanized antibody is typically a human immunoglobulin (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). Said donor antibody may be any suitable non-human antibody, for example a mouse, rat, rabbit, chicken or non-human primate antibody, with the desired specificity, affinity or biological effect. In some cases, selected framework residues from the recipient antibody are replaced with corresponding framework residues from the donor antibody.

- 4 045983 antibodies. Humanized antibodies may also contain residues not found in either the recipient antibody or the donor antibody. Such modifications can be implemented to further improve the function of the antibody. Additional information can be found in: 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 herein by reference in its entirety.

A human antibody is an antibody that has an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or is derived from a non-human source involving the human antibody repertoire or human antibody coding sequences (e.g., from human-derived sources or developed de novo ). Humanized antibodies are specifically excluded from human antibodies.

An isolated antibody is an antibody that has been separated from and/or isolated from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other protein or non-protein materials. In some embodiments, the isolated antibody is purified to an extent sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example, using a rotating beaker sequencer. In some embodiments, the isolated antibody is purified to homogeneity by gel electrophoresis (eg, SDS-PAGE) under reducing or non-reducing conditions, with Coomassie Blue or Silver detection. The isolated antibody includes the antibody in situ within the recombinant cells since at least one component of the antibody's natural environment is missing. In some aspects, the isolated antibody is obtained using at least one purification step.

In some embodiments, the isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, the isolated antibody is provided in the form of a solution containing at least 85%, 90%, 95%, 98%, 99%, and up to 100% of the antibody by weight, with the remainder being other substances dissolved in the solvent.

Affinity refers to the strength of the total amount of noncovalent interactions between one binding site of a molecule (such as an antibody) and its binding partner (such as an antigen). Unless otherwise specified, as used herein, binding affinity refers to the true binding affinity, which reflects the 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can usually be expressed in terms of the dissociation constant (KD). Affinity can be measured by conventional methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as the Biacore® instrument, or using biolayer interferometry technology, using the Octet® instrument.

In the context of 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 means binding that is measurably different from a nonspecific or nonselective interaction . Specific binding can be measured, for example, by determining the binding of a molecule and comparing it with the binding of a control molecule. Specific binding can also be determined using competition with a control molecule similar to the target, for example, an excess of unlabeled target. In this case, specific binding is indicated by competitive inhibition of the binding of the labeled target to the probe by an excess of unlabeled target.

The term kd (c ^-1 ) as used herein refers to the dissociation rate constant of a particular antibody-antigen interaction. The specified value is also called the koff value.

The term k _a (M ^-1 s ^-1 ) as used herein refers to the binding rate constant of a particular antibody-antigen interaction. The specified value is also called the kon value.

The term KD(M) as used herein refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. KD=kd/ka.

The term K _A (M ^-1 ), as used herein, refers to the binding equilibrium constant for a particular antibody-antigen interaction. K _A =k _a /kd.

An affinity matured antibody is an antibody with one or more changes in one or more CDRs or FRs that result in an improvement in the antibody's affinity for an antigen compared to a parent antibody that does not contain the change (or changes). In one embodiment, the affinity matured antibody has an affinity for the target antigen in the nanomolar or picomolar range. Affinity matured antibodies can be prepared using various methods known in the art.

- 5 045983 ki. For example, Marks et al. ('source: Marks et al., Bio/Technology, 1992, 10:779-783, incorporated by reference in its entirety) describe affinity maturation by swapping the VH and _VL domains. Random mutagenesis of CDRs and/or framework residues is described, for example, in the sources: Barbas et al. (Proc. Nat. Acad. Sci. USA, 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.

As 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 (eg, HLA-G). In one example of the assay, HLA-G is applied to a plate and allowed to bind to the first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces the binding of the second antibody, this means that these antibodies are competing. The term competes with also includes combinations of antibodies in which one antibody reduces the binding of another antibody, but no competition is observed when said antibodies are added in the reverse order. Moreover, in some embodiments, the first and second antibodies mutually inhibit binding, regardless of the order in which they are added. In some embodiments, one antibody reduces the binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

The term epitope means the portion of an antigen that is capable of specific binding to an antibody. Epitopes often consist of surface accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics as well as specific charging characteristics. Conformational and non-conformational epitopes differ in that binding to the former, but not to the latter, is lost in the presence of denaturing solvents.

An epitope may contain amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding. The epitope to which the antibody binds can be determined using known epitope detection techniques, such as, for example, testing the antibody for binding to HLA-G variants with different point mutations.

The percentage identity between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the specified 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 percentage of sequence identity. Alignment to determine percent amino acid identity can be accomplished in a variety of ways known in the art, for example, using publicly available software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW software or CLUSTAL OMEGA. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared.

Conservative substitution, or conservative amino acid substitution, refers to the replacement of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables listing analogous amino acids are well known in the art. Polypeptide sequences containing such substitutions are known as conservatively modified variants. For example, the following groups of amino acids are considered conservative substitutions for each other.

Acidic residues D and E Main balances K, RiiH Hydrophilic uncharged residues S, T, N and Q Aliphatic uncharged residues G,A,V,L and I Non-polar uncharged residues S,MiR Aromatic residues F, Y and W Residues containing an alcohol group ShT

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Aliphatic residues I, L, V and M Cycloalkenyl-associated residues F, H, W and Y Hydrophobic residues A, C, F, G, Η, 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 N, KhR Small leftovers A, C, D, G, N, P, S, T and V Very small leftovers A, Git S Residues involved in coil formation A, C, D, E, G, H, K, N, Q, R, S, P and T Flexible balances Q, T, K, S, G, P, D, E and R Group 1 A, S and T Group 2 D and E Group 3 NtiQ Group 4 RhK Group 5 I, LhM Group 6 F, Y and W Group A AtiG Group B D and E Group C NtiQ Group D R, KiN Group E I, L, M, V GroupF F, Y and W Group G SiiT Group With IM

Additional conservative substitutions are described, for example, in Creighton, Proteins: Structures and Molecular Properties 2 ^nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody produced by introducing one or more conservative substitutions of amino acid residues into the original antibody is called a conservatively modified variant.

The term amino acid refers to 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), series (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y) and valine (Val; V).

Treating or treating any disease or disorder refers, in some embodiments, to alleviating the disease or disorder present in the subject. In another embodiment, treating or treating includes alleviating at least one physical parameter that may be indistinguishable to the subject. In yet another embodiment, treating or treating includes modulating the disease or disorder either physically (eg, stabilizing a discernible symptom), physiologically (eg, stabilizing a physical measure), or both. In yet another embodiment, treating or treating includes delaying or preventing the onset of a disease or disorder.

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.

As used herein, the term subject means a mammalian subject.

Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, birds, goats and sheep. In some embodiments, the subject is a human. In some embodiments, the subject suffers from cancer, an autoimmune disease or condition, and/or infection, which can be treated with an antibody of the present invention. In some embodiments, the subject is a person believed to be suffering from cancer, an autoimmune disease or condition, and/or an acute infection and a chronic infection.

2. Antibodies.

The present invention provides antibodies that selectively bind HLA-G

- 7,045,983 people. In some aspects, the antibody selectively binds to the extracellular domain of human HLA-G.

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

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

In some embodiments, the antibody comprises a light chain. In some aspects, said light chain is a kappa light chain. In some aspects, said light chain is a lambda light chain.

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

In some embodiments, the antibody is an antibody fragment. In some aspects, said antibody fragment is an Fv fragment. In some aspects, said antibody fragment is a Fab fragment. In some aspects, said antibody fragment is an F(ab') ₂ fragment. In some aspects, said antibody fragment is a Fab' fragment. In some aspects, said antibody fragment is a scFv (sFv) fragment. In some aspects, said antibody fragment is a scFv-Fc fragment.

In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

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.

In some embodiments, the antibody is an affinity matured antibody. In some aspects, the antibody is an affinity matured antibody derived from an exemplary sequence set forth herein.

In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to an inhibitory GPM receptor. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to ILT2. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to ILT4. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to KIR2DL4. In embodiments, the antibody binds HLA-G but does not block the interaction between HLA-G and ILT2, ILT4, and/or KIRDL4. In some embodiments, the antibody disrupts the HLA-G heterodimer and/or prevents HLAG dimerization.

In some embodiments, the antibody inhibits immunosuppressive function. In some embodiments, the antibody inhibits HLA-G-mediated suppression of NK cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of cytotoxic T lymphocytes. In some embodiments, the antibody inhibits HLA-G-mediated suppression of B cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of neutrophils. In some embodiments, the antibody inhibits indirectly

- 8 045983 new HLA-G suppression of dendritic cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of macrophages. In some embodiments, the antibody inhibits HLA-G-mediated suppression of monocytes. In some embodiments, the antibody inhibits HLA-G-mediated suppression of cytolysis and/or proliferation of NK and/or T cells.

In some embodiments, the antibody prevents or inhibits HLA-G-mediated suppression of phagocytosis. In some embodiments, the antibody mediates HLA-G-mediated induction of regulatory T cells. In some embodiments, the antibody prevents or inhibits the formation or expansion of regulatory T cells.

The antibodies provided by the present invention may be suitable for the treatment of various diseases and conditions, including cancer, autoimmune diseases and infections. In some embodiments, the antibody inhibits HLA-G function on tumor cells. In some embodiments, the antibody inhibits HLA-G function on immune cells. In some embodiments, the antibody inhibits HLAG function on myeloid cells. In some embodiments, the antibody inhibits HLA-G function on subsets of T cells. In some embodiments, the antibody inhibits metastasis. In some embodiments, the antibody inhibits angiogenesis.

In some embodiments, the antibody competes or is capable of competing for binding to human HLA-G with another antibody. In some embodiments, said antibody comprises or includes an antibody that is capable of competing for binding of human HLA-G to a reference antibody, characterized in that said reference antibody binds to an epitope containing positions 195, 197, and/or 198 of SEQ ID NO: 342 , on the human HLA-G polypeptide. In some embodiments, the antibody and the reference antibody cross-compete or are capable of cross-competing for binding human HLA-G to another antibody.

In some embodiments, the antibody binds to an epitope comprising position 195, 197 and/or 198 of SEQ ID NO: 342 on a human HLA-G polypeptide. In some aspects, the epitope comprises or consists of a continuous or discontinuous stretch of amino acids comprising residues 195, 197 and/or 198 of the sequence set forth in SEQ ID NO: 342. In some aspects, said epitope contains a sequence identical to or corresponding to residues 195, 197, and/or 198 of the sequence set forth in SEQ ID NO: 342. In some aspects, said epitope has a sequence that is 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identical to the sequence set forth in SEQ ID NO: 342. In some aspects, the epitope contains 1, 2, 3, 4, 5, 6 , 7, 8, or 9 substitutions relative to the sequence included in the sequence set forth in SEQ ID NO: 342. In some aspects, the epitope contains 1, 2, or 3 substitutions relative to the residues included in the sequence set forth in SEQ ID NO: 342. In some aspects, the antibody contacts any of the moieties shown in FIG. 9.

2.1. CDR-H3 sequences.

In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 76. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 77. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 78. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 79. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 80. In some aspects, the antibody comprises a CDRH3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 81. In some aspects, the antibody contains a CDRH3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 81. In some aspects, the antibody comprises a CDRH3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 81. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 82. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 83. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 83. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 83. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 84. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 85. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 85. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 85. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 86. In certain aspects

- 9 045983 said antibody comprises a CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 87. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 88. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 89. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 90. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 91. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 92. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 93. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 94. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 95. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 96. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 97. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 98. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 99. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 100. In some aspects, said antibody comprises a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 101.

In some aspects, the CDR-H3 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-H3 sequence set forth herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H3 sequences given in the present description. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-H3 sequences provided herein with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.2. VH sequences containing illustrative CDRs.

In some embodiments, the antibody comprises a VH sequence comprising one or more CDR-H sequences containing, consisting of, or essentially consisting of one or more exemplary CDR-H sequences provided herein and variants thereof.

2.2.1. VH sequences containing Kabat's illustrative CDRs.

In some embodiments, the antibody comprises a VH sequence comprising one or more Kabat CDR-H sequences containing, consisting of, or essentially consisting of one or more exemplary Kabat CDR-H sequences provided herein and variants thereof.

2.2.1.1. CDR-H3 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 76. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 77. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 78. In some aspects, said antibody comprises the sequence A VH comprising a Kabat CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 79. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDRH3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: : 80. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 81. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 82. In some aspects, said antibody comprises a VH sequence comprising a sequence

- 10 045983 a Kabat CDR-H3 comprising, consisting of, or essentially consisting of SEQ ID NO: 83. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 84. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 85. In some aspects, said antibody comprises a VH sequence comprising a CDR-H3 sequence according to Kabat, comprising, consisting of, or essentially consisting of SEQ ID NO: 86. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 87. In some aspects, In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 88. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 89. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 90. In some aspects, said antibody comprises a VH sequence, comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 91. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: : 92. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 94. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 95. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 96. In some aspects, said the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 97. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDRH3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 98. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 99. In some aspects, said antibody comprises a VH sequence comprising a CDR- sequence Kabat H3 comprising, consisting of, or essentially consisting of SEQ ID NO: 100. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 101.

2.2.1.2. CDR-H2 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 54-71. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 54. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 55. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 56. In some aspects, said antibody comprises the sequence A VH comprising a Kabat CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 57. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDRH2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: : 58. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 59. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 60. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 61. In some aspects, said the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 62. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 63. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of

- 11 045983 from SEQ ID NO: 64. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 65. In some aspects, said antibody comprises a VH sequence , comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 66. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 67. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 68. In some aspects, said antibody comprises a VH sequence comprising a CDR-H2 sequence according to Kabat, comprising, consisting of, or essentially consisting of SEQ ID NO: 69. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 70. In some aspects, In aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 71.

2.2.1.3. CDR-H1 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 18-34. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 18. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising , consisting of or essentially consisting of SEQ ID NO: 19. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 20. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 21. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDRH1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 22. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 23. In some aspects, said antibody comprises a VH sequence comprising a CDR- sequence Kabat H1 comprising, consisting of, or essentially consisting of SEQ ID NO: 24. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 25. According to In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 26. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 27. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 28. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 29. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 30. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 31. In some aspects, said antibody comprises a VH sequence comprising a CDR- sequence Kabat H1 comprising, consisting of, or essentially consisting of SEQ ID NO: 32. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 33. According to In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 34.

2.2.1.4. CDR-H3 by Kabat + CDR-H2 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101, and a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 54-71. In some aspects, both Kabat CDR-H3 and Kabat CDR-H2 are taken from the same exemplary VH sequence provided herein. For example, in some aspects, both Kabat CDR-H3 and Kabat CDR-H2 are taken from the same illustrative sequence

- 12 045983

VH selected from SEQ ID NO: 170-200.

2.2.1.5. CDR-H3 by Kabat + CDR-H1 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101, and a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 18-34. In some aspects, both Kabat CDR-H3 and Kabat CDR-H1 are taken from the same exemplary VH sequence provided herein. For example, in some aspects, both Kabat CDR-H3 and Kabat CDR-H1 are taken from the same exemplary VH sequence selected from SEQ ID NO: 170-200.

2.2.1.6. CDR-H1 by Kabat + CDR-H2 by Kabat.

In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 18-34, and a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 54-71. In some aspects, both Kabat CDR-H1 and Kabat CDR-H2 are taken from the same exemplary _VH sequence provided herein. For example, in some aspects, both Kabat CDR-H1 and Kabat CDR-H2 are taken from the same exemplary VH sequence selected from SEQ ID NO: 170-200.

2.2.1.7. CDR-H1 by Kabat + CDR-H2 by Kabat + CDR-H3 by Kabat.

In some embodiments, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 18-34, a Kabat CDR-H2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 54-71, and a Kabat CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101. In some aspects, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 sequences are all taken from a single exemplary _VH sequence provided herein. For example, in some aspects, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 sequences are all taken from a single exemplary _VH sequence selected from SEQ ID NO: 170-200.

In some aspects, the antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 18, a Kabat CDR-H2 sequence comprising SEQ ID NO: 54, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 76. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 19, a Kabat CDR-H2 sequence comprising SEQ ID NO: 55, and a Kabat CDR-H3 sequence. comprising SEQ ID NO: 77. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 20, a Kabat CDR-H2 sequence comprising SEQ ID NO: 56, and a CDR-H3 sequence Kabat comprising SEQ ID NO: 78. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, a Kabat CDR-H2 sequence comprising SEQ ID NO: 57, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 79. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 22, a Kabat CDR-H2 sequence comprising SEQ ID NO: 58, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 80. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, a Kabat CDR-H2 sequence comprising SEQ ID NO: 57, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 76. In some aspects, the antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, a Kabat CDR-H2 sequence Kabat comprising SEQ ID NO: 59, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 76. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, sequence Kabat CDR-H2 comprising SEQ ID NO: 60 and a Kabat CDR-H3 sequence comprising SEQ ID NO: 81. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, a Kabat CDR-H2 sequence comprising SEQ ID NO: 59, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 82. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, a Kabat CDR-H2 sequence comprising SEQ ID NO: 59, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 76. In some aspects, said antibody comprises a V _H sequence comprising a CDR-H1 sequence Kabat containing SEQ ID NO: 23, Kabat sequence CDR-H2, with

- 13 045983 containing SEQ ID NO: 59, and a Kabat CDR-H3 sequence containing SEQ ID NO: 81. In some aspects, said antibody contains a V _H sequence containing a Kabat CDR-H1 sequence containing SEQ ID NO: 21, a Kabat CDR-H2 sequence comprising SEQ ID NO: 57, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 83. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, a Kabat CDR-H2 sequence comprising SEQ ID NO: 57, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 84. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 24, a Kabat CDR-H2 sequence comprising SEQ ID NO: 61, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 85. In some aspects, said antibody comprises a VH sequence comprising a CDR- Kabat H1 comprising SEQ ID NO: 24, Kabat CDR-H2 sequence comprising SEQ ID NO: 61, and Kabat CDR-H3 sequence comprising SEQ ID NO: 86. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequence comprising SEQ ID NO: 62, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 87. In some aspects, said antibody comprises the sequence V _H comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 63, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 88. In some aspects said antibody contains a V _H sequence containing a Kabat CDR-H1 sequence containing SEQ ID NO: 26, a Kabat CDR-H2 sequence containing SEQ ID NO: 63, and a Kabat CDR-H3 sequence containing SEQ ID NO: 89 In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequence comprising SEQ ID NO: 63, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 90. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 90. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 28, a Kabat CDR-H2 sequence comprising SEQ ID NO: 62, and a CDR sequence Kabat -H3 comprising SEQ ID NO: 91. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 29, a Kabat CDR-H2 sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 92. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequence comprising SEQ ID NO: : 65, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 93. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a Kabat CDR-H2 sequence, comprising SEQ ID NO: 66, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 94. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 31, a CDR- sequence Kabat H2 comprising SEQ ID NO: 67, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 95. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 32, a Kabat CDR-H2 sequence comprising SEQ ID NO: 68, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 96. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO : 33, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 97. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence, comprising SEQ ID NO: 34, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 98. In some aspects, said antibody comprises a V _H sequence comprising a CDR- sequence Kabat H1 comprising SEQ ID NO: 18, Kabat CDR-H2 sequence comprising SEQ ID NO: 54, and Kabat CDR-H3 sequence comprising SEQ ID NO: 99. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 31, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 100. In some aspects, said antibody comprises the sequence VH containing the Kabat CDR-H1 sequence containing SEQ ID NO: 24, the Kabat CDR-H2 sequence containing SEQ ID NO: 61, and the Kabat CDR-H3 sequence containing SEQ ID NO: 101.

2.2.1.8. Variants of V _H sequences containing Kabat's illustrative CDRs.

- 14 045983

In some embodiments, the VH sequences provided by the present invention comprise a variant of the exemplary Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequence set forth herein.

In some aspects, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an exemplary Kabat CDR-H3 sequence set forth herein. In some aspects, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H sequences according to Kabat3, given in this description. In some aspects, the Kabat CDRH3 sequence comprises, consists of, or consists essentially of any of the exemplary Kabat3 CDR-H sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the Kabat CDR-H2 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary Kabat CDR-H2 sequence set forth herein. In some aspects, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary Kabat CDR-H2 sequences. Kabat sequences given herein. In some aspects, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the exemplary Kabat CDR-H2 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the Kabat CDR-H1 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary Kabat CDR-H1 sequence set forth herein. In some aspects, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H1 sequences according to Kabat, given in this description. In some aspects, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the exemplary Kabat CDR-H1 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.2.2. VH sequences containing illustrative Chothia CDRs.

In some embodiments, the antibody comprises a VH sequence comprising one or more Chothia CDR-H sequences containing, consisting of, or essentially consisting of one or more exemplary Chothia CDR-H sequences provided herein and variants thereof.

2.2.2.1. CDR-H3 by Chothia.

In some embodiments, the antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 76. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 77. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 78. In some aspects, said antibody comprises the sequence A V _H comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 79. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence, comprising, consisting of, or essentially consisting of from SEQ ID NO: 80. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 81. In some aspects, said antibody comprises a VH sequence comprising the sequence A Chothia CDR-H3 comprising, consisting of, or essentially consisting of SEQ ID NO: 82. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 83 In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 84. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence, containing, consisting of or essentially

- 15 045983 consisting of SEQ ID NO: 85. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 86. In some aspects, said antibody comprises the sequence a V _H comprising a Chothia CDR-H3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 87. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of or essentially consisting of from SEQ ID NO: 88. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 89. In some aspects, said antibody comprises a VH sequence comprising the sequence A Chothia CDR-H3 comprising, consisting of, or essentially consisting of SEQ ID NO: 90. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 91 In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 92. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 93. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 94. In some aspects, said the antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 95. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 96. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 97. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 98. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: : 99. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 100. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence Chothia, containing, consisting of or essentially consisting of SEQ ID NO: 101.

2.2.2.2. CDR-H2 by Chothia.

In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 38-50. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 38. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 39. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 40. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 41. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of or essentially consisting of from SEQ ID NO: 42. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 43. In some aspects, said antibody comprises a VH sequence comprising the sequence A Chothia CDR-H2 comprising, consisting of, or essentially consisting of SEQ ID NO: 44. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 45. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 46. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 47. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 48. In some aspects, said antibody contains a V _H sequence containing a Chothia CDR-H2 sequence containing, consisting

- 16 045983 or essentially consisting of SEQ ID NO: 49. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 50.

2.2.2.3. CDR-H1 by Chothia.

In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 1-14. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 1. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising , consisting of or essentially consisting of SEQ ID NO: 2. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDRH1 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 3. In some aspects, said antibody comprises a VH sequence , comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 4. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 5. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 6. In some aspects, said antibody comprises a _VH sequence comprising a CDR sequence A Chothia -H1 comprising, consisting of, or essentially consisting of SEQ ID NO: 7. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 8. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 9. In some aspects, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising , consisting of or essentially consisting of SEQ ID NO: 10. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 11. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 12. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 13. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 14.

2.2.2.4. CDR-H3 for Chothia + CDR-H2 for Chothia.

In some embodiments, the antibody comprises a V _H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101, and a Chothia CDR-H2 sequence comprising, consisting of or essentially consisting of a sequence selected from SEQ ID NO: 38-50. In some aspects, both the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are taken from the same exemplary VH sequence provided herein. For example, in some aspects, both Chothia CDR-H3 and Chothia CDR-H2 are taken from the same exemplary VH sequence selected from SEQ ID NO: 170-200.

2.2.2.5. CDR-H3 for Chothia + CDR-H1 for Chothia.

In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101, and a Chothia CDR-H1 sequence comprising, consisting of or essentially consisting of a sequence selected from SEQ ID NO: 1-14. In some aspects, both the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are taken from the same exemplary _VH sequence provided herein. For example, in some aspects, both Chothia CDR-H3 and Chothia CDR-H1 are taken from the same exemplary V _H sequence selected from SEQ ID NO: 170-200.

2.2.2.6. CDR-H1 for Chothia + CDR-H2 for Chothia.

In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 1-14, and a Chothia CDR-H2 sequence comprising, consisting of or essentially consisting of a sequence selected from SEQ ID NO: 38-50. In some aspects, both the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are taken from the same exemplary _VH sequence provided herein. For example, in some aspects, both Chothia CDR-H1 and Chothia CDR-H2

- 17 045983

Chothia are taken from one illustrative VH sequence selected from SEQ ID NO: 170-200.

2.2.2.7. CDR-H1 for Chothia + CDR-H2 for Chothia + CDR-H3 for Chothia.

In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 1-14, a Chothia CDR-H2 sequence, consisting of, or essentially consisting of from a sequence selected from SEQ ID NO: 3850, and a Chothia CDR-H3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 76-101. In some aspects, both the Chothia CDR-H1 sequence, the Chothia CDR-H2 sequence, and the Chothia CDR-H3 sequence are taken from the same exemplary VH sequence provided herein. For example, in some aspects, both Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are taken from the same exemplary VH sequence selected from SEQ ID NO: 170-200.

In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2 sequence comprising SEQ ID NO: 38, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 76. In some embodiments, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 39, and a CDR-H3 sequence Chothia comprising SEQ ID NO: 77. In some embodiments, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 40, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 78. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 3, a Chothia CDR-H2 sequence comprising SEQ ID NO : 41, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 79. In some embodiments, said antibody comprises a _VH sequence comprising a Chothia CDRNH1 sequence comprising SEQ ID NO: 4, a Chothia CDR-H2 sequence comprising SEQ ID NO: 41, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 80. In some embodiments, the antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 3, a CDR- sequence Chothia H2 comprising SEQ ID NO: 41, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 76. In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2 , a Chothia CDRH2 sequence comprising SEQ ID NO: 42, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 76. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO : 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 43, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 81. In some embodiments, the antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 42, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82. In some embodiments, the antibody comprises a VH sequence comprising a CDR sequence Chothia -H1 comprising SEQ ID NO: 5, a Chothia CDR-H2 sequence comprising SEQ ID NO: 42, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 76. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence containing SEQ ID NO: 2, a Chothia CDR-H2 sequence containing SEQ ID NO: 42, and a Chothia CDR-H3 sequence containing SEQ ID NO: 81. In some embodiments, the above the antibody comprises a VH sequence comprising a Chothia CDRH1 sequence comprising SEQ ID NO: 3, a Chothia CDR-H2 sequence comprising SEQ ID NO: 41, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 83. In some embodiments In an embodiment, said antibody comprises a V _H sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 3, a Chothia CDR-H2 sequence containing SEQ ID NO: 41, and a Chothia CDR-H3 sequence containing SEQ ID NO: 84. In some embodiments, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDRH2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 85. In some embodiments, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a CDR-H3 sequence according to Chothia, containing SEQ ID NO: 86. In some embodiments, the antibody contains a V _H sequence containing a Chothia CDR-H1 sequence, containing SEQ ID NO: 7, a Chothia CDR-H2 sequence, containing SEQ ID NO: 45, and CDR-H3 sequence

- 18 045983 to Chothia, containing SEQ ID NO: 87. In some embodiments, the antibody contains a VH sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 8, a Chothia CDR-H2 sequence containing SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 88. In some embodiments, the antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 8, a Chothia CDR-H2 sequence, comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 89. In some embodiments, said antibody comprises a _VH sequence comprising a Chothia CDRH1 sequence comprising SEQ ID NO: 7, a CDR-H2 sequence a Chothia sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 90. In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 9, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 90. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDRH2 sequence comprising SEQ ID NO: 45, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 91. In some embodiments, said antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence, comprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 92. In some embodiments, said antibody comprises a VH sequence comprising a CDR- sequence Chothia H1 containing SEQ ID NO: 7, Chothia CDR-H2 sequence containing SEQ ID NO: 44, and Chothia CDR-H3 sequence containing SEQ ID NO: 93. In some embodiments, said antibody comprises a VH sequence, comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 94. In some embodiments, said antibody contains a VH sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 11, a Chothia CDR-H2 sequence containing SEQ ID NO: 47, and a Chothia CDR-H3 sequence containing SEQ ID NO: 95. According to some In embodiments, said antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence containing SEQ ID NO: 12, a Chothia CDR-H2 sequence containing SEQ ID NO: 48, and a Chothia CDR-H3 sequence containing SEQ ID NO: : 96. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence, comprising SEQ ID NO: 97. In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 49, and a CDR- sequence Chothia H3 comprising SEQ ID NO: 98. In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2 sequence comprising SEQ ID NO: 38, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 99. In some embodiments, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 11, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 100. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDR-H2 sequence , containing SEQ ID NO: 44, and the Chothia CDR-H3 sequence, containing SEQ ID NO: 101.

2.2.2.8. VH sequence variants containing illustrative Chothia CDRs.

In some embodiments, the V _H sequences provided by the present invention comprise a variant of the exemplary Chothia CDR-H3, CDR-H2, and/or CDR-H1 sequence set forth herein.

In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an exemplary Chothia CDR-H3 sequence set forth herein. In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H3 sequences according to Chothia, given in this description. In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the exemplary Chothia CDR-H3 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the Chothia CDR-H2 sequence contains a variant consisting

- 19 045983 or consists essentially of a variant of the illustrative Chothia CDR-H2 sequence set forth herein. In some aspects, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H2 sequences according to Chothia, given in this description. In some aspects, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the exemplary Chothia CDR-H2 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the Chothia CDR-H1 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary Chothia CDR-H1 sequence set forth herein. In some aspects, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H1 sequences according to Chothia, given in this description. In some aspects, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the exemplary Chothia CDR-H1 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.3. VH sequences.

In some embodiments, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 170-200. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 170. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 171. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 171. the antibody contains a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 172. In some aspects, the antibody contains a VH sequence containing, consisting of, or essentially consisting of SEQ ID NO: 173. In some aspects, the antibody contains a VH sequence , comprising, consisting of, or essentially consisting of SEQ ID NO: 174. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 175. In some aspects, said antibody comprises a VH sequence, comprising, consisting of or essentially consisting of SEQ ID NO: 176. In some aspects, said antibody contains a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 177. In some aspects, said antibody contains a VH sequence comprising, consisting of, or essentially consisting of from SEQ ID NO: 178. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 179. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: : 180. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 181. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 182. In accordance with In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 183. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 184. In some aspects, said antibody contains a VH sequence containing, consisting of, or essentially consisting of SEQ ID NO: 185. In some aspects, said antibody contains a VH sequence containing, consisting of, or essentially consisting of SEQ ID NO: 186. In some aspects, said antibody contains a VH sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 187. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 188. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 189. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 190. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 191. In some aspects, the antibody contains a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 192. In some aspects, the antibody contains a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 192. 193. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 194. In some aspects, the antibody comprises a VH sequence comprising, consisting of

- 20045983 consisting of or essentially consisting of SEQ ID NO: 195. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 196. In some aspects, said antibody comprises a VH sequence comprising, consisting of or essentially consisting of SEQ ID NO: 197. In some aspects, said antibody comprises a _VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 198. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of consisting of SEQ ID NO: 199. In some aspects, said antibody comprises a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 200.

2.3.1. VH sequence variants.

In some embodiments, the VH sequences provided by the present invention comprise, consist of, or consist essentially of a variant of an exemplary VH sequence set forth herein.

In some aspects, the VH sequence comprises, consists of, or consists essentially of a variant of an exemplary _VH sequence provided herein. In some aspects, the V _H sequence comprises, consists of, or consists essentially of a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical to any of illustrative VH sequences given herein.

In some embodiments, the V _H sequence contains, consists of, or consists essentially of any of the exemplary V _H sequences provided herein, with 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.4. CDR-L3 sequences.

In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 149-166. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 149. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 150. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 151. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 152. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 153. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 154. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 155. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 156. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 157. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 158. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 159. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 160. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 161. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 162. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 163. In some aspects, the antibody contains a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 164. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 165. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 166.

In some aspects, the CDR-L3 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-L3 sequence set forth herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-L3 sequences given in on

- 21 045983 worth description. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-L3 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.5. V _L Sequences containing illustrative CDRs.

In some embodiments, the antibody comprises a V _L sequence comprising one or more CDR-L sequences containing, consisting of, or essentially consisting of one or more exemplary CDR-L sequences provided herein and variants thereof.

2.5.1. CDR-L3.

In some embodiments, the antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 149-166. In some aspects, said antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 149. In some aspects, said antibody comprises a VL sequence comprising a CDR-L3 sequence, comprising, consisting of, or essentially consisting of consisting of SEQ ID NO: 150. In some aspects, said antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 151. In some aspects, said antibody comprises a VL sequence comprising a CDR-L sequence L3 comprising, consisting of, or essentially consisting of SEQ ID NO: 152. In some aspects, said antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 153. In some aspects, said antibody contains a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 154. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 155. In some aspects, said antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 156. In some aspects, said antibody comprises a _VL sequence comprising a CDR-L3 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 157. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 158. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 159. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 160. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 161. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 162. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 163. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 164. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 165. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 166.

2.5.2. CDR-L2.

In some embodiments, the antibody comprises a V _L sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 128-145. In some aspects, said antibody comprises a _VL sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 128. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 129. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 130. In some aspects, said antibody comprises a VL sequence comprising a CDR sequence -L2, comprising, consisting of, or essentially consisting of SEQ ID NO: 131. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L2 sequence, comprising, consisting of, or essentially

- 22 045983 consisting of SEQ ID NO: 132. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 133. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 134. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 135. In some aspects In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 136. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 137. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 138. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 139. In some aspects, said antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 140. In some aspects, said antibody comprises the sequence A V _L containing a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 141. In some aspects, said antibody comprises a V L sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 142. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L2 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 143. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 144. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L2 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 145.

2.5.3. CDR-L1.

In some embodiments, the antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 105-124. In some aspects, the antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 105. In some aspects, the antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 106. In some aspects, said antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 107. In some aspects, said antibody comprises a _VL sequence, comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 108. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 109. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 110. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 111. In some aspects, said antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 112. In some aspects, said antibody comprises a _VL sequence, comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 113. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 114. In some aspects, the antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 115. In some aspects, the antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 116. In some aspects, said antibody comprises a _VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 117. In some aspects, said antibody comprises a _VL sequence, comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 118. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 119. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially

- 23 045983 consisting of SEQ ID NO: 120. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 121. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 122. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of or essentially consisting of SEQ ID NO: 123. In some aspects In aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 124.

2.5.4. CDR-L3 + CDR-L2.

In some embodiments, said antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NO: 149-166, and a CDR-L2 sequence comprising, consisting of, or essentially consisting of sequence selected from SEQ ID NO: 128-145. In some aspects, both the CDR-L3 sequence and the CDR-L2 sequence are taken from the same exemplary V _L sequence provided herein. For example, in some aspects, both CDR-L3 and CDR-L2 are taken from the same exemplary V _L sequence selected from SEQ ID NOs: 204-228.

2.5.5. CDR-L3 + CDR-L1.

In some embodiments, said antibody comprises a V _L sequence comprising a CDR-L3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 149-166, and a CDR-L1 sequence comprising, consisting of, or essentially consisting of from the sequence selected from SEQ ID NO: 105-124. In some aspects, both the CDR-L3 sequence and the CDR-L1 sequence are taken from the same exemplary VL sequence provided herein. For example, in some aspects, both CDR-L3 and CDR-L1 are taken from the same exemplary V _L sequence selected from SEQ ID NOs: 204-228.

2.5.6. CDR-L1 + CDR-L2.

In some embodiments, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 105-124, and a CDR-L2 sequence comprising, consisting of, or essentially consisting of from the sequence selected from SEQ ID NO: 128-145. In some aspects, both CDR-L1 and CDR-L2 sequences are taken from the same exemplary VL sequence provided herein. For example, in some aspects, both the CDR-L1 and CDR-L2 sequences are taken from the same exemplary VL sequence selected from SEQ ID NOs: 204-228.

2.5.7. CDR-L1 + CDR-L2 + CDR-L3.

In some embodiments, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 105-124, a CDR-L2 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 128-145, and a CDR-L3 sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 149-166. In some aspects, the sequences, CDR-L1, CDR-L2, and CDR-L3, are all taken from a single exemplary VL sequence provided herein. For example, in some aspects, all of said sequences, CDR-L1, CDRL2, and CDR-L3, are taken from a single exemplary VL sequence selected from SEQ ID NO: 204228.

In some aspects, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, the antibody contains a V _L sequence containing a CDR-L1 sequence containing SEQ ID NO: 106, a CDR-L2 sequence containing SEQ ID NO: 129, and a CDR-L3 sequence SEQ ID NO: 150. In some aspects, said antibody contains a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 107, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a VL sequence comprising a CDR- L1 comprising SEQ ID NO: 108, a CDR-L2 sequence comprising SEQ ID NO: 130, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 109, a CDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO: 152. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 107 , CDR-L2 sequence containing

- 24 045983

SEQ ID NO: 132, and a CDR-L3 sequence SEQ ID NO: 153. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence of SEQ ID NO: 151. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ ID NO: 133, and a CDR sequence -L3 SEQ ID NO: 151. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 154. In some aspects, the antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 112, a CDR-L2 sequence comprising SEQ ID NO: 134, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, the antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 113, a CDR-L2 sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO: 156. In some aspects, the antibody contains a V _L sequence containing a CDR-L1 sequence containing SEQ ID NO: 114, a CDR-L2 sequence containing SEQ ID NO: 136, and a CDR-L3 sequence SEQ ID NO: 157. In some aspects, said antibody contains a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO: 157. In some aspects, said antibody comprises a V _L sequence comprising a CDR sequence -L1 comprising SEQ ID NO: 116, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 117, a CDR-L2 sequence comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 118 , a CDR-L2 sequence comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ ID NO: 158. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR- sequence L2 comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 119, a CDR-L2 sequence comprising SEQ ID NO: 139, and a CDR-L3 sequence SEQ ID NO: 159. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ ID NO: 140, and a CDR-L3 sequence of SEQ ID NO: 160. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 141, and a CDR- sequence L3 SEQ ID NO: 161. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 122, a CDR-L2 sequence comprising SEQ ID NO: 142, and a CDR-L3 sequence SEQ ID NO: 122 : 162. In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 143, and a CDR-L3 sequence SEQ ID NO: 163. According to In some aspects, said antibody comprises a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 143, and a CDR-L3 sequence SEQ ID NO: 164. In some aspects, said antibody comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 123, a CDR-L2 sequence comprising SEQ ID NO: 144, and a CDR-L3 sequence SEQ ID NO: 165. In some aspects, said antibody comprises a _VL sequence. comprising a CDR-L1 sequence containing SEQ ID NO: 124, a CDR-L2 sequence containing SEQ ID NO: 145, and a CDR-L3 sequence SEQ ID NO: 166.

2.5.8. V _L sequence variants containing exemplary CDR-Ls.

In some embodiments, the V _L sequences provided by the present invention comprise a variant of the exemplary CDR-L3, CDR-L2, and/or CDR-L1 sequence set forth herein.

In some aspects, the CDR-L3 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-L3 sequence set forth herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-L3 sequences given in the present description. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-L3 sequences set forth in

- 25 045983 standing description, with 1, 2 or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an exemplary CDR-L2 sequence set forth herein. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-L2 sequences given in the present description. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-L2 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the CDR-L1 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-L1 sequence set forth herein. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-L1 sequences given in the present description. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-L1 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.6. Sequences V _L .

In some embodiments, the antibody comprises a V _L sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 204-228. In some aspects, the antibody comprises a V _L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 204. In some aspects, the antibody contains a V _{L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 205. In some aspects, the antibody contains a V L} sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 205. In some aspects, said antibody comprises a V _L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 206. In some aspects, said antibody comprises a V _{L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 207. In some aspects, said antibody comprises a V L} sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 207. In some aspects, said antibody the antibody contains a _VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 208. In some aspects, the antibody contains a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 209. In some aspects, the antibody contains the sequence a VL comprising, consisting of, or essentially consisting of SEQ ID NO: 210. In some aspects, said antibody comprises a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 211. In some aspects, said antibody comprises a VL sequence comprising, consisting of or essentially consisting of SEQ ID NO: 212. In some aspects, said antibody contains a V _L sequence containing, consisting of, or essentially consisting of SEQ ID NO: 213. In some aspects, said antibody contains a V _L sequence comprising, consisting of or essentially consisting of SEQ ID NO: 214. In some aspects, said antibody comprises a _VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 215. In some aspects, said antibody comprises a VL sequence comprising, consisting of, or essentially consisting of from SEQ ID NO: 216. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 217. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: : 218. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 219. In some aspects, the antibody comprises a _VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 220. In some aspects, the antibody comprises a V _L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 221. In some aspects, the antibody contains a V _{L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 222. In some aspects, the antibody contains a V L} sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 222. In some aspects, said antibody comprises a _VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 223. In some aspects, said antibody comprises a VL sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 224. In some aspects, said antibody contains a VL sequence containing, consisting of, or essentially consisting of SEQ ID NO: 225. In some aspects, said antibody contains a VL sequence containing, consisting of, or essentially consisting of SEQ ID NO: 226. In some aspects, said antibody contains a VL sequence, comprising, consisting of, or essentially consisting of SEQ ID NO: 227. In some aspects, said antibody comprises a V _L sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 228.

- 26 045983

2.6.1. VL sequence variants.

In some embodiments, the VL sequences provided by the present invention comprise, consist of, or consist essentially of a variant of the exemplary _VL sequence set forth herein.

In some aspects, the V _L sequence comprises, consists of, or consists essentially of a variant of the exemplary V _L sequence provided herein. In some aspects, the sequence V _L comprises, consists of, or consists of a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identical to any of the illustrative VL sequences given herein.

In some embodiments, the VL sequence contains, consists of, or consists essentially of any of the exemplary VL sequences provided herein, with 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.7. Couples.

2.7.1. Pairs CDR-H3 - CDR-L3.

In some embodiments, the antibody comprises a CDR-H3 sequence and a CDR-L3 sequence. In some aspects, the CDR-H3 sequence is included in the VH and the CDR-L3 sequence is included in the VL.

In some aspects, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 76-101, and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 149-166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 76, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 77, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. According to some aspects

- 27 045983 there the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 78, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 79, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 80, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 81, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the sequence

- 28 045983

CDR-L3 is SEQ ID NO: 151. In some aspects, the sequence of CDRL3 is SEQ ID NO: 152. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 153. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In accordance with In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. L3 is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 82, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 83, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 84, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence represents

- 29 045983 fight SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, the CDR sequence is -L3 represents SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 85, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 86, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 87, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161.

- 30 045983 In some aspects, the CDR-L3 sequence is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, In some aspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 88, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 89, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 90, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

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In some aspects, the CDR-H3 sequence is SEQ ID NO: 91, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 92, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 93, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 94, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR sequence is

- 32 045983

L3 is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In accordance with In some aspects, the sequence of CDR-L3 is SEQ ID NO: 159. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 160. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 161. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 161. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 161. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 161. L3 is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 95, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 96, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 97, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is

- 33 045983

SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160 In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the sequence CDR-L3 is SEQ ID NO: 164. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 165. In some aspects, the sequence of CDR-L3 is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 98, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 99, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 100, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. According to

- 34 045983 In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects the CDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 101, and the CDR-L3 sequence is selected from SEQ ID NO: 149-166. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In some aspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, the CDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDRL3 sequence is is SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO: 153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 155. In some aspects, the CDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequence is SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO: 158. In some aspects In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In some aspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, the CDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequence is is SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO: 163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In some aspects, the CDR-L3 sequence is SEQ ID NO: : 165. In some aspects, the CDR-L3 sequence is SEQ ID NO: 166.

2.7.1.1. Pair options CDR-H3 - CDR-L3.

In some embodiments, the CDR-H3-CDR-L3 pairs provided by the present invention comprise a variant of the exemplary CDR-H3 and/or CDR-L1 sequence set forth herein.

In some aspects, the CDR-H3 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-H3 sequence set forth herein. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-H3 sequences given in the present description. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-H3 sequences provided herein with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the CDR-L3 sequence comprises a variant of, consists of, or consists essentially of a variant of an exemplary CDR-L3 sequence set forth herein. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence that is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any of the exemplary CDR-L3 sequences given in the present description. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the exemplary CDR-L3 sequences provided herein, with 1, 2, or 3 amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.7.2. VH-VL pairs.

In some embodiments, the antibody comprises a VH sequence and a VL sequence.

In some aspects, the VH sequence is a VH sequence comprising, consisting of, or essentially consisting of SEQ ID NOs: 170-200, and the VL sequence is a _VL sequence comprising, consisting of, or essentially consisting of SEQ ID NOs: 204-228 .

In some aspects, the VH sequence is SEQ ID NO: 170 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the sequence V _L is SEQ ID NO: 212. In some aspects, the sequence

- 35 045983

VL is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the _VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: : 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 171 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the sequence _VL is SEQ ID NO: 208. In some aspects, the sequence VL is SEQ ID NO: 209. In some aspects, the sequence VL is SEQ ID NO: 210. In some aspects, the sequence VL is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, In some aspects, the V _L sequence is SEQ ID NO: 215. In some aspects, the V L sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: : 218. In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V L sequence is SEQ ID NO: 221. In some aspects, the V L sequence is is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. VL is SEQ ID NO: 226. In some aspects, the sequence VL is SEQ ID NO: 227. In some aspects, the sequence V _L is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 172 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V L sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. V _L is SEQ ID NO: 215. In some aspects, the V L sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218 In some aspects, the _VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

- 36 045983

In some aspects, the VH sequence is SEQ ID NO: 173 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V L sequence is SEQ ID NO: 206. In some aspects, the V L sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the _VL sequence is SEQ ID NO: 218. In some aspects, In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V L sequence is SEQ ID NO: 225. In some aspects, the V L sequence is is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 174 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the V _L sequence is SEQ ID NO: 208. In some aspects, the V _L sequence is SEQ ID NO: 209. In some aspects, the V L sequence is SEQ ID NO: 210. In some aspects the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In accordance with In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 217. : 218. In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V L sequence is is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 175 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the sequence _VL is SEQ ID NO: 208. In some aspects, the sequence VL is SEQ ID NO: 209. In some aspects, the sequence VL is SEQ ID NO: 210. In some aspects, the sequence VL is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the _VL sequence is SEQ ID NO: 217.

- 37 045983 but in some aspects the VL sequence is SEQ ID NO: 218. In some aspects the VL sequence is SEQ ID NO: 219. In some aspects the VL sequence is SEQ ID NO: 220. In some aspects the _VL sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V L sequence is SEQ ID NO: 224. In some aspects the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 176 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: : 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the sequence _VL is SEQ ID NO: 212. In some aspects, the sequence VL is SEQ ID NO: 213. In some aspects, the sequence VL is SEQ ID NO: 214. In some aspects, the sequence VL is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the sequence V _L is SEQ ID NO: 223. In some aspects, the sequence V _L is SEQ ID NO: 224. In some aspects, the sequence V _L is SEQ ID NO: 225. In some aspects, the sequence VL is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 177 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the _VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: 207. In some aspects, the sequence V _L is SEQ ID NO: 208. In some aspects, the sequence V _L is SEQ ID NO: 209. In some aspects, the sequence V _L is SEQ ID NO: 210. In some aspects, the sequence VL is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the _VL sequence is SEQ ID NO: 218 In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V L sequence is SEQ ID NO: 225. In some aspects, the V L sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 178 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is

- 38 045983

SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is is SEQ ID NO: 210. In some aspects, the sequence V _L is SEQ ID NO: 211. In some aspects, the sequence V _L is SEQ ID NO: 212. In some aspects, the sequence V L is SEQ ID NO: 213. In accordance with In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217 In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: : 221. In some aspects, the sequence V _L is SEQ ID NO: 222. In some aspects, the sequence V _L is SEQ ID NO: 223. In some aspects, the sequence V _L is SEQ ID NO: 224. In some aspects, the sequence V _L is SEQ ID NO: 225. In some aspects, the sequence V _L is SEQ ID NO: 226. In some aspects, the sequence V _L is SEQ ID NO: 227. In some aspects, the sequence V _L is SEQ ID NO: 228 .

In some aspects, the VH sequence is SEQ ID NO: 179 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the _VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222 In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 180 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: : 207. In some aspects, the sequence V _L is SEQ ID NO: 208. In some aspects, the sequence V _L is SEQ ID NO: 209. In some aspects, the sequence V _L is SEQ ID NO: 210. In some aspects, the sequence V _L is SEQ ID NO: 211. In some aspects, the sequence V _L is SEQ ID NO: 212. In some aspects, the sequence VL is SEQ ID NO: 213. In some aspects, the sequence VL is SEQ ID NO: 214. In accordance with In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218 In some aspects, the sequence VL is SEQ ID NO: 219. In some aspects, the sequence _VL is SEQ ID NO: 220. In some aspects, the sequence _VL is SEQ ID NO: 221. In some aspects, the sequence

- 39 045983

VL is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 181 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the V _L sequence is SEQ ID NO: 212. In some aspects, the V L sequence is SEQ ID NO: 213. In some aspects, the V L sequence is SEQ ID NO: 214. In some aspects, the V sequence is _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence V _L is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In accordance with In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222 In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the _VL sequence is SEQ ID NO: 224. In some aspects, the _VL sequence is SEQ ID NO: 225. In some aspects, the _VL sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 182 and the V L sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the _VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the sequence _VL is SEQ ID NO: 212. In some aspects, the sequence VL is SEQ ID NO: 213. In some aspects, the sequence VL is SEQ ID NO: 214. In some aspects, the sequence V _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence VL is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In accordance with In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the _VL sequence is SEQ ID NO: 221. 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 183 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the V _L sequence is SEQ ID NO: 209. In some aspects, the V _L sequence is SEQ ID NO: 210. In some aspects

- 40 045983 therein, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: : 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. VL is SEQ ID NO: 226. In some aspects, the sequence V _L is SEQ ID NO: 227. In some aspects, the sequence V _L is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 184 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the V _L sequence is SEQ ID NO: 212. In some aspects, the V L sequence is SEQ ID NO: 213. In some aspects, the V L sequence is SEQ ID NO: 214. In some aspects, the V _L sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218. In accordance with In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222 In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the _VL sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 185 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the V _L sequence is SEQ ID NO: 212. In some aspects, the V L sequence is SEQ ID NO: 213. In some aspects, the V L sequence is SEQ ID NO: 214. In some aspects, the V sequence is _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence V _L is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In accordance with In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222 In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the _VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO:226. According to

- 41 045983 In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 186 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: : 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218. In some aspects In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V L sequence is SEQ ID NO: : 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 187 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects the V _L sequence is SEQ ID NO: 215. In some aspects, the V L sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218. In some aspects, the _VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 188 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V L sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. V _L represents

- 42 045983

SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In accordance with In some aspects, the _VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 189 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: : 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218. In some aspects In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the _VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 190 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the sequence _VL is SEQ ID NO: 208. In some aspects, the sequence VL is SEQ ID NO: 209. In some aspects, the sequence VL is SEQ ID NO: 210. In some aspects, the sequence VL represents SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218 In some aspects, the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 225. VL is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 191 and the V _L sequence is selected from SEQ ID NO: 204-228. According to some aspects the sequence

- 43 045983

VL is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211 In some aspects, the _VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 192 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: : 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects the V _L sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: : 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V L sequence is SEQ ID NO: 225. In some aspects, the V L sequence is is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 193 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V _L sequence is SEQ ID NO: 206. In some aspects, the V _L sequence is SEQ ID NO: 207. In some aspects, the V _L sequence is SEQ ID NO: 208. In some aspects, the V _L sequence is SEQ ID NO: 209. In some aspects, the V L sequence is SEQ ID NO: 210. In some aspects, the V _L sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the _VL sequence is SEQ ID NO: : 218. In some aspects, the sequence V _L is SEQ ID NO: 219. In some aspects

- 44 045983 therein, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is is SEQ ID NO: 227. In some aspects, the VL sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 194 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the V _L sequence is SEQ ID NO: 212. In some aspects, the V L sequence is SEQ ID NO: 213. In some aspects, the V L sequence is SEQ ID NO: 214. In some aspects, the V sequence is _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence VL is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In some aspects, the sequence VL is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the _VL sequence is SEQ ID NO: 221. In some aspects, the _VL sequence is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V L sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 195 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the V _L sequence is SEQ ID NO: 208. In some aspects, the V _L sequence is SEQ ID NO: 209. In some aspects, the V _L sequence is SEQ ID NO: 210. In some aspects, the V _L sequence is is SEQ ID NO: 211. In some aspects, the _VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the V _L sequence is SEQ ID NO: 220. In some aspects, the V _L sequence is SEQ ID NO: 221. In some aspects, the V _L sequence is SEQ ID NO: 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects the V _L sequence is SEQ ID NO: 226. In some aspects, the V L sequence is SEQ ID NO: 227. In some aspects, the V L sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 196 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the _VL sequence is SEQ ID NO: 206. : 207. In some aspects, the sequence V _L is SEQ ID NO: 208. Consent

- 45 045983 but in some aspects the VL sequence is SEQ ID NO: 209. In some aspects the VL sequence is SEQ ID NO: 210. In some aspects the _VL sequence is SEQ ID NO: 211. In some aspects the _VL sequence is is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 215. VL is SEQ ID NO: 216. In some aspects, the VL sequence is SEQ ID NO: 217. In some aspects, the VL sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the sequence V _L is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 197 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the _VL sequence is SEQ ID NO: 210. In some aspects, the _VL sequence is SEQ ID NO: 211. In some aspects, the sequence _VL is SEQ ID NO: 212. In some aspects, the sequence VL is SEQ ID NO: 213. In some aspects, the sequence VL is SEQ ID NO: 214. In some aspects, the sequence V _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence VL is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In accordance with In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222 In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the _VL sequence is SEQ ID NO: 224. In some aspects, the _VL sequence is SEQ ID NO: 225. In some aspects, the _VL sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 198 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the V _L sequence is SEQ ID NO: 209. In some aspects, the V _L sequence is SEQ ID NO: 210. In some aspects, the V _L sequence is is SEQ ID NO: 211. In some aspects, the _VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects the V _L sequence is SEQ ID NO: 215. In some aspects, the V L sequence is SEQ ID NO: 216. In some aspects, the V L sequence is SEQ ID NO: 217. In some aspects, the V L sequence is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the _VL sequence is SEQ ID NO: 221. : 222. In some aspects, the V _L sequence is SEQ ID NO: 223. In some aspects, the V _L sequence is

- 46 045983

SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the VL sequence is SEQ ID NO: 226. In some aspects, the VL sequence is SEQ ID NO: 227. In some aspects, the VL sequence is is SEQ ID NO: 228.

In some aspects, the VH sequence is SEQ ID NO: 199 and the VL sequence is selected from SEQ ID NO: 204-228. In some aspects, the VL sequence is SEQ ID NO: 204. In some aspects, the VL sequence is SEQ ID NO: 205. In some aspects, the VL sequence is SEQ ID NO: 206. In some aspects, the VL sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the VL sequence is SEQ ID NO: 212. In some aspects, the VL sequence is SEQ ID NO: 213. In some aspects, the VL sequence is SEQ ID NO: 214. In some aspects, the _VL sequence is is SEQ ID NO: 215. In some aspects, the VL sequence is SEQ ID NO: 216. In some aspects, the V _L sequence is SEQ ID NO: 217. In some aspects, the V _L sequence is SEQ ID NO: 218. In some aspects In some aspects, the _VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222 In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the VL sequence is SEQ ID NO: 225. In some aspects, the _VL sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

In some aspects, the V _H sequence is SEQ ID NO: 200 and the V _L sequence is selected from SEQ ID NO: 204-228. In some aspects, the V _L sequence is SEQ ID NO: 204. In some aspects, the V _L sequence is SEQ ID NO: 205. In some aspects, the V L sequence is SEQ ID NO: 206. In some aspects, the V L sequence is SEQ ID NO: 207. In some aspects, the VL sequence is SEQ ID NO: 208. In some aspects, the VL sequence is SEQ ID NO: 209. In some aspects, the VL sequence is SEQ ID NO: 210. In some aspects, the VL sequence is SEQ ID NO: 211. In some aspects, the sequence _VL is SEQ ID NO: 212. In some aspects, the sequence VL is SEQ ID NO: 213. In some aspects, the sequence VL is SEQ ID NO: 214. In some aspects, the sequence V _L is SEQ ID NO: 215. In some aspects, the sequence VL is SEQ ID NO: 216. In some aspects, the sequence V _L is SEQ ID NO: 217. In some aspects, the sequence VL is SEQ ID NO: 218. In some aspects, the VL sequence is SEQ ID NO: 219. In some aspects, the VL sequence is SEQ ID NO: 220. In some aspects, the VL sequence is SEQ ID NO: 221. In some aspects, the VL sequence is SEQ ID NO: 222. In some aspects, the VL sequence is SEQ ID NO: 223. In some aspects, the VL sequence is SEQ ID NO: 224. In some aspects, the V _L sequence is SEQ ID NO: 225. In some aspects, the V _L sequence is SEQ ID NO: 226. In some aspects, the V _L sequence is SEQ ID NO: 227. In some aspects, the V _L sequence is SEQ ID NO: 228.

2.7.3. CDR-H1 + CDR-H2 + CDR-H3 + CDR-L1 + CDR-L2 + CDR-L3

In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 18, a Kabat CDR-H2 sequence comprising SEQ ID NO: 54, and a Kabat CDR-H3 sequence comprising SEQ ID NO: : 76, and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises the sequence VH containing the Kabat CDR-H1 sequence containing SEQ ID NO: 19, the Kabat CDR-H2 sequence containing SEQ ID NO: 55, and the Kabat CDR-H3 sequence containing SEQ ID NO: 77, and the VL sequence, containing the sequence CDR-L1 containing SEQ ID NO: 105, after

- 47 045983 a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 20, the Kabat CDR-H2 sequence containing SEQ ID NO: 56, and the Kabat CDR-H3 sequence containing SEQ ID NO: 78, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the sequence CDR- L2 comprising SEQ ID NO: 128, and a CDR-L3 sequence of SEQ ID NO: 149. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, a CDR-H2 sequence Kabat containing SEQ ID NO: 57, and the Kabat CDR-H3 sequence containing SEQ ID NO: 79, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO : 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 22, a Kabat CDR-H2 sequence comprising SEQ ID NO: 58, and the Kabat CDR-H3 sequence containing SEQ ID NO: 80, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO: 128, and the CDR sequence -L3 SEQ ID NO: 149. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, a Kabat CDR-H2 sequence comprising SEQ ID NO: 57, and a CDR sequence -H3 by Kabat containing SEQ ID NO: 76, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 106, the CDR-L2 sequence containing SEQ ID NO: 129, and the CDR-L3 sequence SEQ ID NO : 150. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, a Kabat CDR-H2 sequence comprising SEQ ID NO: 59, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 76, and a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 107, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects said antibody contains a V _H sequence containing a Kabat CDR-H1 sequence containing SEQ ID NO: 23, a Kabat CDR-H2 sequence containing SEQ ID NO: 60, and a Kabat CDR-H3 sequence containing SEQ ID NO: 81 , and a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 108, a CDR-L2 sequence comprising SEQ ID NO: 130, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a VH sequence containing a Kabat CDR-H1 sequence containing SEQ ID NO: 23, a Kabat CDR-H2 sequence containing SEQ ID NO: 59, and a Kabat CDR-H3 sequence containing SEQ ID NO: 82, and a V _L sequence, comprising a CDR-L1 sequence comprising SEQ ID NO: 109, a CDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO: 152. In some aspects, said antibody comprises a VH sequence comprising a CDR-H1 sequence Kabat containing SEQ ID NO: 23, Kabat CDR-H2 sequence containing SEQ ID NO: 59, and Kabat CDR-H3 sequence containing SEQ ID NO: 76, and V _L sequence containing CDR-L1 sequence, comprising SEQ ID NO: 107, a CDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence SEQ ID NO: 153. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 23, a Kabat CDR-H2 sequence containing SEQ ID NO: 59, and a Kabat CDR-H3 sequence containing SEQ ID NO: 81, and a V _L sequence containing a CDR-L1 sequence containing SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 21, sequence Kabat CDR-H2 containing SEQ ID NO: 57 and Kabat CDR-H3 sequence containing SEQ ID NO: 83 and V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 111 sequence CDR-L2 comprising SEQ ID NO: 133, and a CDR-L3 sequence of SEQ ID NO: 151. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence, comprising SEQ ID NO: 21, a Kabat CDR-H2 sequence containing SEQ ID NO: 57, and the Kabat CDR-H3 sequence containing SEQ ID NO: 84, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO : 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 24, a Kabat CDR-H2 sequence comprising SEQ ID NO: 61, and the Kabat CDR-H3 sequence containing SEQ ID NO: 85, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO: 128, and the CDR sequence -L3 SEQ ID NO: 154. In some aspects, said antibody comprises a V _H sequence comprising

- 48 045983 Kabat CDR-H1 sequence containing SEQ ID NO: 24, Kabat CDR-H2 sequence containing SEQ ID NO: 61, and Kabat CDR-H3 sequence containing SEQ ID NO: 86, and the VL sequence, comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 154. In some aspects, said antibody comprises a V _H sequence comprising a CDR- sequence Kabat H1 containing SEQ ID NO: 25, Kabat CDR-H2 sequence containing SEQ ID NO: 62, and Kabat CDR-H3 sequence containing SEQ ID NO: 87, and VL sequence containing CDR-L1 sequence, comprising SEQ ID NO: 112, a CDR-L2 sequence comprising SEQ ID NO: 134, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, Kabat CDR-H2 sequence containing SEQ ID NO: 63, and Kabat CDR-H3 sequence containing SEQ ID NO: 88, and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 113, a CDR-L2 sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO: 156. In some aspects, said antibody comprises a _VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a CDR sequence Kabat -H2 containing SEQ ID NO: 63, and the Kabat CDR-H3 sequence containing SEQ ID NO: 89, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 114, the CDR-L2 sequence containing SEQ ID NO: 136, and a CDR-L3 sequence SEQ ID NO: 157. In some aspects, the antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequence comprising SEQ ID NO: 63, and the Kabat CDR-H3 sequence containing SEQ ID NO: 90, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 115, the CDR-L2 sequence containing SEQ ID NO: 135, and a CDR-L3 sequence of SEQ ID NO: 157. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 64, and the Kabat CDR-H3 sequence containing SEQ ID NO: 90, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 116, the CDR-L2 sequence containing SEQ ID NO: 128, and the CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 28, a Kabat CDR-H2 sequence comprising SEQ ID NO: 62, and a Kabat CDR-H3 sequence containing SEQ ID NO: 91, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 117, a CDR-L2 sequence containing SEQ ID NO: 137, and a CDR-L3 sequence SEQ ID NO: 155. According to some In aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence containing SEQ ID NO: 29, a Kabat CDR-H2 sequence containing SEQ ID NO: 64, and a Kabat CDR-H3 sequence containing SEQ ID NO: 92 , and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ ID NO: 158. In some aspects, said antibody comprises a V _H sequence , containing a Kabat CDR-H1 sequence containing SEQ ID NO: 25, a Kabat CDR-H2 sequence containing SEQ ID NO: 65, and a Kabat CDR-H3 sequence containing SEQ ID NO: 93, and a VL sequence containing a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a VH sequence comprising a CDR-H1 sequence at Kabat containing SEQ ID NO: 30, the Kabat CDR-H2 sequence containing SEQ ID NO: 66, and the Kabat CDR-H3 sequence containing SEQ ID NO: 94, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 119, a CDR-L2 sequence comprising SEQ ID NO: 139, and a CDR-L3 sequence SEQ ID NO: 159. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO : 31, Kabat CDR-H2 sequence containing SEQ ID NO: 67, and Kabat CDR-H3 sequence containing SEQ ID NO: 95, and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 120, sequence CDR-L2 comprising SEQ ID NO: 140, and a CDR-L3 sequence SEQ ID NO: 160. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 32, a CDR-H2 sequence Kabat containing SEQ ID NO: 68, and Kabat CDR-H3 sequence containing SEQ ID NO: 96, and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 121, CDR-L2 sequence containing SEQ ID NO: 141, and a CDR-L3 sequence SEQ ID NO: 161. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 33, a Kabat CDR-H2 sequence comprising SEQ ID NO: : 69, and the CDR-H3 sequence of Kabat containing SEQ ID NO: 97, and

- 49 045983 a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 122, a CDR-L2 sequence comprising SEQ ID NO: 142, and a CDR-L3 sequence SEQ ID NO: 162. In some aspects, said antibody comprises a VH sequence , containing the Kabat CDR-H1 sequence containing SEQ ID NO: 34, the Kabat CDR-H2 sequence containing SEQ ID NO: 70, and the Kabat CDR-H3 sequence containing SEQ ID NO: 98, and the VL sequence containing a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 143, and a CDR-L3 sequence SEQ ID NO: 163. In some aspects, said antibody comprises a V _H sequence comprising a CDR-H1 sequence Kabat containing SEQ ID NO: 18, a Kabat CDR-H2 sequence containing SEQ ID NO: 54, and a Kabat CDR-H3 sequence containing SEQ ID NO: 99, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 143, and a CDR-L3 sequence SEQ ID NO: 164. In some aspects, said antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO : 31, Kabat CDR-H2 sequence containing SEQ ID NO: 71, and Kabat CDR-H3 sequence containing SEQ ID NO: 100, and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 123, sequence CDR-L2 comprising SEQ ID NO: 144, and a CDR-L3 sequence of SEQ ID NO: 165. In some aspects, said antibody comprises a V _H sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 24, a CDR- sequence Kabat H2 containing SEQ ID NO: 61 and Kabat CDR-H3 sequence containing SEQ ID NO: 101 and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 124 CDR-L2 sequence containing SEQ ID NO: 145, and CDR-L3 sequence SEQ ID NO: 166.

In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2 sequence comprising SEQ ID NO: 38, and a Chothia CDR-H3 sequence comprising SEQ ID NO: : 76, and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises the sequence V _H containing the Chothia CDR-H1 sequence containing SEQ ID NO: 2, the Chothia CDR-H2 sequence containing SEQ ID NO: 39, and the Chothia CDR-H3 sequence containing SEQ ID NO: 77, and the VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises a VH sequence comprising a CDR- Chothia H1 containing SEQ ID NO: 2, Chothia CDR-H2 sequence containing SEQ ID NO: 40, and Chothia CDR-H3 sequence containing SEQ ID NO: 78, and VL sequence containing CDR-L1 sequence, comprising SEQ ID NO: 105, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 3, a Chothia CDR-H2 sequence containing SEQ ID NO: 41, and a Chothia CDR-H3 sequence containing SEQ ID NO: 79, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 105 , a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 4, a CDR sequence Chothia -H2 containing SEQ ID NO: 41, and Chothia CDR-H3 sequence containing SEQ ID NO: 80, and VL sequence containing CDR-L1 sequence containing SEQ ID NO: 105, CDR-L2 sequence containing SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 3, a Chothia CDR-H2 sequence comprising SEQ ID NO: 41, and a Chothia CDR-H3 sequence containing SEQ ID NO: 76, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 106, a CDR-L2 sequence containing SEQ ID NO: 129, and a CDR-L3 sequence of SEQ ID NO: 150. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 42, and the Chothia CDR-H3 sequence containing SEQ ID NO: 76, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 107, the CDR-L2 sequence containing SEQ ID NO: 128, and the CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 43, and a Chothia CDR-H3 sequence. containing SEQ ID NO: 81, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 108, a CDR-L2 sequence containing SEQ ID NO: 130, and a CDR-L3 sequence SEQ ID

- 50 045983

NO: 151. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 42, and a Chothia CDR-H3 sequence. comprising SEQ ID NO: 82, and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 109, a CDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO: 152. In some aspects said antibody contains a V _H sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 5, a Chothia CDR-H2 sequence containing SEQ ID NO: 42, and a Chothia CDR-H3 sequence containing SEQ ID NO: 76 , and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 107, a CDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence SEQ ID NO: 153. In some aspects, said antibody comprises a VH sequence, containing the Chothia CDR-H1 sequence containing SEQ ID NO: 2, the Chothia CDR-H2 sequence containing SEQ ID NO: 42, and the Chothia CDR-H3 sequence containing SEQ ID NO: 81, and the VL sequence containing the sequence CDR-L1 comprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a V _H sequence comprising a CDR-H1 sequence at Chothia containing SEQ ID NO: 3, a Chothia CDR-H2 sequence containing SEQ ID NO: 41, and a Chothia CDR-H3 sequence containing SEQ ID NO: 83, and a V _L sequence containing a CDR-L1 sequence containing SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ ID NO: 133, and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO : 3, a Chothia CDR-H2 sequence containing SEQ ID NO: 41, and a Chothia CDR-H3 sequence containing SEQ ID NO: 84, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 105, sequence CDR-L2 comprising SEQ ID NO: 128, and a CDR-L3 sequence of SEQ ID NO: 149. In some aspects, said antibody comprises a V _H sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a CDR- sequence Chothia H2 containing SEQ ID NO: 44, and the Chothia CDR-H3 sequence containing SEQ ID NO: 85, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 154. In some aspects, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and the Chothia CDR-H3 sequence containing SEQ ID NO: 86, and the V _L sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence containing SEQ ID NO: 128 , and a CDR-L3 sequence of SEQ ID NO: 154. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 7, a Chothia CDR-H2 sequence comprising SEQ ID NO: 45, and a Chothia CDR-H3 sequence containing SEQ ID NO: 87, and a V _L sequence containing a CDR-L1 sequence containing SEQ ID NO: 112, a CDR-L2 sequence containing SEQ ID NO: 134, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, the antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a CDR-H3 sequence by Chothia containing SEQ ID NO: 88, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 113, a CDR-L2 sequence containing SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO: 156. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence comprising SEQ ID NO: : 89, and a V _L sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 114, a CDR-L2 sequence comprising SEQ ID NO: 136, and a CDR-L3 sequence comprising SEQ ID NO: 157. In some aspects, said antibody comprises a V _H sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 7, a Chothia CDR-H2 sequence containing SEQ ID NO: 44, and a Chothia CDR-H3 sequence containing SEQ ID NO: 90, and the sequence V _L comprising the CDR-L1 sequence comprising SEQ ID NO: 115, the CDR-L2 sequence comprising SEQ ID NO: 135, and the CDR-L3 sequence SEQ ID NO: 157. In some aspects, said antibody comprises a VH sequence comprising the sequence Chothia CDR-H1 containing SEQ ID NO: 9, Chothia CDR-H2 sequence containing SEQ ID NO: 44, and Chothia CDR-H3 sequence containing SEQ ID NO: 90, and VL sequence containing CDR- L1 comprising SEQ ID NO: 116, a CDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a _VH sequence comprising a Chothia CDR-H1 sequence, containing SEQ ID NO: 6, sequence CDR-H2

- 51 045983 to Chothia containing SEQ ID NO: 45, and the Chothia CDR-H3 sequence containing SEQ ID NO: 91, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 117, the sequence CDR-L2, comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence containing SEQ ID NO: 92, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 118, a CDR-L2 sequence containing SEQ ID NO: 137, and a CDR-L3 sequence of SEQ ID NO: 158. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 7, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and the Chothia CDR-H3 sequence containing SEQ ID NO: 93, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 118, the CDR-L2 sequence containing SEQ ID NO: 138, and the CDR-L3 sequence SEQ ID NO: 155. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequence. comprising SEQ ID NO: 94, and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 119, a CDR-L2 sequence comprising SEQ ID NO: 139, and a CDR-L3 sequence SEQ ID NO: 159. In some aspects said antibody contains a VH sequence containing a Chothia CDR-H1 sequence containing SEQ ID NO: 11, a Chothia CDR-H2 sequence containing SEQ ID NO: 47, and a Chothia CDR-H3 sequence containing SEQ ID NO: 95, and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ ID NO: 140, and a CDR-L3 sequence SEQ ID NO: 160. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence containing SEQ ID NO: 12, a Chothia CDR-H2 sequence containing SEQ ID NO: 48, and a Chothia CDR-H3 sequence containing SEQ ID NO: 96, and a VL sequence containing the CDR sequence -L1 comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 141, and a CDR-L3 sequence SEQ ID NO: 161. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence, containing SEQ ID NO: 13, a Chothia CDR-H2 sequence containing SEQ ID NO: 44, and a Chothia CDR-H3 sequence containing SEQ ID NO: 97, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: : 122, a CDR-L2 sequence comprising SEQ ID NO: 142, and a CDR-L3 sequence SEQ ID NO: 162. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, the Chothia CDR-H2 sequence containing SEQ ID NO: 49, and the Chothia CDR-H3 sequence containing SEQ ID NO: 98, and the VL sequence containing the CDR-L1 sequence containing SEQ ID NO: 105, the CDR-L2 sequence comprising SEQ ID NO: 143, and a CDR-L3 sequence SEQ ID NO: 163. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence, comprising SEQ ID NO: 1, a Chothia CDR-H2 sequence, containing SEQ ID NO: 38, and a Chothia CDR-H3 sequence containing SEQ ID NO: 99, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 105, a CDR-L2 sequence containing SEQ ID NO: 143 , and a CDR-L3 sequence of SEQ ID NO: 164. In some aspects, said antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 11, a Chothia CDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequence containing SEQ ID NO: 100, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 123, a CDR-L2 sequence containing SEQ ID NO: 144, and a CDR-L3 sequence SEQ ID NO: 165. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a Chothia CDR-H2 sequence comprising SEQ ID NO: 44, and a Chothia CDR-H3 sequence containing SEQ ID NO: 101, and a VL sequence containing a CDR-L1 sequence containing SEQ ID NO: 124, a CDR-L2 sequence containing SEQ ID NO: 145, and a CDR-L3 sequence SEQ ID NO: 166.

2.7.3.1. VH-VL pair options.

In some embodiments, the VH-VL pairs provided by the present invention comprise a variant of an exemplary VH and/or VL sequence set forth herein.

In some aspects, the VH sequence comprises, consists of, or consists essentially of a variant of an exemplary VH sequence provided herein. In some aspects, the VH sequence comprises, consists of, or consists essentially of a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.1% identical

- 52 045983 identical to any of the illustrative VH sequences given herein.

In some embodiments, the VH sequence contains, consists of, or consists essentially of any of the exemplary VH sequences provided herein, with 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

In some aspects, the VL sequence comprises, consists of, or consists essentially of a variant of an exemplary VL sequence provided herein. In some aspects, the VL sequence contains, consists of, or consists of a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identical to any of the exemplary sequences VL given in this description.

In some embodiments, the VL sequence contains, consists of, or consists essentially of any of the exemplary V _L sequences provided herein, with 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less , 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less amino acid substitutions. In some aspects, these amino acid substitutions are conservative amino acid substitutions.

2.7.4. HC+LC.

In some aspects, 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 aspects, the antibody contains or consists of two identical heavy chains consisting of the HC sequence and two identical light chains consisting of the LC sequence.

In some aspects, said HC sequence is an HC sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 232-262, and said LC sequence is an LC sequence comprising, consisting of, or essentially consisting of the sequences of SEQ ID NO: 300-330. In some embodiments, said HC sequence is an HC sequence consisting of a sequence selected from SEQ ID NOs: 232-262, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 300-330. In some embodiments, said HC sequence is an HC sequence comprising, consisting of, or essentially consisting of a sequence selected from SEQ ID NOs: 266-296, and said LC sequence is an LC sequence comprising, consisting of, or essentially consisting of SEQ ID NO: 300-330. In some embodiments, said HC sequence is an HC sequence consisting of a sequence selected from SEQ ID NOs: 266-296, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOs: 300-330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 232, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. According to

- 53 045983 In some aspects, the specified LC sequence is SEQ ID NO: 318. In some aspects, the specified LC sequence is SEQ ID NO: 319. In some aspects, the specified LC sequence is SEQ ID NO: 320. In some aspects, the specified LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 233, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 234, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. According to

- 54 045983 In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 314. is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324.

In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 235, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 236, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. According to

- 55 045983 In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 307. is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said the LC sequence is SEQ ID NO: 326. In some aspects, the LC sequence is SEQ ID NO: 327. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 237, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 238, and said LC sequence is

- 56 045983 LC sequence consisting of the sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 239, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In accordance with

- 57 045983 In some aspects, the specified LC sequence is SEQ ID NO: 327. In some aspects, the specified LC sequence is SEQ ID NO: 328. In some aspects, the specified LC sequence is SEQ ID NO: 329. In some aspects, the specified LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 240, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 241, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In accordance with

- 58 045983 In some aspects, the specified LC sequence is SEQ ID NO: 321. In some aspects, the specified LC sequence is SEQ ID NO: 322. In some aspects, the specified LC sequence is SEQ ID NO: 323. In some aspects, the specified LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 242, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303.

In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ IDNO:

305. In some aspects, said LC sequence is a SEQ IDNO:

306. In some aspects, said LC sequence is a SEQ IDNO:

307. In some aspects, said LC sequence is a SEQ IDNO:

308. In some aspects, said LC sequence is a SEQ IDNO:

309. In some aspects, said LC sequence is a SEQ IDNO:

310. In some aspects, said LC sequence is a SEQ IDNO:

311. In some aspects, said LC sequence is a SEQ IDNO:

312. In some aspects, said LC sequence is a SEQ IDNO:

313. In some aspects, said LC sequence is a SEQ IDNO:

314. In some aspects, said LC sequence is a SEQ IDNO:

315. In some aspects, said LC sequence is a SEQ IDNO:

316. In some aspects, said LC sequence is a SEQ IDNO:

317. In some aspects, said LC sequence is a SEQ IDNO:

318. In some aspects, said LC sequence is a SEQ IDNO:

319. In some aspects, said LC sequence is a SEQ IDNO:

320. In some aspects, said LC sequence is a SEQ IDNO:

321. In some aspects, said LC sequence is a SEQ IDNO:

322. In some aspects, said LC sequence is a SEQ IDNO:

323. In some aspects, said LC sequence is a SEQ IDNO:

324. In some aspects, said LC sequence is a SEQ IDNO:

325. In some aspects, said LC sequence is a SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 243, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. According to

- 59 045983 In some aspects, the specified LC sequence is SEQ ID NO: 314. In some aspects, the specified LC sequence is SEQ ID NO: 315. In some aspects, the specified LC sequence is SEQ ID NO: 316. In some aspects, the specified LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324.

In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 244, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 245, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, the specified LC sequence is SEQ ID NO: 304. In some aspects, the specified LC sequence is SEQ ID NO: 305. In some aspects, the specified LC sequence is SEQ ID NO: 306. In accordance with

- 60 045983 In some aspects, the specified LC sequence is SEQ ID NO: 307. In some aspects, the specified LC sequence is SEQ ID NO: 308. In some aspects, the specified LC sequence is SEQ ID NO: 309. In some aspects, the specified LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 329. In some aspects, the LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 246, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 247, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. According to

- 61 045983 In some aspects, the specified LC sequence is SEQ ID NO: 301. In some aspects, the specified LC sequence is SEQ ID NO: 302. In some aspects, the specified LC sequence is SEQ ID NO: 303. In some aspects, the specified LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said the LC sequence is SEQ ID NO: 322. In some aspects, the LC sequence is SEQ ID NO: 323. In some aspects, the LC sequence is SEQ ID NO: 324. In some aspects, the LC sequence is SEQ ID NO: 324. In some aspects, the LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 328. is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 248, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. According to

- 62 045983 In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 249, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 250, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. According to

- 63 045983 In some aspects, the specified LC sequence is SEQ ID NO: 323. In some aspects, the specified LC sequence is SEQ ID NO: 324. In some aspects, the specified LC sequence is SEQ ID NO: 325. In some aspects, the specified LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 251, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303.

In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ IDNO:

305. In some aspects, said LC sequence is a SEQ IDNO:

306. In some aspects, said LC sequence is a SEQ IDNO:

307. In some aspects, said LC sequence is a SEQ IDNO:

308. In some aspects, said LC sequence is a SEQ IDNO:

309. In some aspects, said LC sequence is a SEQ IDNO:

310. In some aspects, said LC sequence is a SEQ IDNO:

311. In some aspects, said LC sequence is a SEQ IDNO:

312. In some aspects, said LC sequence is a SEQ IDNO:

313. In some aspects, said LC sequence is a SEQ IDNO:

314. In some aspects, said LC sequence is a SEQ IDNO:

315. In some aspects, said LC sequence is a SEQ IDNO:

316. In some aspects, said LC sequence is a SEQ IDNO:

317. In some aspects, said LC sequence is a SEQ IDNO:

318. In some aspects, said LC sequence is a SEQ IDNO:

319. In some aspects, said LC sequence is a SEQ IDNO:

320. In some aspects, said LC sequence is a SEQ IDNO:

321. In some aspects, said LC sequence is a SEQ IDNO:

322. In some aspects, said LC sequence is a SEQ IDNO:

323. In some aspects, said LC sequence is a SEQ IDNO:

324. In some aspects, said LC sequence is a SEQ IDNO:

325. In some aspects, said LC sequence is a SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 252, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. According to

- 64 045983 In some aspects, the specified LC sequence is SEQ ID NO: 316. In some aspects, the specified LC sequence is SEQ ID NO: 317. In some aspects, the specified LC sequence is SEQ ID NO: 318. In some aspects, the specified LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324.

In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 253, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 254, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In accordance with

- 65 045983 In some aspects, the specified LC sequence is SEQ ID NO: 309. In some aspects, the specified LC sequence is SEQ ID NO: 310. In some aspects, the specified LC sequence is SEQ ID NO: 311. In some aspects, the specified LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said the LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 255, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 256, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In accordance with

- 66 045983 In some aspects, the specified LC sequence is SEQ ID NO: 303. In some aspects, the specified LC sequence is SEQ ID NO: 304. In some aspects, the specified LC sequence is SEQ ID NO: 305. In some aspects, the specified LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said the LC sequence is SEQ ID NO: 324. In some aspects, the LC sequence is SEQ ID NO: 325. In some aspects, the LC sequence is SEQ ID NO: 326. In some aspects, the LC sequence is SEQ ID NO: 326. In some aspects, the LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 257, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

- 67 045983

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 258, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 259, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. According to

- 68 045983 In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 327. is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 260, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303.

In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ IDNO:

305. In some aspects, said LC sequence is a SEQ IDNO:

306. In some aspects, said LC sequence is a SEQ IDNO:

307. In some aspects, said LC sequence is a SEQ IDNO:

308. In some aspects, said LC sequence is a SEQ IDNO:

309. In some aspects, said LC sequence is a SEQ IDNO:

310. In some aspects, said LC sequence is a SEQ IDNO:

311. In some aspects, said LC sequence is a SEQ IDNO:

312. In some aspects, said LC sequence is a SEQ IDNO:

313. In some aspects, said LC sequence is a SEQ IDNO:

314. In some aspects, said LC sequence is a SEQ IDNO:

315. In some aspects, said LC sequence is a SEQ IDNO:

316. In some aspects, said LC sequence is a SEQ IDNO:

317. In some aspects, said LC sequence is a SEQ IDNO:

318. In some aspects, said LC sequence is a SEQ IDNO:

319. In some aspects, said LC sequence is a SEQ IDNO:

320. In some aspects, said LC sequence is a SEQ IDNO:

321. In some aspects, said LC sequence is a SEQ IDNO:

322. In some aspects, said LC sequence is a SEQ IDNO:

323. In some aspects, said LC sequence is a SEQ IDNO:

324. In some aspects, said LC sequence is a SEQ IDNO:

325. In some aspects, said LC sequence is a SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 261, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. According to

- 69 045983 In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324.

In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 262, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 266, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. According to

- 70 045983 In some aspects, the specified LC sequence is SEQ ID NO: 311. In some aspects, the specified LC sequence is SEQ ID NO: 312. In some aspects, the specified LC sequence is SEQ ID NO: 313. In some aspects, the specified LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 267, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 268, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. According to

- 71 045983 In some aspects, the specified LC sequence is SEQ ID NO: 305. In some aspects, the specified LC sequence is SEQ ID NO: 306. In some aspects, the specified LC sequence is SEQ ID NO: 307. In some aspects, the specified LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said the LC sequence is SEQ ID NO: 326. In some aspects, the LC sequence is SEQ ID NO: 327. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 269, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 270, and said LC sequence is

- 72 045983 LC sequence consisting of the sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 271, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In accordance with

- 73 045983 In some aspects, the specified LC sequence is SEQ ID NO: 327. In some aspects, the specified LC sequence is SEQ ID NO: 328. In some aspects, the specified LC sequence is SEQ ID NO: 329. In some aspects, the specified LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 272, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303.

In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ IDNO:

305. In some aspects, said LC sequence is a SEQ IDNO:

306. In some aspects, said LC sequence is a SEQ IDNO:

307. In some aspects, said LC sequence is a SEQ IDNO:

308. In some aspects, said LC sequence is a SEQ IDNO:

309. In some aspects, said LC sequence is a SEQ IDNO:

310. In some aspects, said LC sequence is a SEQ IDNO:

311. In some aspects, said LC sequence is a SEQ IDNO:

312. In some aspects, said LC sequence is a SEQ IDNO:

313. In some aspects, said LC sequence is a SEQ IDNO:

314. In some aspects, said LC sequence is a SEQ IDNO:

315. In some aspects, said LC sequence is a SEQ IDNO:

316. In some aspects, said LC sequence is a SEQ IDNO:

317. In some aspects, said LC sequence is a SEQ IDNO:

318. In some aspects, said LC sequence is a SEQ IDNO:

319. In some aspects, said LC sequence is a SEQ IDNO:

320. In some aspects, said LC sequence is a SEQ IDNO:

321. In some aspects, said LC sequence is a SEQ IDNO:

322. In some aspects, said LC sequence is a SEQ IDNO:

323. In some aspects, said LC sequence is a SEQ IDNO:

324. In some aspects, said LC sequence is a SEQ IDNO:

325. In some aspects, said LC sequence is a SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

329. In some aspects, said LC sequence is a SEQ IDNO:

330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 273, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In accordance with

- 74 045983 In some aspects, the specified LC sequence is SEQ ID NO: 320. In some aspects, the specified LC sequence is SEQ ID NO: 321. In some aspects, the specified LC sequence is SEQ ID NO: 322. In some aspects, the specified LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 274, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 275, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In accordance with

- 75 045983 In some aspects, the specified LC sequence is SEQ ID NO: 314. In some aspects, the specified LC sequence is SEQ ID NO: 315. In some aspects, the specified LC sequence is SEQ ID NO: 316. In some aspects, the specified LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 276, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 277, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. aspects, said LC sequence is SEQ ID NO: 307. According to

- 76 045983 In some aspects, the specified LC sequence is SEQ ID NO: 308. In some aspects, the specified LC sequence is SEQ ID NO: 309. In some aspects, the specified LC sequence is SEQ ID NO: 310. In some aspects, the specified LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said the LC sequence is SEQ ID NO: 329. In some aspects, the LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 278, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 279, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In accordance with

- 77 045983 In some aspects, the specified LC sequence is SEQ ID NO: 302. In some aspects, the specified LC sequence is SEQ ID NO: 303. In some aspects, the specified LC sequence is SEQ ID NO: 304. In some aspects, the specified LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said the LC sequence is SEQ ID NO: 323. In some aspects, the LC sequence is SEQ ID NO: 324. In some aspects, the LC sequence is SEQ ID NO: 325. In some aspects, the LC sequence is SEQ ID NO: 325. In some aspects, the LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 329. is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 280, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310.

In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ IDNO:

312. In some aspects, said LC sequence is a SEQ IDNO:

313. In some aspects, said LC sequence is a SEQ IDNO:

314. In some aspects, said LC sequence is a SEQ IDNO:

315. In some aspects, said LC sequence is a SEQ IDNO:

316. In some aspects, said LC sequence is a SEQ IDNO:

317. In some aspects, said LC sequence is a SEQ IDNO:

318. In some aspects, said LC sequence is a SEQ IDNO:

319. In some aspects, said LC sequence is a SEQ IDNO:

320. In some aspects, said LC sequence is a SEQ IDNO:

321. In some aspects, said LC sequence is a SEQ IDNO:

322. In some aspects, said LC sequence is a SEQ IDNO:

323. In some aspects, said LC sequence is a SEQ IDNO:

324. In some aspects, said LC sequence is a SEQ IDNO:

325. In some aspects, said LC sequence is a SEQ IDNO:

326. In some aspects, said LC sequence is a SEQ IDNO:

327. In some aspects, said LC sequence is a SEQ IDNO:

328. In some aspects, said LC sequence is a SEQ IDNO:

- 78 045983

329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 281, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 282, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. According to

- 79 045983 In some aspects, the specified LC sequence is SEQ ID NO: 323. In some aspects, the specified LC sequence is SEQ ID NO: 324. In some aspects, the specified LC sequence is SEQ ID NO: 325. In some aspects, the specified LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 283, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 284, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the specified LC sequence is SEQ ID NO: 315. In some aspects, the specified LC sequence is SEQ ID NO: 316. In accordance with

- 80 045983 In some aspects, the specified LC sequence is SEQ ID NO: 317. In some aspects, the specified LC sequence is SEQ ID NO: 318. In some aspects, the specified LC sequence is SEQ ID NO: 319. In some aspects, the specified LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 285, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 286, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. According to

- 81 045983 In some aspects, the specified LC sequence is SEQ ID NO: 311. In some aspects, the specified LC sequence is SEQ ID NO: 312. In some aspects, the specified LC sequence is SEQ ID NO: 313. In some aspects, the specified LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 287, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 288, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. According to

- 82 045983 In some aspects, the specified LC sequence is SEQ ID NO: 305. In some aspects, the specified LC sequence is SEQ ID NO: 306. In some aspects, the specified LC sequence is SEQ ID NO: 307. In some aspects, the specified LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said LC sequence is SEQ ID NO: 314. In some aspects, said LC sequence is SEQ ID NO: 315. In some aspects, said LC sequence is SEQ ID NO: 316. In some aspects, said LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said the LC sequence is SEQ ID NO: 326. In some aspects, the LC sequence is SEQ ID NO: 327. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 328. In some aspects, the LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 289, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310.

In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO:

312. In some aspects, said LC sequence is SEQ ID NO:

313. In some aspects, said LC sequence is SEQ ID NO:

314. In some aspects, said LC sequence is SEQ ID NO:

315. In some aspects, said LC sequence is SEQ ID NO:

316. In some aspects, said LC sequence is SEQ ID NO:

317. In some aspects, said LC sequence is SEQ ID NO:

318. In some aspects, said LC sequence is SEQ ID NO:

319. In some aspects, said LC sequence is SEQ ID NO:

320. In some aspects, said LC sequence is SEQ ID NO:

321. In some aspects, said LC sequence is SEQ ID NO:

322. In some aspects, said LC sequence is SEQ ID NO:

323. In some aspects, said LC sequence is SEQ ID NO:

324. In some aspects, said LC sequence is SEQ ID NO:

325. In some aspects, said LC sequence is SEQ ID NO:

326. In some aspects, said LC sequence is SEQ ID NO:

327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 290, and said LC sequence is

- 83 045983 LC sequence consisting of the sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 291, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In accordance with

- 84 045983 In some aspects, the specified LC sequence is SEQ ID NO: 327. In some aspects, the specified LC sequence is SEQ ID NO: 328. In some aspects, the specified LC sequence is SEQ ID NO: 329. In some aspects, the specified LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 292, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 293, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In accordance with

- 85 045983 In some aspects, the specified LC sequence is SEQ ID NO: 321. In some aspects, the specified LC sequence is SEQ ID NO: 322. In some aspects, the specified LC sequence is SEQ ID NO: 323. In some aspects, the specified LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 294, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 295, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. According to

- 86 045983 In some aspects, the specified LC sequence is SEQ ID NO: 315. In some aspects, the specified LC sequence is SEQ ID NO: 316. In some aspects, the specified LC sequence is SEQ ID NO: 317. In some aspects, the specified LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 296, and said LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NO: 300-330. In some aspects, said LC sequence is SEQ ID NO: 300. In some aspects, said LC sequence is SEQ ID NO: 301. In some aspects, said LC sequence is SEQ ID NO: 302. In some aspects, said LC sequence is SEQ ID NO: 303. In some aspects, said LC sequence is SEQ ID NO: 304. In some aspects, said LC sequence is SEQ ID NO: 305. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 306. In some aspects, said LC sequence is SEQ ID NO: 307. In some aspects, said LC sequence is SEQ ID NO: 308. In some aspects, said LC sequence is SEQ ID NO: 309. In some aspects, said LC sequence is SEQ ID NO: 310. In some aspects, said LC sequence is SEQ ID NO: 311. In some aspects, said LC sequence is SEQ ID NO: 312. In some aspects, said LC sequence is SEQ ID NO: 313. In some aspects, said the LC sequence is SEQ ID NO: 314. In some aspects, the LC sequence is SEQ ID NO: 315. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 316. In some aspects, the LC sequence is SEQ ID NO: 317. In some aspects, said LC sequence is SEQ ID NO: 318. In some aspects, said LC sequence is SEQ ID NO: 319. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. In some aspects, said LC sequence is SEQ ID NO: 320. is SEQ ID NO: 321. In some aspects, said LC sequence is SEQ ID NO: 322. In some aspects, said LC sequence is SEQ ID NO: 323. In some aspects, said LC sequence is SEQ ID NO: 324. In some aspects, said LC sequence is SEQ ID NO: 325. In some aspects, said LC sequence is SEQ ID NO: 326. In some aspects, said LC sequence is SEQ ID NO: 327. In some aspects, said LC sequence is SEQ ID NO: 328. In some aspects, said LC sequence is SEQ ID NO: 329. In some aspects, said LC sequence is SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 232, and said LC sequence is an LC sequence consisting of SEQ ID NO: 300. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 233, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 301. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 234, and said LC sequence is a LC consisting of the sequence SEQ ID NO: 302. In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 235, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 303. In some aspects In aspects, said HC sequence is a HC sequence consisting of SEQ

- 87 045983

ID NO: 236, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 304. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 237, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 305. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 238, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 306. In some aspects said HC sequence is an HC sequence consisting of SEQ ID NO: 239, and said LC sequence is an LC sequence consisting of SEQ ID NO: 307. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: : 240, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 308. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 241, and said LC sequence is an LC sequence consisting from the sequence SEQ ID NO: 309. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 242, and said LC sequence is an LC sequence consisting of SEQ ID NO: 310. In some aspects, said sequence The HC is the HC sequence consisting of SEQ ID NO: 243, and the LC sequence is the LC sequence consisting of the sequence SEQ ID NO: 311. In some aspects, the HC sequence is the HC sequence consisting of SEQ ID NO: 244 and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 312. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 245, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 313. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 246, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 314. In some aspects, said HC sequence is is an HC sequence consisting of SEQ ID NO: 247, and said LC sequence is an LC sequence consisting of SEQ ID NO: 315. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 248, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 316. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 249, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 317. In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 250, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 318. In some aspects, said HC sequence is the sequence HC consisting of SEQ ID NO: 251, and the specified LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 319. In some aspects, the specified HC sequence is a HC sequence consisting of SEQ ID NO: 252, and the specified sequence The LC is an LC sequence consisting of the sequence SEQ ID NO: 320. In some aspects, the HC sequence is the HC sequence consisting of SEQ ID NO: 253, and the LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 253. 321. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 254, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 322. In some aspects, said HC sequence is an HC sequence, consisting of SEQ ID NO: 255, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 323. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 256, and said LC sequence is is an LC sequence consisting of the sequence SEQ ID NO: 324. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 257, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 325. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 258, and said LC sequence is an LC sequence consisting of SEQ ID NO: 326. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 259, and the indicated LC sequence is

- 88 045983 an LC sequence consisting of the sequence SEQ ID NO: 327. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 260, and said LC sequence is a LC sequence consisting of the sequence SEQ ID NO: 328. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 261, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 329. In some aspects, said HC sequence is an HC sequence, consisting of SEQ ID NO: 262, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 330.

In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 266, and said LC sequence is an LC sequence consisting of SEQ ID NO: 300. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 267, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 301. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 268, and said LC sequence is a sequence LC consisting of the sequence SEQ ID NO: 302. In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 269, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 303. In some aspects In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 270, and said LC sequence is an LC sequence consisting of SEQ ID NO: 304. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 271, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 305. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 272, and said LC sequence is an LC sequence, consisting of the sequence SEQ ID NO: 306. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 273, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 307. In some aspects, said the HC sequence is the HC sequence consisting of SEQ ID NO: 274, and the LC sequence is the LC sequence consisting of the sequence SEQ ID NO: 308. In some aspects, the specified HC sequence is the HC sequence consisting of SEQ ID NO: 275, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 309. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 276, and said LC sequence is an LC sequence consisting of sequence of SEQ ID NO: 310. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 277, and said LC sequence is an LC sequence consisting of sequence SEQ ID NO: 311. In some aspects, said HC sequence is is an HC sequence consisting of SEQ ID NO: 278, and said LC sequence is an LC sequence consisting of SEQ ID NO: 312. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 279, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 313. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 280, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 314. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 281, and said LC sequence is an LC sequence consisting of SEQ ID NO: 315. In some aspects, said HC sequence is the HC sequence consisting of SEQ ID NO: 282, and the specified LC sequence is the LC sequence consisting of the sequence SEQ ID NO: 316. In some aspects, the specified HC sequence is the HC sequence consisting of SEQ ID NO: 283, and the specified the LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 317. In some aspects, the HC sequence is the HC sequence consisting of SEQ ID NO: 284, and the LC sequence is an LC sequence consisting of the sequence SEQ ID NO: : 318. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 285, and said LC sequence is an LC sequence consisting of

- 89 045983 from the sequence SEQ ID NO: 319. In some aspects, the specified HC sequence is the HC sequence consisting of SEQ ID NO: 286, and the specified LC sequence is a LC sequence consisting of the sequence SEQ ID NO: 320. In some aspects In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 287, and said LC sequence is an LC sequence consisting of SEQ ID NO: 321. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 288, and the LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 322. In some aspects, the HC sequence is an HC sequence consisting of SEQ ID NO: 289, and the LC sequence is an LC sequence, consisting of the sequence SEQ ID NO: 323. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 290, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 324. In some aspects, said the HC sequence is the HC sequence consisting of SEQ ID NO: 291, and the LC sequence is the LC sequence consisting of the sequence SEQ ID NO: 325. In some aspects, the specified HC sequence is the HC sequence consisting of SEQ ID NO: 292, and said LC sequence is an LC sequence consisting of the sequence SEQ ID NO: 326. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 293, and said LC sequence is an LC sequence consisting of sequence SEQ ID NO: 327. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 294, and said LC sequence is an LC sequence consisting of SEQ ID NO: 328. In some aspects, said HC sequence is an HC sequence consisting of SEQ ID NO: 295, and said LC sequence is an LC sequence consisting of SEQ ID NO: 329. In some aspects, said HC sequence is a HC sequence consisting of SEQ ID NO: 296. and said LC sequence is the LC sequence consisting of the sequence SEQ ID NO: 330.

2.8. Consensus sequences.

Some embodiments of the present invention provide anti-HLA-G antibodies comprising one or more sequences defined by consensus sequences. Each consensus sequence is based, at least in part, on one or more alignments of two or more suitable anti-HLA-G CDR sequences presented herein. Based on such alignments, one skilled in the art will appreciate that different amino acid residues may be suitable for use at certain positions of these CDRs. Accordingly, each consensus sequence spans two or more suitable anti-HLA-G CDR sequences.

2.8.1. CDR-H3 consensus sequences.

In some embodiments, the antibody comprises a CDR-H3 sequence defined by the consensus sequence 6-Y2-Uz-K-A-U-R-R-U ₉ -y1o (SEQ ID NO: 7684), where Y ₂ is I, P, Q, T or V; Y ₃ represents A, F, K or R; Y ₉ represents A, D, Q or V; Y ₁₀ represents D, R or Y.

According to some aspects, when Y2 is I; Y3 is A or R; Y ₉ represents F; and Y ₁₀ is Y. In some aspects, when Y 2 is V; Y3 represents R; Y9 represents A, D, Q or V; and Y ₁₀ is D, R or Y. In some aspects, when Y ₃ is R; Y ₂ represents I, T or V; Y ₉ represents A, D or Q; and Y ₁₀ is D, R or Y. In some aspects, when Y ₉ is D; Y ₂ represents I, P, Q or V; Y ₃ represents A, F, K or R; and Y ₁₀ is Y. In some aspects, when Y ₁₀ is Y; Y ₂ represents I, P, R or V; Y ₃ represents A, F, K or R; and Y ₉ is D. In some aspects, when Y 10 is D; Y2 represents V; Y3 represents R; and Y9 is A or V.

According to some aspects, when Y2 is V; Y3 represents R; Y ₉ represents D; and Y ₁₀ is Y. In some aspects, when Y ₂ is I; Y3 represents A; Y ₉ represents D; and Y ₁₀ is Y. In some aspects, when Y 2 is P; Y3 represents K; Y ₉ represents D; and Y ₁₀ is Y. In some aspects, when Y ₂ is V; Y ₃ represents R; Y ₉ represents V; and Y ₁₀ represent

- 90 045983 is D. In some aspects, in cases where Y ₂ is V; Y ₃ represents R; Y ₉ represents Q; and Y ₁₀ is R. In some aspects, when Y 2 is T; Y ₃ represents R; Y ₉ represents D; and Y ₁₀ is Y. In some aspects, when Y 2 is V; Y ₃ represents R; Y ₉ represents A; and Y ₁₀ is D. In some aspects, when Y 2 is I; Y ₃ represents R; Y ₉ represents D; and Y ₁₀ is Y. In some aspects, when Y ₂ is Q; Y ₃ represents F; Y ₉ represents D; and Y ₁₀ represents Y.

In some embodiments, the antibody comprises a CDRH3 sequence defined by the consensus sequence GG-0 ₃ ^ ₄ -0 ₅ -YSRGP^nDV (SEQ ID NO: 85-93), where F ₃ is E, G, Q, or T; F ₄ represents A, H, P, Q or V; F ₅ represents K or T; and F11 is F, L or M.

In some aspects, F3 is G; in cases where F4 represents A or Q; F ₅ represents T; and F11 is V. In some aspects, _F3 is T; in cases where F ₄ represents H, P or V; F ₅ represents I, T or Y; and F ₁₁ is V. In some aspects, F ₄ is H; in cases where F ₃ represents T; F ₅ represents T; and F11 is F, L, or M. In some aspects, _F4 is V; in cases where F ₃ represents E, T or Q; F ₅ represents K or T; and F11 is L. In some aspects, _F5 is T; in cases where F ₃ represents E, G, T or Q; F ₄ represents A, H, Q or V; and F| । is F, L or M. In some aspects, F11 is L; in cases where F3 is E, G, T or Q; F4 represents A, H, P, Q or V; and F5 represents I, K or T.

According to some aspects, in cases where F3 is T; in cases where F ₄ represents H; F ₅ represents T; and F11 represents M. According to some aspects, in cases where _F3 represents T; in cases where F ₄ represents H; F ₅ represents T; and F11 is F. According to some aspects, in cases where _F3 is T; in cases where F ₄ represents P; F ₅ represents I; and F ₁₁ is L. According to some aspects, in cases where F ₃ is G; in cases where F ₄ represents Q; F ₅ represents T; and F11 represents L. According to some aspects, in cases where _F3 represents G; in cases where F ₄ represents A; F ₅ represents T; and F11 represents L. According to some aspects, in cases where F3 represents T; in cases where F4 represents H; F5 represents T; and F11 represents L. According to some aspects, in cases where _F3 represents T; in cases where F ₄ represents H; F ₅ represents T; and F11 represents L. According to some aspects, in cases where F3 represents T; in cases where F ₄ represents V; F ₅ represents K; and F11 represents L. According to some aspects, in cases where _F3 represents Q; in cases where F ₄ represents V; F ₅ represents T; and F11 represents L. According to some aspects, in cases where _F3 represents E; in cases where F ₄ represents V; F ₅ represents T; and F ₁₁ represents L.

2.8.2. Chothia CDR-H2 consensus sequences.

In some embodiments, the antibody comprises a Chothia CDR-H2 sequence defined by the consensus sequence Ye ₂ -Se ₄ -S (SEQ ID NOs: 38 and 4445), where ε ₂ is H or Y and ε ₄ is A or G .

According to some aspects, when ε ₂ represents H; ε ₄ is A or G. In some aspects, when ε 4 is G, ε 2 is H or Y.

According to some aspects, when ε2 represents Y; ε4 is G. In some aspects, when ε2 is H; ε4 is G. In some aspects, when ε2 is H; ε4 represents A.

In some embodiments, the antibody comprises a Chothia CDR-H2 sequence defined by the consensus sequence a ₁ -a ₂ -SGS (SEQ ID NOs: 39, 4142 and 49), wherein α1 is A, H or S; and α ₂ represents S or Y.

According to some aspects, when α1 is S; α2 represents S or Y.

According to some aspects, when α1 is S; α2 represents S. According to some aspects, in cases where α1 represents S; α2 is Y. In some aspects, when α1 is H; α2 represents Y. In some aspects, when α1 represents A; α2 represents Y.

In some embodiments, the antibody comprises the sequence

- 91 045983

Chothia CDR-H2 defined by the consensus sequence β1- e ₂ -SGe ₅ -e ₆ (SEQ ID NO: 5660), where β1 is A or S; β ₂ represents G or S; β ₅ represents I or S; and β ₆ is T or V.

In some aspects, when β1 is S, _β2 is G or S; β ₅ represents I or S; and β ₆ is T or V. In some aspects, when β ₂ is S, β 1 is A or S; _β5S ; and β ₆ is T or V. In some aspects, when β ₅ is S, β1 is A or S; β ₂ represents S; and β ₆ is T or V. In some aspects, when β ₆ is T, β 1 is S; β ₂ represents G or S; and β ₅ represents I or T.

According to some aspects, when β1 is A; β ₂ represents S; β ₅ represents S; and β ₆ is V. In some aspects, when β ₁ is S; β ₂ represents G; β ₅ represents I; and β ₆ represents T. According to some aspects, in cases where β 1 represents S; β ₂ represents S; β5 represents S; and β6 is T.

2.8.3. Chothia CDR-H1 consensus sequences.

In some embodiments, the antibody comprises a Chothia CDR-H1 sequence defined by the consensus sequence GGSISS-iL-il ₈ -ily (SEQ ID NOs: 1-4 and 13-14), where Ω7 is S or A; Ω8 represents D, S or N; and Ω ₉ is T, N, Y or absent.

According to some aspects, in cases where Ω7 is S; Ω8 represents D, N or S; and Ω ₉ is T, Y or absent.

According to some aspects, in cases where Ω8 represents D; Ω7 represents S or A; and Ω ₉ is N, T or Y.

According to some aspects, in cases where Ω ₉ represents T; Ω7 represents S; and Ω8 represents D or S. According to some aspects, in cases where Ω ₉ represents Y; Ω7 represents S; and Ω8 represents D or S.

According to some aspects, in cases where Ω7 is S; Ω8 represents D; and Ω ₉ represents Y. According to some aspects, in cases where Ω 7 represents S; Ω8 represents S; and Ω ₉ represents T. According to some aspects, in cases where Ω 7 represents S; Ω8 represents D; and Ω ₉ represents T. According to some aspects, in cases where Ω 7 represents A; Ω8 represents D; and Ω ₉ represents N. According to some aspects, in cases where Ω 7 represents S; Ω8 represents N; and Ω ₉ is missing. According to some aspects, in cases where Ω7 is S; Ω8 represents S; and Ω ₉ represents Y.

In some embodiments, the antibody comprises a Chothia CDR-H1 sequence defined by the consensus sequence GYSIv ₅ -SGv ₈ (SEQ ID NO: 6-9), where v ₅ is S or L and v ₈ is F, H or Y .

In some aspects, when v ₅ is S, v ₈ is F, H, or Y.

In some aspects, when v ₅ is S, v ₈ is F. In some aspects, when v ₅ is S, v ₈ is H. In some aspects, when v ₅ is S, v ₈ is Y. In some aspects, in cases where v ₅ is L, v ₈ is Y.

In some embodiments, the antibody comprises a Chothia CDR-H1 sequence defined by the consensus sequence GFTFk ₅ -k ₆ -k ₇ (SEQ ID NO: 10-12), where κ ₅ is D or S; κ ₆ represents D, N or S; and κ ₇ represents S or Y.

According to some aspects, in cases where κ ₅ represents S; κ ₆ represents D or S; and κ ₇ is S or Y. In some aspects, when κ ₇ is Y; κ5 represents D or S; and κ6 is N or D.

According to some aspects, when κ5 is D; κ6 represents N; and κ7 is Y. In some aspects, when κ5 is S; κ6 represents D; and κ7 is Y. In some aspects, when κ5 is S; κ6 represents S; and κ7 represents S.

2.8.4. Kabat CDR-H2 consensus sequences.

In some embodiments, the antibody comprises a Kabat CDR-H2 sequence defined by the consensus sequence e1-Ie ₃ -e ₄ -e ₅ -e ₆ -e7-Te ₉ -YNPSL- 92 045983

KS (SEQ ID NOs: 54-65 and 69-70), where P1 represents A, E, G or S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₅ represents N or S; β ₆ represents A or G; β ₇ represents A, L or S; and β ₉ A, N, L, V or Y.

According to some aspects, in cases where βι represents S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₅ represents N or S; β ₆ represents A or G; β ₇ represents A, L or S; and β ₉ is A, N, L, V or Y. In some aspects, when βι is G; β ₃ represents A or Y; β ₄ represents H or Y; β ₅ represents G or S; β ₆ represents A or G; β ₇ represents S; and β ₉ is A or Y. In some aspects, when β ₃ is Y; βι represents A, E, G or S; β ₄ represents H or Y; β ₅ represents S; β ₆ represents A or G; β ₇ represents S; and β ₉ is A, N, V or Y. In some aspects, when β ₃ is S; βι represents S; β ₄ represents S or Y; β ₅ represents N or S; β ₆ represents A or G; β ₇ represents L or S; and β ₉ is Y. In some aspects, when β ₃ is H; βι represents S; β ₄ represents H or Y; β ₃ represents S; β ₆ represents G; β ₇ represents A or S; and β ₉ is L or Y. In some aspects, when β ₄ is Y; βι represents S or G; β ₃ represents A, H, S or Y; β ₅ represents N or S; β ₆ represents A or G; β ₇ represents L or S; and β9 is L or Y. In some aspects, when _β4 is H; P1 represents A, E, G, S; β ₃ represents H or Y; β ₅ represents S; β ₆ represents A or G; β ₇ represents A or S; and β ₉ is A, N, Y or V. In some aspects, when β ₅ is S; P1 is A, E, G or S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₆ represents A or G; β ₇ represents A or S; and β ₉ is A, L, N, Y or V. In some aspects, when β ₆ is G; P1 is A, E, G or S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₅ represents S; β ₇ represents S; and β ₉ is A, N, L, V, or Y. In some aspects, when β ₆ is A; P1 is G or S; β ₃ represents S or Y; β ₄ represents H or Y; β ₅ represents N or S; β ₇ represents L or S; and β ₉ is A or Y. In some aspects, when β ₇ is S; βι represents A, E, G or S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₅ represents S; β ₆ represents A or G; and β ₉ is A, L, N, V, or Y. In some aspects, when β ₉ is Y; βι represents G or S; β ₃ represents A, H, S or Y; β ₄ represents H, S or Y; β ₅ represents N or S; β ₆ represents A or G; and β ₇ is A, L or S. In some aspects, when β ₉ is A; βι represents G; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents A or G; and β ₇ represents S.

According to some aspects, in cases where βι represents S; β ₃ represents Y; β ₄ represents Y; represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y. In some aspects, when βι represents S; β ₃ represents S; β ₄ represents S; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y. In some aspects, when βι represents S; β ₃ represents H; β ₄ represents H; β ₅ represents S; β ₆ represents G; and β ₇ is A; and β ₉ represents Y. In some aspects, when βι represents S; β ₃ represents H; β ₄ represents Y; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents L. In some aspects, when βι represents S; β ₃ represents H; β ₄ represents Y; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y. In some aspects, when βι represents G; β ₃ represents A; β ₄ represents Y; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y. In some aspects, when βι represents S; β ₃ represents S; β ₄ represents Y; β ₅ represents N; β ₆ represents A; and β7 is L; and β9 is Y. In some aspects, when βι is S; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y. In some aspects, when βι represents G; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents A; and β ₇ represents S; and β ₉ represents A. In some aspects, when βι represents G; β ₃

- 93 045983 represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ is Y. In some aspects, when β 1 is A; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents G; and b7 is S; and β ₉ is V. In some aspects, when β 1 is G; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ is A. In some aspects, when β 1 is E; β ₃ represents Y; β ₄ represents H; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ is N. In some aspects, when β ₁ is S; β ₃ represents S; β ₄ represents Y; β ₅ represents S; β ₆ represents G; and β ₇ represents S; and β ₉ represents Y.

2.8.5. Kabat CDR-H1 consensus sequences.

In some embodiments, the antibody comprises a Kabat CDR-H1 sequence defined by the consensus sequence 8-8-Δ ₃ -Δ ₄ -Υ-No-Δ ₇ (SEQ ID NOs: 1821, 23 and 34), where Δ3 is D or S; Δ ₄ represents T or Y; and Δ7 is A, G or S.

According to some aspects, when Δ3 is D; Δ ₄ represents T or Y; and Δ7 is G. In some aspects, when Δ3 is S; Δ ₄ represents T or Y; and Δ7 is A, G, or S. In some aspects, when _Δ4 is T; Δ3 represents D or S; and Δ7 is A, G, or S. In some aspects, when _Δ4 is Y; Δ3 represents D or S; and Δ7 is G. In some aspects, when Δ7 is G; Δ3 represents D or S; and Δ ₄ represents T or Y.

According to some aspects, when Δ3 is D; Δ ₄ represents Y; and Δ7 is G. In some aspects, when Δ3 is S; Δ ₄ represents T; and Δ7 is A. In some aspects, when Δ3 is S; Δ ₄ represents T; and Δ7 is G. In some aspects, when Δ3 is D; Δ ₄ represents T; and Δ7 is G. In some aspects, when Δ3 is S; Δ ₄ represents T; and Δ7 is S. In some aspects, when Δ3 is S; Δ ₄ represents Y; and Δ7 represents G.

In some embodiments, the antibody comprises a Kabat CDR-H1 sequence defined by the consensus sequence SG-0 ₃ -YW-0 ₆ (SEQ ID NO: 2429), where θ ₃ represents F, H or Y; and θ ₆ is F, G, I, L or T.

In some aspects, when θ ₃ is H, θ ₆ is I or T. In some aspects, when θ ₃ is Y, θ ₆ is F, G, or L. In some aspects, in in cases where θ ₆ represents T, θ ₃ represents F or H.

According to some aspects, when θ ₃ is Y, θ ₆ is G. According to some aspects, when θ ₃ is Y, θ ₆ is F. According to some aspects, when θ ₃ is H, θ ₆ is I. In some aspects, when θ ₃ is F, θ ₆ is T. In some aspects, when θ ₃ is Y, θ ₆ is L. In some aspects, when θ ₃ is H, θ ₆ is T.

2.8.6. CDR-L3 consensus sequences.

In some embodiments, the antibody comprises a CDR-L3 sequence defined by the consensus sequence Qn ₂ -n ₃ -n ₄ -HSPYT (SEQ ID NO: 149-153), where π ₂ represents Q or W; π ₃ represents A, T or V; and π ₄ represents I or V.

According to some aspects, in cases where π ₂ represents Q; π ₃ represents A, T or V; and π ₄ is I or V. In some aspects, when π ₃ is A; π ₂ represents Q or W; and π ₄ is I or V. According to some aspects, in cases where π ₄ is V; π ₂ represents Q or W; and π ₃ represents A, T or V.

According to some aspects, in cases where π ₂ represents Q; π ₃ represents A; and π ₄ represents V. According to some aspects, in cases where π ₂ represents W; π3 represents A; and π4 represents V. According to some aspects, in cases where π ₂ represents Q; π ₃ represents V; and π ₄ represents V. According to some aspects, in cases where π ₂ represents Q; π ₃ represents T; and π ₄ represents

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V. According to some aspects, in cases where π 2 represents Q; π ₃ represents A; and π ₄ represents I.

In some embodiments, the antibody comprises a CDR-L3 sequence defined by the consensus sequence Q-QA ₃ -SA ₅ -YPPT (SEQ ID NO: 154-158), where λ ₃ represents F, H or V; and λ ₅ represents I, L or S.

According to some aspects, in cases where λ ₃ represents H; λ ₅ represents I, L or S. In some aspects, when λ ₅ represents H; λ ₃ represents F, H or V.

In some aspects, when λ ₃ is H, λ ₅ is S. In some aspects, when λ ₃ is H, λ ₅ is L.

According to some aspects, when λ ₃ is F, λ ₅ is S. According to some aspects, when λ ₃ is V, λ ₅ is S. According to some aspects, when λ ₃ represents H, λ ₅ represents I.

In some embodiments, the antibody comprises a CDR-L3 sequence defined by the consensus sequence QQ-<^-<^-<^-<^-P-1-T (SEQ ID NOs: 160-161 and 163-164), where ω ₃ represents A, L, V or Y; ω ₄ represents G, P, V or Y; ω ₅ represents S, L or F; and ω ₆ is D, L, S or Y.

According to some aspects, when ω ₅ represents S; ω ₃ represents V or Y; ω ₄ represents G or V; and ω ₆ represents D or S.

According to some aspects, when ω3 is A; ω4 represents Y; ω5 represents L; and ω6 is Y. According to some aspects, in cases where ω3 is L; ω4 represents P; ω5 represents F; and ω6 is L. In some aspects, when ω3 is Y; ω4 represents V; ω5 represents S; and ω6 is D. According to some aspects, in cases where ω3 is V; ω4 represents G; ω5 represents S; and ω6 represents S.

2.8.7. CDR-L2 consensus sequences.

In some embodiments, the antibody comprises a CDR-L2 sequence defined by the consensus sequence ψ ₁ -Λ-8-ψ4-Κ-Λ-ψ ₇ (SEQ ID NOs: 128, 130, 132, 134-138, 143 and 145), where ψ1 represents D or G; ψ ₄ represents Λ, D, N, R, S, T or Y; and ψ7 represents Λ, N, S or T.

According to some aspects, in cases where ψι represents G; ψ ₄ represents Λ, D, N, R, S, T or Y; and ψ7 is A, N, or T. In some aspects, when ψ1 is D; ψ ₄ represents S or T; and ψ ₇ is S or T. In some aspects, when ψ ₄ is S; ψι represents G or D; and ψ7 is S or T. In some aspects, when ψ4 is N; ψ1 represents G or D; and ψ ₇ is A or T. In some aspects, when ψ ₄ is T; ψ1 represents G or D; and ψ ₇ is T. According to some aspects, in cases where ψ ₇ is T; ψ1 represents G or D; and ψ ₄ represents Λ, N, R, S, T or Y.

According to some aspects, in cases where ψι represents G; ψ ₄ represents S; and _ψι represents T. According to some aspects, in cases where ψι represents G; ψ ₄ represents A; and _ψι represents T. According to some aspects, in cases where ψι represents N; ψ ₄ represents S; and _ψι represents A. According to some aspects, in cases where ψι represents G; ψ ₄ represents N; and _ψι represents T. According to some aspects, in cases where ψι represents D; ψ ₄ represents S; and _ψι represents S. According to some aspects, in cases where ψι represents D; ψ4 represents S; and ψ7 represents T. According to some aspects, in cases where ψι represents G; ψ ₄ represents D; and _ψι represents N. According to some aspects, in cases where ψι represents G; ψ ₄ represents Y; and _ψι represents T. According to some aspects, in cases where ψι represents G; ψ ₄ represents R; and _ψι represents T. According to some aspects, in cases where ψι represents G; ψ4 represents T; and ψ7 represents T.

2.8.8. CDR-L1 consensus sequences.

In some embodiments, the antibody comprises a CDR-L1 sequence defined by the consensus sequence f^L-B^-fz-U-B-fe-fy-b-A (SEQ ID NOs: 105-112 and 117), where f1 represents is E, G, K, Q or R; f ₅ represents A or S; f ₉ represents L, D, N, S or T; and f ₁₀ represents P or Y.

- 95 045983

According to some aspects, in cases where φ ₁ represents R; f ₅ represents Q or S; f ₉ represents A, S or T; and φ ₁₀ represents S or Y. According to some aspects, in cases where φ 1 represents G; f ₅ represents Q or S; f ₉ represents A or D; and φ ₁₀ represents P or Y. According to some aspects, in cases where φ 1 represents Q; f ₅ represents A or S; f ₉ represents N or S; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₅ represents S; f ₁ represents E, G, Q or R; f ₉ represents A, D, S or T; and φ ₁₀ is P or Y. According to some aspects, in cases where φ ₅ is A; φ1 represents K or Q; f ₉ represents N or S; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₉ represents S; φ1 represents E, K, Q or R; f ₅ represents A or S; and φ ₁₀ represents Y. According to some aspects, in cases where φ 9 represents A; φ1 represents G or R; f ₅ represents S; and φ ₁₀ is P or Y. According to some aspects, in cases where φ ₁₀ is Y; f ₁ represents E, G, K, Q or R; f ₅ represents A or S; and f9 represents A, D, N, S or T.

According to some aspects, in cases where φ1 is R; φ5 represents S; f ₉ represents S; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₁ represents G; f ₅ represents S; f ₉ represents D; and φ ₁₀ represents Y. According to some aspects, in cases where φ 1 represents Q; f5 represents A; f ₉ represents N; and φ ₁₀ represents Y. According to some aspects, in cases where φ 1 represents G; f ₆ represents S; f ₉ represents A; and φ ₁₀ represents R. According to some aspects, in cases where φ ₁ represents R; f ₅ represents S; f ₉ represents T; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₁ represents Q; f ₅ represents S; f ₉ represents S; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₁ represents K; f ₅ represents A; f ₉ represents S; and φ ₁₀ represents Y. According to some aspects, in cases where φ 1 represents E; f ₅ represents S; 49 represents S; and φ ₁₀ represents Y. According to some aspects, in cases where φ ₁ represents R; f ₅ represents S; f ₉ represents A; and f ₁₀ represents Y.

In some embodiments, the antibody comprises a CDR-L1 sequence defined by the consensus sequence RASQSa ₆ -a ₇ -Sa ₉ -La ₁₁ (SEQ ID NOs: 119 and 123-124), wherein σ ₆ is I or V; σ ₇ represents N or S; σ9 is N, W or Y; σ _η represents A or N.

According to some aspects, when σ ₆ is 1, σ ₇ is N or S; σ ₉ represents W or Y; and _σπ is A or N. In some aspects, when σ7 is S, σ6 is I or V; σ9 represents N or Y; and σπ is A or N. In some aspects, when _σπ is A, σ6 is I or V; σ7 represents N or S; and σ9 is N or W.

According to some aspects, in cases where σ6 represents I; σ7 represents N; σ9 represents W; and σ11 represents A. According to some aspects, in cases where σ ₆ represents I; σ ₆ represents S; σ ₉ represents Y; and σ _π represents N. According to some aspects, in cases where σ 6 represents V; σ6 represents S; σ ₉ represents N; and σ _π represents A.

In some embodiments, the antibody comprises a CDR-L1 sequence defined by the consensus sequence GrG^^^-Y^-C-G^-E-A (SEQ ID NOs: 113-116), where G1 is E or R; G ₂ represents A or V; G ₈ represents A, D or S; and G ₁₀ is A or S.

According to some aspects, in cases where G ₁ is E; G ₂ represents A or V; G8 A or S; and G9 is A or S. In some aspects, when G2 is A; G1 represents E; G8 represents A or S; and G9 is A or S. In some aspects, when G2 is V; G1 represents E or R; G8 A or D; and G9 is A or S. In some aspects, when G8 is A; G1 represents E; G2 represents A or V; and G9 is S. In some aspects, when _G9 is S; G ₁ represents E; G ₂ represents A or V; and G ₈ is A. In some aspects, in cases where G ₉ is A; G ₁ represents E or R; G ₂ represents A or V; and G ₈ D or S.

According to some aspects, in cases where G ₁ is E; G ₂ represents A; G ₈ represents A; and G ₉ is S. In some aspects, in cases where G ₁ is E; G ₂ represents A; G ₈ represents S; and G ₉ represents

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A. In some aspects, when G ₁ is R; G ₂ represents V; G 8 represents A; and G ₉ is A. In some aspects, in cases where G 1 is E; G2 represents V; G8 represents A; and G ₉ represents S.

3. Germ line.

In some embodiments, an antibody that specifically binds HLA-G is an antibody comprising a variable region encoded by a specific germline, gene, or variant thereof. Exemplary antibodies of the present invention comprise variable regions encoded by the germline heavy chain variable region genes VH3-23, VH4-39, VH3-11 and VH4-0B, or variants thereof; and the light chain variable region germline genes VK1-33, VK3-20, VK1-12 and VK1-05, or variants thereof. One skilled in the art will appreciate that the CDR sequences of the present invention may also be useful in combination with variable regions encoded by other germline variable region genes, or variants thereof. In particular, the CDR sequences of the present invention may be useful in combination with variable regions encoded by germline variable region genes or variants thereof structurally similar to the germline variable region genes described above. For example, in some embodiments, the CDR-H sequence of the present invention may be combined with a variable region encoded by a germline variable region gene selected from the VH1 or VH3 families, or a variant thereof. In some embodiments, the CDR-L sequence of the present invention may be combined with a variable region encoded by a germline variable region gene selected from the ^3, Wk1, Vk3, and Vk4 families, or a variant thereof.

4. Affinity.

In some embodiments, the affinity of said antibody for HLA-G, as indicated by KD, is less than about 10 ^-5 M, less than about 10 ^-6 M, less than about 10 ^-7 M, less than about 10 -8 M, less than about 10 ^-9 M, less than about 10 ^-10 M, less than about 10 ^-11 M, or less than about 10 ^-12 M. In some embodiments, the affinity of the antibody is from about 10 ^-7 M to 10 ^-11 M. In some embodiments, the affinity of the antibody is from about 10 ^-7 M to 10 ^-10 M. In some embodiments, the affinity of the antibody is from about 10 ^-7 M to 10 ^-9 M. In some embodiments, the affinity of the antibody is from about 10 ^-7 M to 10 -8 M. In some embodiments, the affinity of the antibody is from about 10 -8 M to 10 ^-11 M. In some embodiments, the affinity of the antibody is from about 10 -8 M to 10 ^-10 M. In some embodiments, the affinity of the antibody is from about ^10-9 M to ^10-11 M. In some embodiments, the affinity of the antibody is from about ^10-10 M to ^10-11 M.

In some embodiments, the affinity of the antibody for human HLA-G is from about 1.00x10-8 M to 9.43x10 ^-10 M. In a certain embodiment, the affinity of the antibody for human HLA-G is about 1.00x10-8 M. approximately 1.08x10-8 M, approximately 1.10x10-8 M, approximately 1.13x10-8 M, approximately 1.14x10-8 M, approximately 1.16x10-8 M, approximately 1.29x10-8 M, approximately 1 ,40x10-8 M, approximately 1.41x10-8 M, approximately 1.46x10-8 M, approximately 1.67x10-8 M, approximately 1.79x10-8 M, approximately 1.81x10-8 M, approximately 2.04x10 -8 M, approximately 2.30x10-8 M, approximately 2.49x10-8 M, approximately 2.59x10-8 M, approximately 2.94x10-8 M, approximately 2.95x10-8 M, approximately 3.11x10-8 M, approximately 3.98x10-9 M, approximately 4.11x10-9 M, approximately 4.20x10-9 M, approximately 4.33x10-9 M, approximately 4.39x10-9 M, approximately 4.42x10-9 M, approximately 4.72x10-9 M, approximately 5.24x10-9 M, approximately ^5.30x10-9 M, approximately 5.35x10-9 M, approximately 5.40x10-9 M, approximately 5.55x10-9 M, approximately 5 .56x10-9 M, approximately ^5.80x10-9 M, approximately 5.89x10-9 M, approximately 5.92x10-9 M, approximately 5.98x10-9 M, approximately 5.99x10-9 M, approximately 6.10x10 -9 M, approximately 6.34x10-9 M, approximately 6.66x10-9 M, approximately 6.75x10-9 M, approximately 7.19x10-9 M, approximately 7.69x10-9 M, approximately 7.93x10-9 M, approximately 8.23x10-9 M, approximately 8.34x10-9 M, approximately 8.37x10-9 M, approximately 8.62x10-9 M, approximately 8.82x10-9 M, approximately 9.21x10-9 M, approximately 9.51x10-9 M, approximately 1.62x10-10 M, approximately ^1.63x10-10 M, 1.64x10-10 approximately 1.65x10-10 M, approximately 1.66x10-10 M, approximately 1.71 x10- ^10M , approximately 1.72x10-10M, approximately 1.86x10-10M approximately 1.78x10-10M, approximately 1.97x10-10M, approximately 1.98x10-10M, approximately 1.99x10-10M, approximately 2.29 x 10-10 M, approximately 3.24 x 10-10 M, approximately 6.47 x 10-10 M, approximately 6.96 x 10-10 M, approximately 7.84 x 10-10 M, approximately 9.41 x 10-10 M or approximately 9 ,43x10-10 M.

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In some embodiments, the antibody, when bound to human HLA-G, has a kon of from about 1.41/10 ⁵ M ^-1 -s ^-1 to about 1.07/106 M ^-1 -s ^-1 . In some embodiments, said antibody, when bound to human HLA-G, has a kon of about 1.41/10 ⁵ M ^-1 -s ^-1 , about 1.49/10 ⁵ M ^-1 -s ^-1 , about 1.66/ 10 ⁵ M ^-1 -s ^-1 , approximately

2.90/10 ⁵ M ^-1 -s ^-1 , approximately 3.60/10 ⁵ M ^-1 -s ^-1 , approximately 3.74/10 ⁵ M ^-1 -s ^-1 , approximately

3.78/10 ⁵ M ^-1 -s ^-1 , approximately 4.03/10 ⁵ M ^-1 -s ^-1 , approximately 4.30/10 ⁵ M ^-1 -s ^-1 , approximately

4.32/10 ⁵ M ^-1 -s ^-1 , approximately 4.34/10 ⁵ M ^-1 -s ^-1 , approximately 4.60/10 ⁵ M ^-1 -s ^-1 , approximately

4.64/10 ⁵ M ^-1 -s ^-1 , approximately 4.80/10 ⁵ M ^-1 -s ^-1 , approximately 4.84/10 ⁵ M ^-1 -s ^-1 , approximately

4.87/10 ⁵ M ^-1 -s ^-1 , approximately 4.91/10 ⁵ M ^-1 -s ^-1 , approximately 4.96/10 ⁵ M ^-1 -s ^-1 , approximately

4.97/10 ⁵ M ^-1 -s ^-1 , approximately 4.98/10 ⁵ M ^-1 -s ^-1 , approximately 5.01/10 ⁵ M ^-1 -s ^-1 , approximately

5.14/10 ⁵ M ^-1 -s ^-1 , approximately 5.19/10 ⁵ M ^-1 -s ^-1 , approximately 5.20/10 ⁵ M ^-1 -s ^-1 , approximately

5.26/10 ⁵ M ^-1 -s ^-1 , approximately 5.27/10 ⁵ M ^-1 -s ^-1 , approximately 5.30/10 ⁵ M ^-1 -s ^-1 , approximately

5.61/10 ⁵ M ^-1 -s ^-1 , approximately 5.90/10 ⁵ M ^-1 -s ^-1 , approximately 6.31/10 ⁵ M ^-1 -s ^-1 , approximately

6.32/10 ⁵ M ^-1 -s ^-1 , approximately 6.36/10 ⁵ M ^-1 -s ^-1 , approximately 6.46/10 ⁵ M ^-1 -s ^-1 , approximately

6.53/10 ⁵ M ^-1 -s ^-1 , approximately 6.66/10 ⁵ M ^-1 -s ^-1 , approximately 6.84/10 ⁵ M ^-1 -s ^-1 , approximately

7.20/10 ⁵ M ^-1 -s ^-1 , approximately 7.24/10 ⁵ M ^-1 -s ^-1 , approximately 7.48/10 ⁵ M ^-1 -s ^-1 , approximately

7.36/10 ⁵ M ^-1 -s ^-1 , approximately 7.58/10 ⁵ M ^-1 -s ^-1 , approximately 7.77/10 ⁵ M ^-1 -s ^-1 , approximately

7.92/10 ⁵ M ^-1 -s ^-1 , approximately 7.94/10 ⁵ M ^-1 -s ^-1 , approximately 7.96/10 ⁵ M ^-1 -s ^-1 , approximately

8.03/10 ⁵ M ^-1 -s ^-1 , approximately 8.24/10 ⁵ M ^-1 -s ^-1 , approximately 8.26/10 ⁵ M ^-1 -s ^-1 , approximately

8.55/10 ⁵ M ^-1 -s ^-1 , approximately 8.63/10 ⁵ M ^-1 -s ^-1 , approximately 8.66/10 ⁵ M ^-1 -s ^-1 , approximately

8.74/10 ⁵ M ^-1 -s ^-1 , approximately 8.79/10 ⁵ M ^-1 -s ^-1 , approximately 8.92/10 ⁵ M ^-1 -s ^-1 , approximately

8.96/10 ⁵ M ^-1 -s ^-1 , approximately 9.09/10 ⁵ M ^-1 -s ^-1 , approximately 9.31/10 ⁵ M ^-1 -s ^-1 , approximately

9.35/10 ⁵ M ^-1 -s ^-1 , approximately 9.38/10 ⁵ M ^-1 -s ^-1 , approximately 9.46/10 ⁵ M ^-1 -s ^-1 , approximately

9.54/10 ⁵ M ^-1 -s ^-1 , approximately 9.73/10 ⁵ M ^-1 -s ^-1 , approximately 9.83/10 ⁵ M ^-1 -s ^-1 , approximately

9.84/10 ⁵ M ^-1 -s ^-1 , approximately 9.91/10 ⁵ M ^-1 -s ^-1 , approximately 1.05/10 ⁶ M ^-1 -s ^-1 or approximately 1.07/10 ⁶ M ^-1 -s ^-1 .

In some embodiments, the antibody, upon binding to human HLA-G, has a koff of from about 1.06/10 ² s ^-1 to about 8.55/10 ⁵ s ^-1 . In some embodiments, the antibody has a koff of about 1.06/ 10 ^-2 s ^-1 , approximately 1.13/10 ^-2 s ^-1 , approximately 1.87/10 ^-2 s ^-1 , approximately 2.13/10 ^-2 s - ¹ , approximately 3.62/10 ^{- 3} s ^-1 , approximately 3.66/10 ^-3 s ^-1 , approximately 3.75/10 ^-3 s - ¹ , approximately 3.78/10 ^-3 s ^-1 , approximately 3.83/10 ^-3 s ^-1 , approximately 3.96/10 ^-3 s ^-1 , approximately 4.17/10 ^-3 s ^-1 , approximately 4.27/10 ^-3 s ^-1 , approximately 4.29/10 ^-3 s ^-1 , approximately 4.41/10 ^-3 s ^-1 , approximately 4.42/10 ^-3 s ^-1 , approximately 4.46/10 ^-3 s ^-1 , approximately 4.54/10 ^-3 s ^-1 , approximately 4.65/10 ^-3 s ^-1 , approximately 4.85/10 ^-3 s ^-1 , approximately 4.88/10 ^-3 s ^-1 , approximately 4.89/10 ^-3 s ^-1 , approximately 4, 98/10 ^-3 s ^-1 , approximately 5.26/10 ^-3 s ^-1 , approximately 5.44/10 ^-3 s ^-1 , approximately 5.47/10 ^-3 s ^-1 , approximately 5.71/ 10 ^-3 s ^-1 , approximately 5.72/10 ^-3 s ^-1 , approximately 5.84/10 ^-3 s ^-1 , approximately 5.90/10 ^-3 s ^-1 , approximately 5.92/10 ^{- 3} s ^-1 , approximately 5.93/10 ^-3 s ^-1 , approximately 6.24/10 ^-3 s ^-1 , approximately 6.25/10 ^-3 s ^-1 , approximately 6.28/10 ^-3 s ^-1 , approximately 6.49/10 ^-3 s ^-1 , approximately 6.50/10 ^-3 s ^-1 , approximately 6.71/10 ^-3 s ^-1 , approximately 6.78/10 ^-3 s ^-1 , approximately 6.83/10 ^-3 s ^-1 , approximately 6.98/10 ^-3 s ^-1 , approximately 7.17/10 ^-3 s ^-1 , approximately 7.42/10 ^-3 s ^-1 , approximately 8.12/10 ^-3 s ^-1 , approximately 8.16/10 ^-3 s ^-1 , approximately 8.26/10 ^-3 s ^-1 , approximately 8.64/10 ^-3 s ^-1 , approximately 8, 76/10 ^-3 s ^-1 , approximately 8.91/10 ^-3 s ^-1 , approximately 9.31/10 ^-3 s ^-1 , approximately 9.32/10 ^-3 s ^-1 , approximately 9.87/ 10 ^-3 s ^-1 , approximately 1.82/10 ^-4 s ^-1 , approximately 4.38/10 ^-4 s ^-1 , approximately 4.59/10 ^-4 s ^-1 , approximately 4.99/10 ^{- 4} s ^-1 , approximately 5.73/10 ^-4 s ^-1 , approximately 6.03/10 ^-4 s ^-1 or approximately 8.55/10 ^-5 s ^-1 .

In some aspects, K _D , k _a and kd are determined at 25°C. In some embodiments, _KD , _ka , and kd are determined using surface plasmon resonance. In some embodiments, the specified K _D , ka and kd are determined in accordance with the methods described in the examples.

5. HLA-G inhibition.

In some aspects, the antibody reduces the affinity of HLA-G for its ligand(s). In some aspects, the antibody disrupts the binding of HLA-G to beta-2-microglobulin and/or a cognate peptide thereof. In some aspects, the antibody prevents dimerization or oligomerization of HLA-G.

In some aspects, the antibody inhibits the function of HLA-G on tumor cells. In some aspects, the antibody inhibits the function of HLA-G on immune cells. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to an inhibitory ITIM receptor. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to ILT2. According to some

- 98 045983 In other embodiments, the antibody blocks the interaction and/or binding of HLA-G with ILT4. In some embodiments, the antibody blocks the interaction and/or binding of HLA-G to KIR2DL4.

In some embodiments, the antibody inhibits immunosuppressive function. In some embodiments, the antibody inhibits HLA-G-mediated suppression of NK cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of cytotoxic T lymphocytes. In some embodiments, the antibody inhibits HLA-G-mediated suppression of B cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of neutrophils. In some embodiments, the antibody inhibits HLA-G-mediated suppression of dendritic cells. In some embodiments, the antibody inhibits HLA-G-mediated suppression of macrophages. In some embodiments, the antibody inhibits HLA-G-mediated suppression of monocytes. In some embodiments, the antibody inhibits HLA-G-mediated suppression of cytolysis and/or proliferation of NK and/or T cells.

In some embodiments, the antibody prevents or inhibits HLA-G-mediated suppression of phagocytosis. In some embodiments, the antibody mediates HLA-G-mediated induction of regulatory T cells. In some embodiments, the antibody prevents or inhibits the formation or expansion of regulatory T cells. In some embodiments, the antibody inhibits tumor growth through antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP).

In some aspects, the reduction is a decrease of about 10% or less, a decrease of about 20% or less, a decrease of about 30% or less, a decrease of about 40% or less, a decrease of about 50% or less, a decrease of about 60% or less, a decrease of about 70% or less, a decrease of about 80% or less, a decrease of about 90% or less, or a decrease of about 100%. In some aspects, the increase is an increase of about 10% or more, an increase of about 20% or more, an increase of about 30% or more, an increase of about 40% or more, an increase of about 50% or more, an increase of about 60% or more, an increase of about 70% or more, an increase of about or more than 80%, an increase of about 90% or more, or an increase of 100%.

6. HLA-G analysis.

In some embodiments, the antibody binds to an HLA-G epitope. An epitope often consists of a continuous series of amino acids, such as, but not limited to, 5-6 amino acids. In some embodiments, the epitope contains or consists of a continuous or discontinuous series of amino acids. In some embodiments, the continuous or discontinuous series of amino acids is part of the HLA-G domain. In some embodiments, the domain comprises or consists of an alpha-3 domain.

In some aspects, HLA-G has a sequence identical to the amino acid sequence set forth in SEQ ID NO: 342. In some aspects, the epitope has an amino acid sequence included in the amino acid sequence set forth in SEQ ID NO: 342. In some aspects, the epitope has an amino acid sequence that is 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identical to the sequence set forth in SEQ ID NO: SEQ ID NO: 342.

In some aspects, the epitope comprises or consists of a continuous or discontinuous stretch of amino acids comprising residues 195, 197, and/or 198 of the sequence set forth in SEQ ID NO: 342. In some aspects, the epitope comprises a sequence identical to or corresponding to residues 195, 197, and /or 198 sequence that is part of the sequence presented in SEQ ID NO: 342. In some aspects, the specified epitope has a sequence of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95 % identical to the sequence included in the sequence shown in SEQ ID NO: 342. In some aspects, the specified epitope contains 1, 2, 3, 4, 5, 6, 7, 8 or 9 substitutions relative to the sequence included in the sequence presented in SEQ ID NO: 342. In some aspects, the specified epitope contains 1, 2, or 3 substitutions relative to residues of the sequence included in the sequence presented in SEQ ID NO: 342. In some aspects, the specified antibody comes into contact with any of the residues presented in in fig. 9.

In some aspects, the antibody competes with any of the antibodies provided herein. Competition may be, for example, without limitation, binding competition, inhibition competition, or any other form of competition. In some aspects, the antibody competes with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 an

- 99 045983 title 38410, 38418, 38422, 38426, 38381, 38358, 37323, 38373, 38375, 38379, 38389, 33303 or 33357. In some aspects, said antibody competes with any of the antibodies provided in fig. 2 or 3. In some aspects, said antibody competes with 1, 2, 3, 4, 5, 6, 7, or 8 antibodies 38373, 38375, 38379, 38418, 38422, 38426, 38410, or 38381. In some aspects, said antibody competes with 38358. In some aspects, said antibody competes with 1, 2, 3, 4, 5, 6, 7, 8, or 9 antibodies 38373, 38375, 38379, 38418, 38422, 38426, 38410, or 38381 or 38358. In some aspects, said antibody competes with one or both of antibodies 37323 and/or 38389. In some aspects, said antibody competes with one or both of antibodies 33303 and/or 33357.

7. Glycosylation options.

In some embodiments, the antibody may be modified to increase, decrease, or eliminate its degree of glycosylation. Glycosylation of polypeptides is typically either N-linked or O-linked.

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 other than proline, are recognition sequences for the enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Accordingly, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site.

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.

The addition or deletion of N-linked glycosylation sites to an antibody can be accomplished by altering the amino acid sequence so as to create or delete one or more of the tripeptide sequences described above. The addition or deletion of Linked Glycosylation sites can be accomplished by adding, deleting or substituting (as appropriate) one or more serine or threonine residues in the antibody sequence.

In some embodiments, the antibody is glycosylated. In some embodiments, the antibody is deglycosylated. Carbohydrates can be removed using standard techniques. In some embodiments, the antibody is aglycosylated, for example, through expression in a non-glycosylation system.

8. Fc options.

In some embodiments, amino acid modifications may be introduced into the Fc region of an antibody of the present invention to produce a variant Fc region. In some embodiments, the Fc region variant has some, but not all, effector functions. Such antibodies may be useful, for example, in applications for which the in vivo half-life of the antibody is important, but certain effector functions are unnecessary or detrimental. Examples of effector functions include complement-dependent cytotoxicity (CDC) and antibody-directed complement-mediated cytotoxicity (ADMC). Numerous substitutions or deletions providing measures of effector function are known in the art.

In some embodiments, Fc is modified. In some embodiments, the hinge of an IgG1 or IgG4 antibody is modified. Modification of the hinge region stabilizes the antibody and prevents the formation of unwanted bispecific antibodies. In some embodiments, the modification comprises L234A, L235A, and/or G237A in accordance with the Kabat numbering scheme, or residues numbered 117, 118, and 120, respectively, wherein residues are numbered in accordance with any of SEQ ID NO: 334. In some embodiments implementation, said modification comprises EU S228P or S241P according to the Kabat numbering scheme or residue number 108 according to SEQ ID NO: 335. In some embodiments, an IgG Fc is engineered to modulate the effector function of an antibody (see Wang et al., Protein Cell, 2018, Jan; 9(1): 63-73), which is incorporated by reference herein in its entirety, including all drawings).

Non-limiting examples of in vitro assays for assessing the ADCC activity of a molecule of interest are provided in US Pat. No. 5,500,362 and US Pat. No. 5,821,337; in: 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, 82:14991502; and Bruggemann et al., J. Exp. Med 1987, 166:1351-1361. Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. In an alternative or additional embodiment, the ADCC activity of a molecule of interest can be assessed in vivo using an animal model such as that described in Clynes et al., Proc. Natl. Acad. Sci. U.S.A. 1998, 95:652-656.

C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and therefore does not have CDC activity. Examples of C1q binding assays include those described in WO 2006/029879 and WO 2005/100402.

- 100 045983

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.

Binding and in vivo clearance of FcRn (determination of half-life) can also be measured, for example, using methods described in Petkova et al., Intl. Immunol 2006, 18:1759-1769.

9. Obtaining antibodies.

9.1. Obtaining antigens.

The HLA-G antigen for use in antibody production may be intact HLA-G or an HLA-G fragment. Said intact HLA-G or HLA-G fragment may be in the form of an isolated protein or expressed by the cell. Other forms of HLA-G suitable for antibody production will be apparent to those skilled in the art.

9.2. Monoclonal antibodies.

Monoclonal antibodies can be produced, for example, using the hybridoma method first described in Kohler et al., Nature, 1975, 256:495-497, and/or recombinant DNA methods (see, for example, US Patent No. 4816567 ). Monoclonal antibodies can also be produced, for example, using phage or yeast libraries. See, for example, US Pat. No. 8,258,082 and US Pat. No. 8,691,730.

In the hybridoma method, a mouse or other suitable host animal is immunized to stimulate the production of lymphocytes that produce or are capable of producing antibodies that specifically bind to the protein used for immunization. Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with the myeloma cells using a suitable fusion agent such as polyethylene glycol to produce a hybridoma cell. See Goding JW, Monoclonal Antibodies: Principles and Practice ^3rd ed. (1986) Academic Press, San Diego, CA.

The hybridoma cells are seeded and cultured in a suitable culture medium that contains one or more substances that inhibit the growth or survival of unfused parental myeloma cells. For example, if the original myeloma cells lacked the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), hybridoma culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), substances that prevent the growth of HGPRT-deficient cells.

Suitable myeloma cells are cells that efficiently fuse to support stable production of high levels of antibody by the selected antibody-producing cells; and sensitive to environmental conditions such as the presence or absence of HAT media. Of these cells, 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 Center, San Diego, Calif.), and SP-2 or X63-Ag8- cells. 653 (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies. See, for example, Kozbor, J. Immunol, 1984, 133:3001.

Once hybridoma cells that produce antibodies with the desired specificity, affinity and/or biological activity have been identified, selected clones can be subcloned using serial dilution procedures and cultured by standard methods. See Goding, above. Suitable culture media for this purpose include, for example, DMEM or RPMI-1640. In addition, hybridoma cells can be cultured in vivo o as ascites tumors in the animal body.

DNA encoding monoclonal antibodies can be easily isolated and sequenced using standard procedures (eg, using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of said monoclonal antibodies). Accordingly, hybridoma cells can serve as a suitable source of DNA encoding antibodies with the desired properties. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as bacteria (eg, E. coli), yeast (eg, Saccharomyces or Pichia spp.), COS cells, Chinese hamster ovary (CHO) cells, or myelomas that do not otherwise produce antibody, to obtain said monoclonal antibodies.

9.3. Humanized antibodies.

Humanized antibodies can be produced by replacing most or all of the structural portions of a monoclonal antibody with corresponding human antibody sequences. This creates a hybrid molecule in which only the antigen-specific variable region, or CDR, consists of non-human sequence. Methods for producing humanized antibodies include those described, for example, in 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 patents

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US No. 5585089, No. 5693761, No. 5693762 and No. 6180370.

9.4. Human antibodies.

Human antibodies can be produced using various techniques known in the art, for example, using transgenic animals (eg, humanized mice). See, for example, 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 US Pat. Nos. 5,591,669, 5,589,369, and 5,545,807. Human antibodies may 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, 222:581597; and US Patent Nos. 5,565,332 and 5,573,905). Human antibodies can also be produced by in vitro activated B cells (see, for example, US Pat. No. 5,567,610 and US Pat. No. 5,229,275). Human antibodies may also be derived from yeast libraries (see, for example, US Pat. No. 8,691,730).

10. Vectors, host cells and recombinant methods.

The present invention also provides isolated nucleic acids encoding anti-HLA-G antibodies, vectors and host cells containing said nucleic acids, and recombinant techniques for producing said antibodies.

To recombinantly produce an antibody, the nucleic acid encoding it can be isolated and inserted into a replicable vector for further cloning (ie, DNA amplification) or expression. In some aspects, said nucleic acid can be produced by homologous recombination, for example as described in US Pat. No. 5,204,244.

Many different vectors are known in the art. Vector components typically 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 US Pat. No. 5,534,615.

Suitable host cells include any prokaryotic (eg bacterial), lower eukaryotic (eg yeast) or higher eukaryotic cells (eg mammalian cells). Suitable prokaryotes include eubacteria such as gram-negative or gram-positive organisms, for example enterobacteria 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 suitable E. coli host for cloning is E. coli 294, but other strains such as E. coli B, E. coli X1776 and E. coli W3110 are also suitable.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are also suitable as hosts for cloning or expression of anti-HLA-G antibody-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is a commonly used lower eukaryotic host microorganism. However, several other genera, species and strains are also available and suitable for use, 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 Penicillium, Tolypocladium and Aspergillus (A. nidulans and A. niger ).

Suitable mammalian host cells include COS-7 cells, HEK293 cells; newborn hamster kidney (BHK) cells; Chinese hamster ovary (CHO) cells; mouse Sertoli cells; African green monkey kidney cells (VERO-76); and so on.

The host cells used to produce the anti-HLA-G antibody of the present invention can be cultured in a variety of media. Commercially available media such as, for example, Ham's P10 medium, minimal essential medium (MEM), RPMI-1640 and Dulbecco's modified Eagle's medium (DMEM) are suitable for culturing host cells. Additionally, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and US Pat. 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.

Hormones and/or other growth factors (such as insulin, transferrin or epidermal growth factor), salts (such as sodium, calcium, magnesium chloride and phosphate), buffers (such as HEPES), may be added to any of these media as necessary. nucleotides (such as adenosine and thymidine), antibiotics, trace elements (by definition, inorganic compounds typically present in final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary additives may also be included in suitable concentrations known to those skilled in the art.

Culture conditions, such as temperature, pH, etc., are those previously used for the host cell selected for expression and will be apparent to one skilled in the art.

Using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is about

- 102 045983 is produced intracellularly, then in the first step, debris particles, that is, host cells or lysed fragments, are removed, for example, by centrifugation or ultrafiltration. For example, in the source: Carter et al. (Bio/Technology, 1992, 10:163-167) describes a procedure for isolating antibodies that are secreted into the periplasmic space of E. coli. Briefly, the cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA and phenylmethylsulfonyl fluoride (PMSP) for approximately 30 minutes. Cellular debris can be removed by centrifugation.

In some embodiments, the antibody is produced in a cell-free system. In some aspects, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225, incorporated herein by reference in its entirety. In some aspects, the cell-free system uses a cell-free extract of a eukaryotic cell or prokaryotic cell. In some aspects, said prokaryotic cell is E. coli. Cell-free expression of an antibody may be useful, for example, if the antibody accumulates in the cell as an insoluble aggregate, or if the yield from periplasmic expression is negligible.

If the antibody is secreted into the medium, supernatants from such expression systems are typically first concentrated using a commercially available protein concentration filter, such as an Amicon® or Millipore® Pellcon® ultrafiltration unit. At any of the steps described, a protease inhibitor, such as PMSP, can be added to inhibit proteolysis, as well as antibiotics to prevent the growth of unintended contaminants.

The antibody composition obtained from cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis and affinity chromatography; in particular, affinity chromatography is a suitable purification method. The suitability of protein A as an affinity ligand depends on the type and isotype of any immunoglobulin Fc domain in the antibody. Protein A can be used to purify antibodies based on human γ1, γ2 or γ4 heavy chains. (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13). Protein G is suitable for all mouse isotypes and for human γ3 (Guss et al., EMBO J., 1986,5:1567-1575).

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(styrene divinyl)benzene provide higher flow rates and shorter processing times than agarose can provide. If the antibody contains a CH3 domain, BakerBond ABX® resin is suitable for purification.

Other protein purification techniques are also available and can be used by one skilled in the art, such as ion exchange column fractionation, ethanol precipitation, reverse phase HPLC, silica gel chromatography, heparin-Sepharose® chromatography, chromatofocusing, SDS-PAGE electrophoresis and precipitation ammonium sulfate.

After any preliminary purification step(s), the mixture containing the antibody of interest and contaminants can be subjected to low pH hydrophobic interaction chromatography using an elution buffer with a pH of about 2.5 to about 4.5, which is typically carried out at low pH. salt concentrations (eg, from about 0 to about 0.25 M salt).

11. Pharmaceutical compositions and methods of administration.

Any of the antibodies of the present invention may be presented in any suitable pharmaceutical composition and administered by any suitable route. Suitable routes of administration include, but are not limited to, inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary and subcutaneous administration.

The pharmaceutical composition may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipients may be used, and one skilled in the art will be able to select suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients listed below are intended to be illustrative and not limiting. Additional pharmaceutical excipients include, for example, those described in: Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) ^6th Ed. (2009), incorporated herein by reference in its entirety.

In some embodiments, said pharmaceutical composition comprises an antifoaming agent. Any suitable antifoaming agent may be used. In some aspects, said antifoam agent is selected from alcohol, ether, oil, wax, silicone, surfactant, and combinations thereof. In some aspects, said antifoam agent is selected from mineral oil, vegetable oil, ethylene bis-stearamide, paraffin wax, ester wax, fatty alcohol wax, long chain fatty alcohol, fatty acid soap, fatty acid ester, silicone glycol, fluorosilicone, polyethylene glycol copolymer, and polypropylene glycol, polydimethyl

- 103 045983 xyloxane silica, ether, octyl alcohol, caprylic alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone and combinations of the above.

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.

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 sodium monoglutamate.

In some embodiments, said pharmaceutical composition comprises a carrier or excipient. Illustrative examples of carriers or excipients include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum and guar gum.

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

In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethylcellulose, hydroxypropylcellulose and magnesium oxide.

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

In some embodiments, said pharmaceutical composition comprises a solvent. In some aspects, said solvent is a saline solution, such as sterile isotonic saline or dextrose solution. In some aspects, said solvent is water for injection.

In some embodiments, the pharmaceutical compositions are in the form of particles, such as microparticles or nanoparticles. Microparticles and nanoparticles can be obtained from any suitable material, such as a polymer or lipid. In some aspects, said microparticles or nanoparticles are micelles, liposomes, or polymersomes. In some embodiments, the composition of the present invention is a pharmaceutical composition or a unit dosage form. The pharmaceutical compositions and unit dosage forms of the present invention contain a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.

Also included herein are anhydrous pharmaceutical compositions and dosage forms containing the antibody, since water may promote degradation of some antibodies.

The anhydrous pharmaceutical compositions and dosage forms provided by the present invention can be prepared using anhydrous or low-moisture ingredients and under low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient that contains a primary or secondary amine may be anhydrous if significant contact with moisture and/or humidity is expected during manufacture, packaging and/or storage.

The preparation and storage of an anhydrous pharmaceutical composition should be carried out in such a way as to preserve its anhydrous nature. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water, such that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, unit dose containers (eg, vials), blister packs, and blister packs.

According to some embodiments, said pharmaceutical composition additionally

- 104 045983 but contains one antibody or both antibodies, to an immunoinhibitory receptor or ligand, and/or to an immunostimulatory receptor and/or ligand. In some embodiments, said pharmaceutical composition further comprises an effective amount of at least one of the following: an anti-ILT2 antibody; anti-ILT-4 antibody; anti-ILT4 antibody; anti-KIR2DL4 antibody; anti-HLA-E antibody; anti-NKG2A antibody; anti-HLA-P antibody; anti-PD-L1 antibody; anti-PD-I antibody; anti-CTLA4 antibody; anti-CD38 antibody; anti-CD73 antibody; anti-A2A receptor antibody; anti-A2B receptor antibody; antibody against dual A2A/A2B receptor or a combination thereof; anti-CD39 antibody; anti-CD73 antibody; anti-CD47 antibody; and/or a small molecule inhibitor. In some embodiments, the pharmaceutical composition further comprises an anti-Tim-3 antibody; anti-TIGIT antibody; anti-Vista antibody; anti-CD94 antibody; anti-ILT2 antibody, anti-ILT4 antibody, anti-PD-L1 antibody and/or anti-CD47 antibody; small molecule inhibitor; bispecific T cell recruiter, agent for CAR T cell therapy, CAR NK cell therapy, CAR macrophage therapy, engineered cell therapy and/or adoptive T cell therapy; oncolytic virus; chemotherapeutic agent; and/or a therapeutic agent with ADCC function that uses competent effector antibodies, for example, anti-CD19, anti-CD20, anti-EGPR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2, anti-CD3 and/or anti-CCR4. In some embodiments, the ADCC therapy is an enhanced ADCC therapy. In some embodiments, the effector is enhanced through afucosylation, point mutations, or other means.

11.1. Parenteral dosage forms.

In some embodiments, parenteral dosage forms are provided. Parenteral dosage forms may be administered to subjects by a variety of routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically involves bypassing the subject's natural defenses against contaminants, parenteral dosage forms are generally sterile or may be sterilized before administration to the 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 injectable base, suspensions ready for injection, and emulsions.

Suitable bases 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: USP Water for Injection; aqueous bases such as, but not limited to, sodium chloride injection, Ringer's solution for injection, dextrose injection, dextrose-sodium chloride injection and lactated Ringer's solution for injection; water-miscible bases such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous bases such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

Excipients that increase the solubility of one or more antibodies as described herein may also be included in these parenteral dosage forms.

11.2. Dosage and unit dosage forms.

For therapy in humans, the physician will determine the dosage regimen he or she considers most appropriate for prophylactic or curative therapy and is appropriate to the age, weight, condition, and other factors specific to the patient being treated.

The amount of antibody or composition that will be effective in preventing or treating a disorder or one or more symptoms thereof will depend on the nature and severity of the disease or condition and the route by which the antibody is administered. The frequency and dosage will also vary depending on factors specific to each subject, depending on the specific therapy being administered (eg, therapeutic or prophylactic agents), the severity of the disorder, disease or condition, route of administration, and age, body weight, response and subject's history. Effective doses can be extrapolated from dose response curves obtained in vitro or in animal model test systems.

In some embodiments, exemplary doses of the composition include milligrams or micrograms of antibody per kilogram of body weight of the subject or sample (e.g., from about 10 μg per kilogram to about 50 milligrams per kilogram, from about 100 μg per kilogram to about 25 milligrams per kilogram, or from approximately 100 micrograms per kilogram to approximately 10 milligrams per kilogram). In a specific embodiment, the dosage by weight of an antibody of the present invention that is administered to prevent, treat, manage, or alleviate 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 body weight

- 105 045983 subjects; or more. In another embodiment, the dosage of said composition or composition of the present invention that is administered to prevent, treat, manage, or alleviate a disorder or one or more symptoms thereof in a subject is from 0.1 mg to 200 mg, from 0.1 mg up to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 25 mg, from 0.1 mg to 20 mg, from 0.1 mg to 15 mg, from 0.1 mg to 10 mg, from 0.1 mg to 7.5 mg, from 0.1 mg to 5 mg, from 0.1 to 2.5 mg, from 0.25 mg to 20 mg, from 0.25 to 15 mg, from 0.25 up to 12 mg, from 0.25 to 10 mg, from 0.25 mg to 7.5 mg, from 0.25 mg to 5 mg, from 0.25 mg to 2.5 mg, from 0.5 mg to 20 mg, from 0.5 to 15 mg, from 0.5 to 12 mg, from 0.5 to 10 mg, from 0.5 mg to 7.5 mg, from 0.5 mg to 5 mg, from 0.5 mg to 2.5 mg, from 1 mg to 20 mg, from 1 mg to 15 mg, from 1 mg to 12 mg, from 1 mg to 10 mg, from 1 mg to 7.5 mg, from 1 mg to 5 mg or from 1 mg to 2.5 mg.

The dose may be administered according to a suitable schedule, for example, once, twice, three times or several times weekly. In some cases, it may be necessary to use antibody dosages beyond the range described herein, as will be apparent to those skilled in the art. Additionally, it should be noted that the clinician or treating physician knows how and when to interrupt, adjust, or discontinue therapy based on the subject's response.

Other therapeutically effective amounts may be suitable for use in other diseases and conditions, as is well known to those skilled in the art. Likewise, an amount sufficient to prevent, manage, treat or alleviate such disorders, but not sufficient to cause or sufficient to reduce adverse events associated with the antibodies of the present invention, is also included in the dosages and dosing schedules described herein. In addition, if multiple doses of a composition of the present invention are administered to a subject, not all doses will necessarily be the same. For example, the dose administered may be increased to improve the prophylactic or therapeutic effect of the composition or may be decreased to reduce one or more side effects experienced by a particular subject.

In some embodiments, treatment or prevention may be initiated with one or more loading doses of an antibody or composition of the present invention, followed by one or more maintenance doses.

In some embodiments, a dose of an antibody or composition of the present invention may be administered to achieve a steady-state concentration of said antibody in the blood or serum of a subject. The steady-state concentration can be determined by measurement in accordance with techniques known to those skilled in the art, or based on the physical characteristics of the subject, such as height, weight and age.

In some embodiments, administration of the same composition may be repeated and said administrations may be separated in time 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 other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and said administrations may be separated in time 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.

12. Therapeutic use.

In therapeutic applications, the antibodies of the present invention are administered to a mammal, typically a human, in a pharmaceutically acceptable dosage form such as those known in the art and described above herein. For example, the antibodies of the present invention may be administered to a human intravenously as a bolus, or may be administered by continuous infusion over a period of time, by intramuscular, intraperitoneal, intraspinal, subcutaneous, intraarticular, intrasynovial, intrathecal, or intratumoral routes. Antibodies are also administered by peritumoral, intralesional or perisolate routes in appropriate cases to provide both local and systemic therapeutic effects. Intraperitoneal administration may be particularly suitable, for example, in the treatment of ovarian tumors.

Antibodies of the present invention may be suitable for treating any disease or condition in which HLA-G is involved, such as cancer, autoimmune disease and infection.

The antibodies of the present invention can be used to treat any suitable cancer. Exemplary 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's lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, epenoid

- 106 045983 dimoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing's sarcoma, eye cancer, germ cell tumor, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic cancer, glioma, head and neck cancer, leukemia hairy cell carcinoma, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal carcinoma, intraocular melanoma, islet cell tumor, Kaposi's 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 cell carcinoma of the neck with occult primary midline carcinoma involving the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's 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, cancer skin, 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 cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, neuroblastoma, cervical cancer, and hematologic cancer.

The antibodies of the present invention can be used to treat any suitable autoimmune disease. Exemplary 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-CBM/anti-BMK nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune vegetative dystonia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIAD), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura ( ATP), autoimmune thyroid disease, autoimmune urticaria, axonal and neuronal neuropathies, Balo's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMS), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, colitis, congenital heart block, Coxsackie myocarditis, CREST syndrome, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis , Devic's disease (neuromyelitis of the optic nerve), 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, glomerulone frit, 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-Schönlein purpura, gestational herpes, 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 sclerosis, woody conjunctivitis, linear IgA dermatosis (LAD), lupus (SLE), Lyme disease (chronic), Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Moray ulcer, Mucha-Habermann disease, multiple sclerosis , myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's neuromyelitis), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Personage-Turner syndrome, pars plana inflammation (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndromes type I, II and III, polymyalgia rheumatica, polymyositis, post-infarction syndrome, post-cardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary

- 107 045983 Sclerous cholangitis, psoriasis, psoriatic arthritis, idiopathic fibrosis of the lungs, gangrenous pyoderma, true erythrocyte aplasia, Raineo phenomenon, reactive arthritis, sympathetic reflex dystrophy, recurrent polychondritis, restless legs syndrome. Matical fever, rheumatoid arthritis , sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, autoimmunity against testicular and/or sperm antigens, stiff man syndrome, subacute bacterial endocarditis (SAB), Susac syndrome, sympathetic ophthalmia, Takayasu 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 called granulomatosis with polyangiitis ( GPA).

The antibodies of the present invention can be used to treat any suitable infection. Exemplary suitable infections include, for example, hepatitis A virus, hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus (HIV), and other viral infections.

Some embodiments involve treating a subject suffering from cancer, chronic infection, or an inflammatory disease, comprising the step of administering to said subject a pharmaceutical composition containing an effective amount of any of the antibodies provided herein. Some embodiments include treating a subject suffering from cancer with a chronic infection; or an inflammatory disease, comprising the step of administering to said subject a pharmaceutical composition comprising an effective amount of any of the antibodies provided herein in combination with an effective amount of another antibody provided herein. In some embodiments, the cancer is a hematologic cancer.

Some embodiments provide a method of modulating the function of the immune system in a subject in need thereof, comprising the step of contacting a population of immune cells of the subject with a pharmaceutical composition containing an effective amount of an antibody provided herein under conditions that modulate the immune system. Some embodiments provide a method of 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 provided herein in combination with an effective amount of another antibody provided herein. In some embodiments, the antibody comprises a bispecific antibody or a complexing antibody.

In some embodiments, the bispecific antibody or complexing antibody is administered in an amount sufficient to achieve 1, 2, 3, 4, 5, 6, 7, or 8 of:

a) inhibition of immune suppression;

b) decreasing levels of regulatory T cells;

c) increased activity of myeloid cells;

d) increasing the activity of cytotoxic T lymphocytes, NK cells, B cells, neutrophils, monocytes, macrophages and/or dendritic cells;

e) increasing phagocytic activity;

f) inhibiting metastasis;

g) inhibiting tumor growth; and/or

h) induction of tumor regression.

In some embodiments, the bispecific antibody binds HLA-G and HLA-E.

In some embodiments, the method of modulating immune system function in a subject in need thereof further comprises administering chemotherapy, administering radiation therapy, and/or administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise one or more immunostimulating agents. In some embodiments, the one or more immunostimulating agents comprise an inhibitory immune cell receptor antagonist. In some embodiments, the inhibitory receptor is at least one of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-1, CD39, CD73, PD-L1, PD-L2, LAG-3, TIGIT, B7 -H3, B7-H4, Tim3, neuritin, BTLA, CECAM-1, CECAM5, VISTA, LAIR1, CD160, 2B4, TGP-B, NKG2A and/or killer cell immunoglobulin-like receptor (KIR).

In some embodiments, the one or more immunostimulatory agents comprise an immune cell co-stimulatory receptor agonist. In some embodiments, said co-stimulatory receptor comprises any one or more of OX40, CD2, CD27, ICAM-1, LPA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAPPR ,HVEM,

- 108 045983

CD7, LIGHT, NKG2C, SLAMP7, NKp30, NKp46, NKp80, CD160 and/or CD83 ligand.

In some embodiments, the one or more immunostimulating agents comprise a cytokine. In some embodiments, said cytokine is at least one of IL-1, IL-2, IL-5, IL-7, IL-10, IL-12, IL-15, IL-21, and/or IL-27 . In some embodiments, the one or more immunostimulating agents comprise an oncolytic virus. In some embodiments, the oncolytic virus includes one or more oncolytic viruses from herpes simplex virus, vesicular stomatitis virus, adenovirus, Newcastle disease virus, vaccinia virus, or Maraba virus. In some embodiments, the one or more immunostimulating agents comprise a chimeric antigen receptor T cell. In some embodiments, the immunostimulating agents comprise a bispecific or multispecific T cell-directed antibody. In some embodiments, the one or more immunostimulatory agents comprise or consist of an ADCC-competent antibody that may target CD19, CD20, EGPR, Her2, SLAMP7, CD52, BCMA, GD2, CD38, or CCR4. In some embodiments, the ADCC-competent antibody is an effector antibody enhanced by afucosylation, point mutations, or other means.

In some embodiments, the one or more immunostimulatory agents comprise a bispecific T cell recruiter, a CART therapy, a CAR NK cell therapy, a CAR macrophage therapy, an adoptive T cell therapy.

13. Options for diagnostic use and diagnostic methods.

In some embodiments, the antibodies of the present invention are used in diagnostic applications and/or diagnostic methods. For example, an anti-HLA-G antibody may be suitable for use in HLA-G protein assays. In some aspects, the antibody can be used to detect HLA-G expression in various cells and tissues. In some embodiments, the antibody can be used to detect soluble HLA-G in liquids. In some embodiments, the fluids comprise or consist of blood, serum, ascites, and/or other fluids. These tests may be useful, for example, in the evaluation of cancer and autoimmune disease.

In some embodiments, the diagnostic method includes or consists of detecting tumor-expressed HLA-G. In some embodiments, the diagnostic method includes or consists of detecting soluble HLA-G. In some embodiments, the detection method includes or consists of detecting HLA-G expression on immune cells.

In some diagnostic applications, the antibody may be labeled with a detectable moiety. Suitable detectable moieties include, but are not limited to, radioisotopes, fluorescent tags, and enzyme-substrate tags. According to another embodiment of the present invention, the anti-HLA-G antibody does not need to be labeled, and its presence can be detected using a labeled antibody that specifically binds to the anti-HLA-G antibody.

14. Reagents for affinity purification.

The antibodies of the present invention can be used as affinity purification agents. During this process, antibodies can be immobilized on a solid support, such as resin or filter paper, using methods well known in the art. The immobilized antibody is brought into contact with a sample containing the HLA-G protein (or fragment thereof) to be purified, after which the support is washed with a suitable solvent that removes substantially all of the material in the sample except the HLA-G protein, which is bound to the immobilized antibody. antibody. Finally, the support is washed with another suitable solvent, such as glycine buffer, pH 5.0, which dissociates the HLA-G protein from the antibody.

15. Sets.

In some embodiments, the anti-HLA-G antibody of the present invention is provided in kit form, i.e. a packaged combination of reagents in predetermined quantities with instructions for performing the procedure. In some embodiments, the procedure is a diagnostic assay. In other embodiments, the procedure is a therapeutic procedure.

In some embodiments, the kit further comprises a solvent for reconstituting the anti-HLA-G antibody. In some embodiments, the anti-HLA-G antibody is provided in the form of a pharmaceutical composition.

Examples

Example 1. Selection of antibodies to HLA-G.

Antibodies to HLA-G were selected from a synthetic library of human antibodies present on the surface of yeast cells in IgG format, as generally described, for example, in the references:

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WO2009036379; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670 (each of which is incorporated herein by reference in its entirety), and more specifically described below. The sequences and characteristics of antibodies isolated from the specified recombinant library are presented in table. S.

Eight untrained synthetic yeast human antibody libraries, each with ~10E+09 diversity, were propagated as described in references: WO2009036379; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670; each of which is incorporated herein by reference in its entirety. The first two rounds of selection were performed using the magnetic bead sorting method on the Miltenyi MACS® system as described in Siegel et al., J. Immunol. Meth., 2004, 286:141-153. Subsequent rounds of selection were performed using flow cytometry-based sorting. For all rounds of selection, the antigen was biotinylated human HLA-G, and decreasing concentrations of the antigen were used in each subsequent round. In addition to selection on antigen, several rounds of selection have been used to reduce the amount of nonspecific binding agents using soluble membrane proteins from CHO cells (see WO2014179363 and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670, each which are incorporated herein by reference in their entirety). Along with CHO cell proteins, recombinant HLA-A/B/C proteins were deselected to preserve specific binding to HLA-G. After the final round of sorting, yeasts were plated and individual colonies were recovered for characterization and assignment of clones for affinity maturation.

Antibody variable domains of interest were synthesized, codon-optimized to maximize transient expression in host cells. These variable regions were cloned into expression vectors containing human immunoglobulin constant domains and their sequences were confirmed. Paired antibody heavy and light chain vectors were transfected into Expi293 cells using the ExpiFectamine system (Invitrogen). On day 4, transient cultures were harvested and the IgG titer in the clarified cell culture supernatant was assessed using biolayer interferometry (BLI) using Octet (ForteBio) in addition to standards. The antibodies were then purified on a protein A column and eluted using low pH glycine. Purified antibody samples were then buffer exchanged or dialyzed into buffers compatible with the subsequent assay.

Antibody purity was assessed by passing samples through SDS-PAGE and through an analytical size exclusion chromatography column.

Light chain shuffling: Heavy chain plasmids were extracted from the untrained products (described herein) and transformed into a prepared untrained light chain library of 10E+06 diversity. Selection was performed as described above using one round of MACS sorting and three rounds of FACS sorting with decreasing amounts of biotinylated HLA-G antigen for the respective rounds.

Example 2. Affinity maturation.

Optimization of untrained clones was performed using four maturation strategies; diversification of CDR-H1 and CDR-H2; CDR-H3 diversification; diversification of CDR-L1, L2 and L3; rearrangements of diversified heavy and light chains.

Selection of CDR-H1 and CDR-H2: CDR-H3 regions from clones selected by group light chain diversification, light chain diversification, and clones from screened untrained libraries were independently recombined into finished libraries with CDR-H1 and CDR-H2 variants with diversity >10E +8. Selection was carried out using the HLA-G antigen. Decreasing antigen concentrations were used for affinity pressure, and HLA-G specificity was maintained by deselection against HLA-A/B/C antigens.

CDR-H3 selection: After characterization of the CDR-H1 and CDR-H2 variants, clones binding to non-HLA-G HLA antigens were removed. Also, if necessary, undesirable chemical properties of the variable regions were eliminated. The remaining clones obtained from the CDRH1 and CDR-H2 selection procedure were subjected to additional rounds of affinity maturation via CDR-H3 dimer scanning mutagenesis. Selection using HLA-G as the antigen was performed generally as described above, except for the use of FACS sorting for all selection rounds.

Selection of CDR-L1, L2, L3: Clones obtained from the CDR-H1 and CDR-H2 selection procedure were subjected to additional rounds of affinity maturation through light chain mutagenesis. The CDR-L1 and CDR-L2 diversity were obtained from a ready-made library, and the CDR-L3 diversity was obtained by scanning monomeric mutagenesis. Selection was carried out using HLA-G as the antigen, starting with one round of MACS followed by three rounds of FACS using the method for CDR-L1, L2, L3 described herein.

Diversified heavy and light chain shuffling: The products of the CDR-H3 diversification and the CDR-L1, L2, L3 diversification described above were recombined and selected using HLA-G as the antigen generally as described above, except using FACS sorting for all selection rounds.

- 110 045983

Example 3: Binding affinity of anti-HLA-G antibodies to recombinant HLA-G.

Binding kinetics were measured using the Octet Red96 system (Pall ForteBio) at 30°C in running buffer (1x Pall ForteBio Kinetics Buffer, diluted in 1x PBS, pH 7.4). Briefly, 0.16 μg/mL biotinylated recombinant HLA-G/β2m/peptide heterotrimer was loaded onto streptavidin (SA) biosensors to a binding reaction of approximately 0.25 nm. After a short baseline step in running buffer, the biosensors were exposed to full-length anti-HLA-G mAbs at varying concentrations (1.5, 3.0, or 30 nM) for the binding step. The dissociation of the complex was monitored by repeated immersion of the sensors in the running buffer for up to 30 min. Data were processed using ForteBio Octet DataAnalysis software (version 10) with background subtraction of non-HLA-G biosensors. Each sensorgram was fitted to a 1:1 Langmuir binding model to determine binding and dissociation rates by full local or partial local fitting. KD was calculated from the ratio of kd to k _a . Monovalent affinity values were obtained using identical methods, except that Fabs were used instead of IgG.

In fig. 1 shows a table with the avidity and monovalent affinity values of anti-HLA-G antibodies for the recombinant HLA-G protein. For the data in FIG. 1 R ² value >0.98. N.O.=undefined when using Fab. KD values for avidity ranged from 11.7 nM to subpicomolar with dissociation rates ( _koff ) ranging from 0.007 s ^-1 to the Octet dissociation rate limit (1.0x 10 ^-7 s ^-1 ). Monovalent KD values ranged from 0.187 nM to 208 nM, but monovalent affinity values for clones with lower avidity were not determined.

Example 4: Antibodies that bind to HLA-G and are sorted separately from other antibodies.

Binding to the heterotrimer of recombinant HLA-G during epitope binning was determined using the Octet Red96 system (Pall ForteBio) at 30°C in running buffer (1x Pall ForteBio Kinetics Buffer, diluted in 1x PBS, pH 7.4). Briefly, 0.16 μg/mL biotinylated recombinant HLA-G/β2m/peptide heterotrimer was loaded onto streptavidin (SA) biosensors to a binding reaction of approximately 0.25 nm. After a short baseline step in running buffer, the biosensor was immersed in 20 μg/mL of each mAb and allowed to saturate the HLA-G binding reaction. For the competitive binding step, concentrations of each mAb equimolar to the saturating mAb concentrations were used.

Epitope binning was performed in all directions (each mAb was used as both a saturating mAb (binding step 1) and a competing mAb (binding step 2)). Sensograms reflecting auto-blocking are shown in gray. Sensograms without auto-blocking are shown in black; black sensorgrams correspond to pairwise mAb binning. Sensograms only for the second stage of binding are shown in Fig. 2.

In fig. 2A shows sensograms obtained by biolayer interferometry, showing that the tested antibodies that bind HLA-G can be divided into three different chemical groups, one of which can be further divided. Gray sensorgrams indicate autoblocking; black sensorgrams indicate pairwise binning. The Y-axis indicates the amount of saturating antibody; The X-axis indicates the amount of competing antibody.

In fig. Figure 2B shows biolayer sensograms for antibodies (Fabs) that bind HLA-G and can be divided into two subgroups of the broader group 1. Group 1a Fabs do not block competing Group 1b Fabs. However, group 1b Fabs block group la Fabs. As described above, gray sensorgrams indicate auto-blocking, and black sensorgrams indicate pairwise binning. The Y axis corresponds to the saturating Fab, and the X axis corresponds to the competing Fab.

Example 5 Antibodies against HLA-G that block the interaction/binding of HLA-G with recombinant ILT2 and ILT4.

Binding block assays for the recombinant HLA-G heterotrimer and the recombinant extracellular domain of ILT2 or ILT4 proteins were performed using the Octet Red96 system (Pall ForteBio) at 30°C in running buffer (1x Pall ForteBio Kinetics Buffer, diluted in 1x PBS, pH 7.4) . Briefly, 0.16 μg/mL biotinylated recombinant HLA-G/β2m/peptide heterotrimer was loaded onto streptavidin (SA) biosensors to a binding reaction of approximately 0.25 nm. After a short baseline run in running buffer, the biosensor was immersed in a solution of each mAb at a concentration of at least 200 nM (up to 0.5 μM for weakly binding mAbs) and allowed to saturate the HLA-G binding reaction. Immediately after this, a second coupling step was performed by dipping into wells containing dimerized ILT2 or ILT4. Dimers were prepared by preincubating His-tagged ILT2 or ILT4 with anti-His mAb (MAB050, R&D Systems). The binding response of ILT2/ILT4 with saturated HLA-G mAb (black sensograms) was compared with HLA-G binding in the absence of anti-HLA-G mAb (gray sensograms).

Sensograms from the second binding stage are shown in Fig. 3. The given sensograms correspond to antibodies that bind and completely block the interaction of HLA-G with ILT2 and ILT4,

- 111 045983 for example, group 1a and group 1b antibodies 38381 and 38358, respectively. As indicated, gray sensograms correspond to ILT2 or ILT4 binding in the absence of antibody; Black sensorgrams correspond to ILT2 or ILT4 binding in the presence of antibody.

In fig. 3 also shows sensorgrams obtained by biolayer interferometry for antibodies that bind but do not block the interaction of HLA-G with ILT2 or ILT4, for example, group 3 antibodies, such as 33357. Sensograms in gray correspond to the binding reaction of ILT2 or ILT4 in the absence of the antibody; Black sensorgrams correspond to ILT2 or ILT4 binding in the presence of antibody.

The sensorgrams shown also include antibodies that bind and block the interaction of HLA-G with ILT2 or ILT4 with intermediate effect, such as group 2 antibody 38389.

Example 6 Antibodies against HLA-G bind to HLA-G naturally expressed on JEG-3 cells.

Parental JEG-3 cells or HLA-G knockout cells (JEG-3 KO) were incubated with 100 nM anti-HLA-G antibodies for 2 h at 4°C in wash buffer (phosphate buffered saline (PBS), 2% fetal bovine serum (FBS) and 2 mM EDTA). Cells were then washed in wash buffer and incubated with AFC-conjugated secondary antibody (goat anti-human IgG kappa chain) at a dilution of 1:500 in wash buffer for 30 min at 4°C. Cells were then washed and resuspended in 1% paraformaldehyde/wash buffer, followed by sample collection using a BD Fortessa X-20 flow cytometer (Becton Dickinson). Sample data were exported as FCS files and analyzed using FlowJo v10 software (Tree Star, Inc.).

The results are shown in Fig. 4. The shaded histogram represents the binding of the isotype control to JEG-3 cells at the same concentration.

Example 7 Antibodies against HLA-G neutralize suppression mediated by the interaction of HLA-G with ILT2 or ILT4 in an NKL killing assay.

Antibodies against HLA-G neutralize the inhibition of NKL cytotoxicity through ILT2-HLA-G or ILT4-HLA-G interaction. NKL cells (effector cells) were co-incubated with 721.221 cells (target cells) expressing or not expressing (±) HLA-G at an E:T ratio of 4:1 overnight at 37°C. 721.221 cells were preincubated with Fab fragments or full-length intact anti-HLA-G antibodies at a nanomolar concentration (200 nM) for 60 min at 37°C. Before antibody pretreatment, 721.221 cells were labeled with 1:1000 CellTrace Violet (CTV) (Invitrogen) in PBS at 37°C.

After overnight co-incubation, cells were washed once in 4°C wash buffer (phosphate buffered saline, 2% FBS, 2 mM EDTA) and then stained with 1:2000 irreversible viability dye Fixable Viability Dye eFluor™ 780 ( Invitrogen) for 30 minutes at 4°C.

Cells were washed again in wash buffer at 4°C, resuspended in wash buffer, and % 721.221 cell death was analyzed by flow cytometric analysis on a BD Celesta flow pitometer. The percentage of dead 721.221 cells was determined by gating on C TV-positive cells and then dividing the Fixable Viability Dye positive portion of these cells by the total number of CTV-positive cells.

Antibody MEM-G/9 is a commercially available antibody (see: Fournel et al., Tissue Antigens 200: 55: 510-518 (1999), which is incorporated by reference herein in its entirety, with all drawings).

In fig. 5A (Fab fragments) and 5B (intact IgG) show the effect on NKL cells endogenously expressing ILT2. For each antibody, the percentage of dead cells (indicated in the figures as a unique clone number) is shown along with control values corresponding to minimum and maximum killing in the presence and absence of HLA-G, respectively. As can be seen in FIG. 5, group 1 antibodies demonstrated the best blockade of the antibodies tested.

In fig. 5C demonstrates dose-dependent blockade of HLA-G-mediated suppression of NKL killing by endogenously expressed ILT2 for a specific anti-HLA-G group 1 Fab.

In fig. 5D demonstrates dose-dependent blockade of HLA-G-mediated suppression of NKL killing by engineered ILT4 expression (an engineered cell line modified by ILT2 knockout and retroviral transduction to express ILT4) for a specific anti-HLA-G group 1 Fab fragment.

Example 8 Anti-HLA-G Fab fragments reverse HLA-G-mediated suppression of macrophage phagocytosis, NK cell cytotoxicity, and CD8+ T cell activity.

The CD14+ cell-enriched population was differentiated into adherent macrophages by incubation at 37°C with 5% CO2 for 7 days in complete RPMI medium (cRPMI) with recombinant human MCSF. Cells were harvested after 7 days, washed, and resuspended in cRPMI. Cells were seeded in a 96-well round-bottom plate at a density of 50,000 cells/well in 50 μl cRPMI and incubated

- 112 045983 at 37°C, 5% CO2, before combining with target cells.

Target cells consisting of either parental 721.221 or 721.221-HLA-G cells were stained with CTV (1:1000) at 37°C in PBS, washed, and plated in cRPMI at a density of 25,000 cells per well. Cells were then incubated with anti-CD47 antibody in the presence or absence of anti-HLA-G Fab for 1 h at 37°C with 5% CO2. The 721.221 and antibody mixture was then combined with macrophages and incubated either for 2 hours or overnight at 37°C with 5% CO2. The final ratio of macrophages to target cells 721.221 was 2:1. After 2 hours or overnight incubation, cells were blocked with wash buffer/BD Fc Block™/2% mouse serum for 20 minutes and then stained with anti-CD 11b and live/dead cell dye for 20 minutes. Cells were then washed, resuspended in wash buffer, and analyzed on a BD Fortessa flow cytometer. Sample data were exported as FCS files and analyzed using FlowJo v10 software.

In a 2-h assay format, macrophages were assayed for the presence of CTV as an indicator of phagocyte uptake of target CTV+ cells. Live cells were gated for CD11b'/CTV' and their number was reported as a percentage of the total number of living macrophages. The overnight assay assessed macrophage killing activity by measuring the absolute number of remaining live CTV+ cells per well.

In fig. 6A shows a comparison of 2-hour and overnight assay results using anti-HLA-G (Fab) antibody. The overnight assay produced similar results to the 2-hour assay with direct measurement of phagocytosis of target cells. In fig. 6B shows the results for Fab fragments of each anti-HLA-G antibody that were tested in an overnight assay to determine the level of restored phagocytic activity.

To demonstrate that anti-HLA-G antibody neutralizes the inhibition of cytotoxicity of primary human NK cells, HLA-G-expressing target cells (721.221-HLA-G) were preincubated with a representative group 1 antibody (Fab fragment) and then co-cultured with primary ( effector) human NK cells from 3 different donors in the ratio E:T=4:1 overnight at 37°C.

Before antibody pretreatment, 721.221 cells were labeled with 1:1000 CellTrace Violet (CTV) (Invitrogen) in PBS at 37°C.

After overnight co-incubation, cells were washed once in 4°C wash buffer (phosphate buffered saline, 2% FBS, 2 mM EDTA) and then stained and then stained with 1:2000 irreversible viability dye Fixable Viability Dye eFluor 780 (Invitrogen) for 30 min at 4°C. Cells were washed, resuspended in wash buffer, and % 721.221 cell dead was analyzed by flow cytometry analysis on a BD Celesta flow cytometer. The percentage of dead 721,221 cells was determined by gating on CTV-positive cells and then dividing the Fixable Viability Dye-positive portion of these cells by the total number of CTV-positive cells.

The results are shown in Fig. 6C. The percentage of dead target cells for group 1 antibody (Fab) is shown along with control values corresponding to co-cultures of 721.221 target cells expressing and not expressing HLA-G (denoted in the figures as HLA-G and non-HLA-G, respectively). Isotype control Fab (Ctrl Fab) was used as a negative control.

To demonstrate anti-HLA-G antibody reversal of HLA-G-mediated suppression of cytotoxic function of primary CD8+ T cells, human CD8+ T cells treated with CD3/CD28 activator (ImmunoCultTM, Stem Cell Technologies) were mixed with antibody-pretreated cells for 1 h 721.221 (with and without HLA-G expression) and co-cultured overnight at 37°C. After overnight co-incubation, monensin solution (ThermoFisher) and eFluor 450-CD107a (ThermoFisher) were added; the final amount of each reagent was 0.5 μg/ml for antibody and 2 μM for monensin. The assay mixture was incubated for 4 hours.

After incubation, cells were washed and stained in several steps, including the following: (1) live/dead cell staining using Fixable Viability Dye eFluor 780 (ThermoFisher); (2) Fc blocking with staining buffer (phosphate buffered saline, 2% FBS, 2 mM EDTA) containing 6% normal mouse serum and 5 μl of Human TruStain FcX™ Fc blocker per sample (Biolegend), for 15 min at 4°C; (3) CD8 and ILT2 staining with Alexa Fluor 700-CD8 (Biolegend, clone SKI) and PE-CD85j/ILT2 (Biolegend, clone HP-F1, ThermoFisher); fixation and permeabilization using fixation/permeabilization reagent (ThermoFisher); (5) intracellular staining with Brilliant Violet 711-conjugated anti-IFN-γ antibody (Biolegend, clone 4S.B3) and AFC-conjugated anti-TNF-α antibody (Biolegend, clone MAb11), diluted in permeabilization buffer (ThermoFisher) for 20 min at 4°C. After the staining steps, cells were washed, centrifuged and resuspended in staining buffer, followed by

- 113 045983 rum samples on a BD Fortessa X-20 flow cytometer using a high throughput sampler.

FCS data were analyzed using FlowJo analysis software version 10 (FlowJo, LLC). Gates were set to select single cells, live cells, and cell types of interest. CD8' T cell populations were defined based on CD8'ILT2' or CD8'ILT2 ^- . To determine the percentage of cells positive for CD107a, IFN-γ, or TNF-α, all CD8+ T cell populations were gated and determined using cells with all but one fluorescent detectable label and unstimulated cells.

The results shown in Fig. 6D demonstrate that blockade of HLA-G with an anti-HLAG antibody (a representative clone of group 1) restored the expression of CD107a, IFN-γ, and TNF-α in CD8+ ILT2' T cells in a dose-dependent manner. There was no effect of HLA-G expression on target cells or anti-HLA-G antibody treatment on CD8+ILT2 ^cells (data not shown).

Example 9. Anti-HLA-G antibodies that selectively bind HLA-G and do not bind to classical HLA class I antigens.

Antibody binding to HLA antigens (97 different antigens spanning HLA-A, -B and -C haplotypes) was determined using the HLA class I LABScreen Single Antigen (One Lambda) combination assay. Antibodies at concentrations above 300 nM were incubated with single antigen-coated LABScreen beads in binding buffer (phosphate buffered saline, 10% FBS, 2 mM EDTA) for 45 min in the dark at room temperature with gentle shaking. The beads were washed twice with 200 μl of 1x LABScreen wash buffer in a 96-well V-bottom plate by centrifugation at 1500 g and removal of the buffer by aspiration. The beads were then incubated with PE-conjugated secondary antibodies (goat anti-human or anti-mouse polyclonal antibody in 1x wash buffer) for 30 min at room temperature in the dark with gentle shaking. After incubation, the beads were washed twice, resuspended in 90 μl of wash buffer, and then transferred to a 96-well flat-bottom plate. Capture was performed on a Luminex 100 instrument and the data was output as a CSV file. The results based on the average fluorescent intensity values for all individual groups of HLA antigen beads were tabulated.

Antibody 87G is a commercially available antibody and is a blocking antibody (see sources: Odum et al., Eur. J. Immunol. 22: 2121-2131 (1991) and Lee et al., Immunity, 591600 Volume 3, Issue 5 (1995), each of which is incorporated by reference herein in its entirety, with all drawings).

The results are presented in Fig. 7. Binding values (average fluorescence signal) to each individual HLA antigen for each anti-HLA-G antibody are shown.

Example 10 Antibodies against HLA-G that do not bind to classical HLA class antigens expressed at physiological levels on B-LCL cells.

Antibody binding to native HLA class Ia proteins at physiological levels was assessed by flow cytometry in a population of 28 B-LCL cell lines (shown in Table X). Cells were obtained from the International Histocompatibility Working Group cell collection, which includes a pool of B-LCL cell lines that have been HLA-typed. Cells were maintained in supplemented RPMI1640 medium containing 15% fetal bovine serum.

For antibody binding, anti-HLA antibodies were first conjugated to DyLight 650 (Thermo Fisher) by primary amine labeling through the NHS ester moiety. Unconjugated dye was removed by passing the antibody formulation through a resin to remove the dye. Conjugation efficiency ranged from 1 to 3 moles of DyLight 650 per mole of antibody. B-LCL cells (ranging from 10,000 to 100,000 cells per well) were incubated with 300 nM labeled antibodies in cold PBS containing 10% FBS and human Fc blocker (BD Biosciences). After 2 h at 4°C, cells were washed twice in cold wash buffer (phosphate buffered saline, 2% FBS, 2 mM EDTA) followed by sample collection with a BD FACS Celesta instrument. To assess overall HLA class I expression, anti-HLA class I antibody clone W6/32 conjugated to FITC was incubated separately with each individual cell line. All cell lines were strongly positive for class I expression (data not shown). Data were exported as FCS files and analyzed using FlowJo v10 software. Gating was performed on live singlet cells using DAPI to distinguish live/dead cells. The geometric mean MFI is shown for each B-LCL cell line.

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Table X

op IHW ID Alternate ID Floor Ethnicity / Population group Use in IHW HLAA* HLA B* HLA Cw* IHW09367 LCK Asians 13 0203 1102 4601 380201 0702 1202 IHW0945X FH70EY M 13 3002 6802 0801 5301 0401 07 IHW093X3 FH9 M Other 13 2402 3303 4801 44032 0801 0701 IHW09397 DUG150 Unknown 13 02 68010 1 5802 4501 0602 1601 IHW09057 TOPIC M Jews 10, 12 6601 3801 1203 IHW090I0 ΑΜΑ M Algerians 10, 12 6802 5301 0401 IHW09436 EH48 M White Caucasians 13 2402 0201 4427 070201 07020 1 0704 IHW01167 1413-1090 M White Caucasians SERN 68010 2 0201 0801 4402 0701 0501 IHW01075 1344-8354 and White Caucasians SERN 2402 0301 4001 5101 03040 1 0102 IHW01185 1416-1337 M White Caucasians SERN 0205 2501 4901 4402 0701 0501 IHW09431 EH43 M African Americans 13 3001 3301 5301 8101 04 08 IHW01124 1362-8563 M White Caucasians SERN 0201 2902 3501 4403 0401 1601 IHW01133 1362-8572 and White Caucasians SERN 2902 2601 4403 4402 1601 0501 IHW01092 1346-8603 M White Caucasians SERN 0201 1101 0702 3501 0702 0401 IHW09371 ISH4 Asians 13 0218 1101 1501 4601 0102 04010 1 IHW09433 EH45 M Asians 13 1101 02 3802 4101 0702 17 IHW09380 EH6 M Latin Americans 13 2402 2901 2702 0705 1505 02020 2 IHW09411 EH29 and Latin Americans 13 0201 2902 1516 440301 1402 1601 IHW09401 TER-259 White/American Indians USA 13 3201 6802 0801 44020101 0102 07 IHW09398 EH18 and African Americans 13 3601 7401 5301 5703 0401 0701 IHW09382 EH8 and African Americans 13 SINGING 1 3402 8201 270502 0302 0102 IHW01026 1332-8257 and White Caucasians SERN 0301 3001 3501 0702 0401 0702 IHW09409 EH27 M Native Americans 13 31010 2 3401 35010 1 380201 0401 0702 IHW09452 EH64 Unknown 13 02 3201 44 1801 05 07 IHW01028 1332-8259 and White Caucasians SERN 0301 0301 3501 2705 0401 02020 2 IHW01061 1341-8465 and White Caucasians SERN 0201 68010 2 0702 0702 0702 0702 IHW01099 1347-8434 m White Caucasians SERN 2501 0101 0801 1501 0701 0602 IHW01136 1362-8575 m White Caucasians SERN 0101 1101 0702 5101 0702 1502

The results are shown in Fig. 8. Binding levels are presented as geometric mean fluorescence intensities. Cells of the class I negative cell line 721.221, expressing or not expressing HLA-G, were used as controls.

Example 11: Critical amino acid determinants of HLA-G required for anti-HLA-G antibody binding.

LCL 721.221 cells transiently expressing various HLA-G point mutants were generated using the Neon® Transfection System (ThermoFisher Scientific). Cells were transfected with 1 μg of plasmid per point mutation in a 10 μl reaction format. Cells were cultured for 72 h before staining with anti-HLA-G antibodies.

LCL 721.221 cells (expressing various point mutants or a domain swap variant where the primary amino acid sequence encoding the alpha-3 domain was replaced with the same sequence from HLA-A*1101) were incubated with each antibody (100 nM) in wash buffer ( phosphate buffered saline, 2% FBS, 2 mM EDTA) for 60 min at 4°C. Cells were then washed with cold wash buffer and incubated with fluorescently labeled secondary antibody at 4°C for 30 min. Numbered antibodies were incubated with 1:500

- 115 045983 R-phycoeryrin-labeled goat anti-human IgG antibody (Jackson ImmunoResearch). W6/32 was incubated with 1:500 Alexa Fluor 488 goat anti-mouse IgG antibody (Jackson ImmunoResearch). MEMG/9 (Invitrogen) was preconjugated to allophycocyanin. After incubation with the secondary antibody, cells were washed and resuspended in cold wash buffer before analysis by flow cytometry on a BD Celesta instrument. Sample data were exported as FCS files and analyzed using FlowJo v10 software. As shown in FIG. 9, mutation of residues 195, 197 and/or 198 results in loss of binding by anti-HLA-G group 1 antibodies, indicating that these residues are critically important, although it is unlikely that they represent the sole determinants for group 1 antibody binding. Interestingly, the biochemical group defined in Octet as group 1a (Fig. 2B) can be further subdivided based on either sensitivity to mutation of residue 197 (eg, 38379) or mutation of residue 198 (eg, 38410).

In fig. 9A shows an assessment of the binding of anti-HLA-G antibodies to various forms of HLA-G after site-directed mutagenesis. In fig. 9B shows representative histograms for antibody binding to each of the three point mutants (P195S, Y197A, Y197H, E198A).

Example 12 Tumor growth inhibition by anti-HLA-G antibody with and without effector function in a xenograft mouse model using HLA-G-expressing 721.221 cells.

NOD/SCID mice were implanted subcutaneously in the right flank with 10 million HLA-G-expressing 721.221 cells in Matrigel. On day 29 postimplantation, mice were randomly assigned to groups based on tumor volume and dosed intraperitoneally with 300 μg of either effector-competent anti-human HLA-G IgG1 antibody (hIgG1 WT) or the same anti-HLA-G antibody with Fc domain mutations , neutralizing interactions with the Fc receptor (hIgG1_AAA), or were left without treatment. The second dose of antibody was administered three days later. The data presented in Fig. 10 show the percentage change in tumor volume six days after initial treatment. These results demonstrate that anti-HLA-G antibody can inhibit the growth of tumors expressing HLA-G by engaging Fc receptor-dependent effector mechanisms, which may include antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP).

In table S shows the sequences referred to herein.

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Table S

Sequences

SEQ ID NO: Region Scheme/Clone Subsequence 1 CDR-H1 Chothia GGSISSSDY 2 CDR-H1 Chothia GGSISSSST 3 CDR-H1 Chothia GGSISSSDT 4 CDR-H1 Chothia GGSISSADN 5 CDR-H1 Chothia GGSVSSSST 6 CDR-H1 Chothia GYSISSGY 7 CDR-H1 Chothia GYSILSGY 8 CDR-H1 Chothia GYSISSGH 9 CDR-H1 Chothia GYSISSGF 10 CDR-H1 Chothia GFTFDNY eleven CDR-H1 Chothia GFTFSDY 12 CDR-H1 Chothia GFTFSSS 13 CDR-H1 Chothia GGSISSSN 14 CDR-H1 Chothia GGSISSSSY 15 16 17 18 CDR-H1 Kabat SSDYYWG 19 CDR-H1 Kabat SSSTYWA 20 CDR-H1 Kabat SSSTYWG 21 CDR-H1 Kabat SSDTYWG 22 CDR-H1 Kabat SADNYWG 23 CDR-H1 Kabat SSSTYWS 24 CDR-H1 Kabat SGYYWG

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25 CDR-H1 Kabat SGYYWF 26 CDR-H1 Kabat SGHYWI 27 CDR-H1 Kabat SGFYWT 28 CDR-H1 Kabat SGYYWL 29 CDR-H1 Kabat SGHYWT thirty CDR-H1 Kabat NYAMH 31 CDR-H1 Kabat DYYMS 32 CDR-H1 Kabat SSAMA 33 CDR-H1 Kabat SSNWWS 34 CDR-H1 Kabat SSSYYWG 35 36 37 38 CDR-H2 Chothia YYSGS 39 CDR-H2 Chothia SSSGS 40 CDR-H2 Chothia HHSGA 41 CDR-H2 Chothia HYSGS 42 CDR-H2 Chothia AYSGS 43 CDR-H2 Chothia SYNAL 44 CDR-H2 Chothia YHSGS 45 CDR-H2 Chothia YHSAS 46 CDR-H2 Chothia SARAGI 47 CDR-H2 Chothia ASSGSV 48 CDR-H2 Chothia SGSGIT 49 CDR-H2 Chothia SYSGS 50 CDR-H2 Chothia SSSGST 51

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52 53 54 CDR-H2 Kabat SIYYSGSTYYNPSLKS 55 CDR-H2 Kabat SISSSGSTYYNPSLKS 56 CDR-H2 Kabat SIHHSGATYYNPSLKS 57 CDR-H2 Kabat SIHYSGSTLYNPSLKS 58 CDR-H2 Kabat SIHYSGSTYYNPSLKS 59 CDR-H2 Kabat GIAYSGSTYYNPSLKS 60 CDR-H2 Kabat SISYNALTYYNPSLKS 61 CDR-H2 Kabat SIYHSGSTYYNPSLKS 62 CDR-H2 Kabat GIYHSASTAYNPSLKS 63 CDR-H2 Kabat GIYHSGSTYYNPSLKS 64 CDR-H2 Kabat AIYHSGSTVYNPSLKS 65 CDR-H2 Kabat GIYHSGSTAYNPSLKS 66 CDR-H2 Kabat AISARAGITYYADSVKG 67 CDR-H2 Kabat YIASSGSVIYYADSVKG 68 CDR-H2 Kabat TISGSGITTWYADSVKG 69 CDR-H2 Kabat EIYHSGSTNYNPSLKS 70 CDR-H2 Kabat SISYSGSTYYNPSLKS 71 CDR-H2 Kabat YISSSGSTIYYADSVKG 72 73 74 75 76 CDR-H3 GVRRAVPFDY 77 CDR-H3 GIARAVPFDY 78 CDR-H3 GPKRAVPFDY

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79 CDR-H3 GVRRAVPFVD 80 CDR-H3 GVRRAVPFQR 81 CDR-H3 GTRRAVPFDY 82 CDR-H3 GVRRAVPFAD 83 CDR-H3 GIRRAVPFDY 84 CDR-H3 GQFRAVPFDY 85 CDR-H3 GGTHTYSRGPMDV 86 CDR-H3 GGTHTYSRGPDFDV 87 CDR-H3 GGTPIYSRGPLDV 88 CDR-H3 GGGQTYSRGPLDV 89 CDR-H3 GGGATYSRGPLDV 90 CDR-H3 GGTHTYSRGPLDV 91 CDR-H3 GGTVKYSRGPLDV 92 CDR-H3 GGQVTYSRGPLDV 93 CDR-H3 GGEVTYSRGPLDV 94 CDR-H3 RIGYSYGTAPPFDV 95 CDR-H3 HGTPRADFDI 96 CDR-H3 GSRHLNAFNR 97 CDR-H3 GVYHYDPYGMDV 98 CDR-H3 TELGKMHFDY 99 CDR-H3 GSPRYMQD 100 CDR-H3 HSSLGTHNWFDP 101 CDR-H3 EGALSYSWLAAFDI 102 103 104 105 CDR-L1 RASQSVSSSYLA

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106 CDR-L1 GASQSVSSDYLA 107 CDR-L1 QASQAVSSNYLA 108 CDR-L1 GASQSVSSAFLA 109 CDR-L1 RASQSVSSTYLA 110 CDR-L1 QASQSVSSSYLA 111 CDR-L1 KASQAVSSSYLA 112 CDR-L1 EASQSVSSSYLA 113 CDR-L1 EASQSVSASYLA 114 CDR-L1 EASQSVSSAYLA 115 CDR-L1 RVSQSVSDAYLA 116 CDR-L1 EVSQSVSASYLA 117 CDR-L1 RASQSVSSAYLA 118 CDR-L1 RASNAVSSSYLA 119 CDR-L1 RASQSINSWLA 120 CDR-L1 AASQGISSDLA 121 CDR-L1 RASQDISTYLN 122 CDR-L1 RSSQSLLHSNGYNYLD 123 CDR-L1 RASQSISSYLN 124 CDR-L1 RASQSVSSNLA 125 126 127 128 CDR-L2 GASSRAT 129 CDR-L2 GAYSLAT 130 CDR-L2 GASARAT 131 CDR-L2 GASSREA 132 CDR-L2 GASNRAA

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133 CDR-L2 GASSRQD 134 CDR-L2 GASNRAT 135 CDR-L2 DASSRAS 136 CDR-L2 DASTRAT 137 CDR-L2 GASDRAN 138 CDR-L2 GASYRAT 139 CDR-L2 DASSLES 140 CDR-L2 SASSTQS 141 CDR-L2 DAFNLET 142 CDR-L2 LGSNRAS 143 CDR-L2 GASRRAT 144 CDR-L2 AASSLQS 145 CDR-L2 GASTRAT 146 147 148 149 CDR-L3 QQAVHSPYT 150 CDR-L3 QWAVHSPYT 151 CDR-L3 QQWHSPYT 152 CDR-L3 QQTVHSPYT 153 CDR-L3 QQAIHSPYT 154 CDR-L3 QQHSSYPPT 155 CDR-L3 QQHSLYPPT 156 CDR-L3 QQFSSYPPT 157 CDR-L3 QQVSSYPPT 158 CDR-L3 QQHSIYPPT 159 CDR-L3 QQYDSHIT

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160 CDR-L3 QQAYLYPIT 161 CDR-L3 QQLPFLPIT 162 CDR-L3 MQALGGPWT 163 CDR-L3 QQYVSDPIT 164 CDR-L3 QQVGSSPIT 165 CDR-L3 QQSHLVPRT 166 CDR-L3 QQANHHPPFT 167 168 169 170 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSS 171 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWAWIRQPPGKGLEWIGSISSSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGIARAVPFDYWGQGTLVTVSS 172 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWGWIRQSPGKGLEWIGSIHHSGATYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGPKRAVPFDYWGQGTLVTVSS 173 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFVDWGQGTLVTVSS 174 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSA DNYWGWIRQPPGKGLEWIGSIHYSGSTYYNPS LKSRVTISVDTSKNTQFSLKLSSVTAADTAVY YCARGVRRAVPFQRWGQGTLVTVSS 175 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGPEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSS 176 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSS

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177 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGSISYNALTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGTRRAVPFDYWGQGTLVTVSS 178 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFADWGQGTLVTVSS 179 VH QLQLQESGPGLVKPSETLSLTCTVSGGSVSSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSS 180 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSICNQFSLKLSSVTAADTAVY YCARGTRRAVPFDYWGQGTLVTVSS 181 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGTRRAVPFDYWGQGTLVTVSS 182 VH 183 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPMDVWGQGTTVTVSS 184 VH QLQLQESGPRLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTS1CNQFSLKLSSVTAADTAVYY CARGGTHTYSRGPFDVWGQGTTVTVSS 185 VH LVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSICNQFSLKLSSVTAADTAVYY CARGGT PIYSRGPLDVWGQGTTVTVS S 186 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKDQFSLKLSSVTAADTAVYYC ARGGGQTYSRGPLDVWGQGTTVTVSS 187 VH QVQLQESGPGLVKPPETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGGATYSRGPLDVWGQGTTVTVSS 188 VH QVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSGSTYYNPSL

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KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPLDVWGQGTTVTVSS 189 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG FYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPLDVWGQGTTVTVSS 190 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWLWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTVKYSRGPLDVWGQGTTVTVSS 191 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGQVTYSRGPLDVWGQGTTVTVSS 192 VH QVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSGSTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGEVTYSRGPLDVWGQGTTVTVSS 193 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFDNY AMNWVRQAPGKGLEWVSAISARAGITYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARRIGYS YGTAR P FDVWGQGTTVTVS S 194 VH QVQLVESGGGLVQPGGSLRLSCAASGFTFSDY YMSWIRQAPGKGLEWVSYIASSGSVIYYADSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHGTPRAFDIWGQGTTVTVSS 195 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSS AMAWVRQAPGKGLEWVSTISGSGITTWYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKGSRHLNAFNRWGQGTTVTVSS 196 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSS NWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSL KSRVTISVDKSKNQFSLKLSSVTAADTAVYYC ARGVYHYDPYGMDVWGQGTTVTVSS 197 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS SYYWGWIRQPPGKGLEWIGSISYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CART EL GKMH FD YWGQ GT LVTVS S 198 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY GARGS PRYMQDWGQGT LVTVS S 199 VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDY YMSWIRQAPGKGLEWVSYISSSGSTIYYADSV

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KGRFTISRDNAICNSLYLQMNSLRAEDTAVYY CARHSSLGTHNWFDPWGQGTLVTVSS 200 VH QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC AREGALSYSWLAAFDIWGQGTMVTVSS 201 202 203 204 V _L EIVLTQSPGTLLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIK 205 Vl EIVLTQSPGTLLSLSPGERATLSCGASQSVSSD YLAWYQQKPGQAPRLLIYGAYSLATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQWAVHSP YTFGGGTKVEIK 206 Vl EIVLTQSPGTLSLSPGERATLSCQASQAVSSN YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIK 207 Vl EIVLTQSPGTLLSLPGERATLSCGASQSVSSA FLAWYQQKPGQAPRLLIYGASARATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIK 208 Vl EIVLTQSPGTLLSLSPGERATLSCRASQSVSST YLAWYQQKPGQAPRLLIYGASSREAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQTVHSP YTFGGGTKVEIK 209 Vl EIVLTQSPGTLSLSPGERATLSCQASQAVSSN YLAWYQQKPGQAPRLLIYGASNRAAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAIHSP YTFGGGTKVEIK 210 Vl EIVLTQSPGTLSLSPGERATLSCQASQSVSSS YLAWYQQKPGQAPRLLIYGASNRAAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIK 211 Vl EIVLTQSPGTLLSLSPGERATLSCKASQAVSSS YLAWYQQKPGQAPRLLIYGASSRQDGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIK

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212 V _L EIVLTQSPGTLLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSSYP PTFGGGTKVEIK 213 Vl EIVLTQSPGTLLSLSPGERATLSCEASQSVSSS YLAWYQQKPGQAPRLLIYGASNRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIK 214 Vl EIVLTQSPGTLLSLSPGERATLSCEASQSVSAS YLAWYQQKPGQAPRLLIYDASSRASGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQFSSYP PTFGGGTKVEIK 215 Vl EIVLTQSPGTLLSLSPGERATLSCEASQSVSSA YLAWYQQKPGQAPRLLIYDASTRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVSSYP PTFGGGTKVEIK 216 Vl EIVLTQSPGTLSLSPGERAALSCRVSQSVSDA YLAWYQQKPGQAPRLLIYDASSRASGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVSSYP PTFGGGTKVEIK 217 Vl EIVLTQSPGTLSLSPGERATLSCEVSQSVSAS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIK 218 Vl EIVLTQSPGTLLSLSPGERATLSCRASQSVSSA YLAWYQQKPGQAPRLLIYGASDRANGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIK 219 Vl EIVLTQSPGTLSLSPGERATLSCRASNAVSSS YLAWYQQKPGQAPRLLIYGASDRANGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSIYP PTFGGGTKVEIK 220 Vl EIVLTQSPGTLSLSPGERATLSCRASNAVSSS YLAWYQQKPGQAPRLLIYGASYRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIK 221 Vl DIQMTQSPSTLSASVGDRVTITCRASQSINSW LAWYQQKPGICAPKLLISDASSLESGVPSRFS GSGSGTEFTLTISSLQPDDFATYYCQQYDSHI TFGGGTKVEIK 222 Vl DIQMTQSPSSVSASVGDRVTITCAASQGISSD LAWYQQKPGICAPKLLIYSASSTQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQAYLYP ITFGGGTKVEIK

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223 V _L GVQMTQSPSSLSASVGDRVTITCRASQDISTY LNWYQQKPGKAPKLLIYDAFNLETGVPSRFSG SGSGTDFTFTISSLQPEDIATYYCQQLPFLPI TFGGGTKVEIK 224 Vl DIVMTQSPLSLPVTPGEPASISCRSSQSLLHS NGYNYLDWYLQKPGQS PQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQA LGGPWTFGGGTKVEIK 225 Vl EIVLTQSPGTLLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASRRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYVSDP ITFGGGTKVEIK 226 Vl EIVLTQSPGTLLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASRRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVGSSP ITFGGGTKVEIK 227 Vl DIQMTQSPSSLSASVGDRVTITCRASQSISSY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQSHLVPR TFGGGTKVEIK 228 Vl EIVMTQSPATLSVSPGERATLLSCRASQSVSSN LAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQANHHPP FTFGGGTKVEIK 229 230 231 232 IGG1AAAHC 33343 PSS SLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPICDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISICAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 233 IGG1 AAA HC 37268 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWAWIRQPPGKGLEWIGSISSSGSTYYNPS LKSRVTISVDTSICNIQFSLKLSSVTAADTAV

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YYCARGIARAVPFDYWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAK TKPREEQYNST YRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 234 IGGI AAA HC 37269 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWGWIRQSPGKGLEWIGSIHHSGATYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGPKRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLG TQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI S RT P E VT CVWD VS HE D P E VKFNWYVD GVE VH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGF YPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 235 IGG1 AAA HC 37271 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFVDWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLG TQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI S RT P EVT CVWD VS HE D P E VKFNWYVD GVE VH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFY PSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 236 IGGI AAA HC 37272 SSSL GTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI S RT P EVT CVWD VS HE D P E VKFNWYVD GVE VH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK

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EYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 237 IGG1 AAA HC 37277 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGPEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGT QTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI S RT P E VT CVWD VS HE D P E VKFNWYVD GVE VH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFY PSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 238 IGG1 AAA HC 38373 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQ TYICNVNHKPSNTICVDKKVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQP ENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK 239 IGG1 AAA HC 38375 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGSISYNALTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGTRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQ TYICNVNHKPSNTICVDKKVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISICAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQ PENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK

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240 IGG1 AAA HC 38379 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFADWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQ TLPPSREEMTKNQVSLTCLVKGFYPS DIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 241 IGG1 AAA HC 38381 QLQLQESGPGLVKPSETLSLTCTVSGGSVSSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSICNQFSLKLSSVTAADTAVY YCARGVRRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGT QTYICNVNHKPSNTICVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWES NGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 242 IGG1 AAA HC 38383 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSICNQFSLKLSSVTAADTAVY YCARGTRRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVICDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY ICNVNHKPSNTICVDKKVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWES NGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 243 IGG1 AAA HC 38386 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNIQFSLKLSSVTAADTAVY YCARGIRRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLG TQTYICNVNHKPSNTICVDKKVEPKS

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CDKTHTCPPCPAPEAAGAPSVFLFPPKPICDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYS KL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 244 IGG1 AAA HC 37273 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSICNQFSLKLSSVTAADTAVY YCARGQFRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVICDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGT QTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNST YRWSVLTVLHQDWLN GICEYKCKVSNICALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 245 IGG1 AAA HC 33361 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPMDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TQTYICNVNHKPSNTKVDKICVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPICD T LMIS RT P E VT C VWD VS H EDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFY PSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 246 IGG1 AAA HC 35624 QLQLQESGPRLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPFDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNST YRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

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VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 247 IGG1 AAA HC 38410 LVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTPIYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSL GTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPICDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 248 IGG1 AAA HC 38418 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKDQFSLKLSSVTAADTAVYYC ARGGGQTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKL\TQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 249 IG G1 AAA HC 38420 QVQLQESGPGLVKPPETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGGATYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGT QTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWES NGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 250 IGG1 AAA HC 38421 QVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSICNQFSLKLSSVTAADTAVYY CARGGTHTYSRGPLDVWGQGTTVTVSSASTKG

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PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQD WL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 251 IGG1 AAA HC 38422 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG FYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGT QTYICNVNHKPSNTICVDKKVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDT LMI SRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA V EWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 252 IGG1 AAA HC 38424 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWLWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTVKYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EW ESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 253 IGG1 AAA HC 38425 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGQVTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TQTYICNVNHKPSNTKVDKICVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPICD T LMIS RT P E VT C VWD VS H EDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPRE

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PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 254 IGG1 AAA HC 38426 QVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSGSTAYNPSL KSRVTISVDTSICNQFSLKLSSVTAADTAVYY CARGGEVTYSRGPLDVWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSL GTQTYICNVNHKPSNTICVDKKVEP KSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKD T LMIS RT P E VT C VWD VS H EDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVK GFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 255 IGG1 AAA HC 37323 EVQLLESGGGLVQPGGSLRLSCAASGFTFDNY AMNWVRQAPGKGLEWVSAISARAGITYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARRIGYSYGTAPPFDVWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTA.ALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGT QTYICNVNHKPSNTICVDKKVE PKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPK DTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTICNQVSLTCLVKGFYPS DIAVEWES NGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK 256 IGG1 AAA HC 38389 QVQLVESGGGLVQPGGSLRLSCAASGFTFSDY YMSWIRQAPGKGLEWVSYIASSGSVIYYADSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHGTPRAFDIWGQGTTVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTYICNV SNG QPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 257 IGG1 AAA HC 38358 EVQLLESGGGLVQPGGSLRLSCAASGTFSSS AMAWVRQAPGKGLEWVSTISGSGITTWYADSV

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KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKGSRHLNAFNRWGQGTTVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVICDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTICVDKICVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTC WVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNST YRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 258 IGG1 AAA NS 33303 P SSSLGTQTYICNVNHKPSNTKVDICKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPICDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDI A VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 259 IGG1 AAA HC 33342 SSSL GTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI S RT P E VT CVWD VS HE D P E VKFNWYVD GVE VH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVK GFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 260 IGG1 AAA HC 33299 SL GTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGAPSVFLFPPKPICDTLMIS RTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN

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K 261 IGG1 AAA NS 33351 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDY YMSWIRQAPGKGLEWVSYISSSGSTIYYADSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSSLGTHNWFDPWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGTQ TYICNVNHKPSNTICVDKKVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPICDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWES NGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK 262 IGG1 AAA HC 33357 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC AREGALSYSWLAAFDIWGQGTMVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSL GTQTYICNVNHKPSNTICVDKKVEP KSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKD T LMIS RT P E VT C VWD VS H EDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVK GFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 263 264 265 266 IGG4 HC 33343 SSSL GTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGKEYK

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CKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 267 IGG4 NS 37268 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWAWIRQPPGKGLEWIGSISSSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGIARAVPFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTY TCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 268 1GG4 NS 37269 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWGWIRQSPGKGLEWIGSIHHSGATYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGPKRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLG TKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPICDTLMISR T R E VT S WVD VS QE D R E VQ FNW YVDGVE VHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGF YPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 269 IGG4 NS 37271 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNTQFSLKLSSVTAADTAVY YCARGVRRAVPFVDWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSL GTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPICDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTC LVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 270 IGG4 NS 37272 QLQLQESGPGLVKPSETLSLTCTVSGGSISSA DNYWGWIRQPPGKGLEWIGSIHYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFQRWGQGTLVTVSSASTKGPSV

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FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGK EYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTICNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 271 IGG4 NS 37277 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGPEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGT KTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPICDTLMISR T R E VT S WVD VS QE D R E VQ FNW YVDGVE VHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTICNQVSLTCLVKGFY PSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 272 IGG4 NS 38373 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSICNIQFSLKLSSVTAADTAV YYCARGVRRAVPFDYWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTK TYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 273 IGG4 NS 38375 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGSISYNALTYYNPS LKSRVTISVDTSKNIQFSLKLSSVTAADTAVY YCARGTRRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGT KTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR T R E VT S WVD VS QE D R E VQ FNW YVDGVE VHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVK GFYPSDIAVEWES

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NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 274 IGG4 NS 38379 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSICNQFSLKLSSVTAADTAVY YCARGVRRAVPFADWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGTK TYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPICDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 275 IGG4 NS 38381 QLQLQESGPGLVKPSETLSLTCTVSGGSVSSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGVRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGT KTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 276 IGG4 NS 38383 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS STYWSWIRQPPGKGLEWIGGIAYSGSTYYNPS LKSRVTISVDTSKITQFSLKLSSVTAADTAVY YCARGTRRAVPFDYWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGT KTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR T P E VT C WVD VS QE D P E VQ FNW YVDGVE VHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTICNQVSLTCLVK GFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 277 IGG4 NS 38386 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARGIRRAVPFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS

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WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPICDTLMISR T R E VT S WVD VS QE D R E VQ FNW YVDGVE VHNA KTKPREEQFNST YRWSVLTVLHQDWLNGKE Y KCKVSNKGLPSSIEKTI SKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 278 IGG4 NS 37273 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS DTYWGWIRQPPGKGLEWIGSIHYSGSTLYNPS LKSRVTISVDTSICNTQFSLKLSSVTAADTAV YYCARGQFRAVPFDYWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNST YRWSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 279 IGG4 NS 33361 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPMDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT P E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNST YRWSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 280 IGG4 NS 35624 QLQLQESGPRLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPFDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT P E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNST YRWSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK

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SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 281 IGG4 NS 38410 LVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTPIYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSS'VV TVPS SSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPICDTLM IS RT R E VT C VWDVS Q E D R E VQ FNWYVDGVE V HNAKTKPREEQFNSTYRWSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQV YTLPPSQEEMTKNQVSLTCLV KGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS PGK 282 IGG4 NS 38418 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKDQFSLKLSSVTAADTAVYYC ARGGGQTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPICDTLMI S RT P EVT CVVVDVS QE DP EVQ FNWYVD GVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTICNQVSLTCLVKGF YPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS PGK 283 IGG4 NS 38420 QVQLQESGPGLVKPPETLSLTCAVSGYSISSG HYWIWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGGATYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGT KTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT P E VT C V WDV SQEDPEVQ FNWYVD GVE VHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 284 IGG4 NS 38421 QVQLQESGPGLVKPSETLSLTCAVSGYSILSG YYWFWIRQPPGKGLEWIGGIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPLDVWGQGTTVTVSSASTKGP

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SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT R E VT S V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQ K 285 IGG4 NS 38422 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG FYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTHTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGT KTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPICDTLMI S RT R E VT WITH VWD VS QE D R E VQ FNWYVD GVE VH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP GK 286 IGG4 NS 38424 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWLWIRQPPGKGLEWIGGIYHSASTAYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGTVKYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 287 IGG4 NS 38425 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG HYWTWIRQPPGKGLEWIGAIYHSGSTVYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC ARGGQVTYSRGPLDVWGQGTTVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLG TKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT R E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT

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LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG K 288 IGG4 NS 38426 VPSSSL GTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPICDTLMI S RT R E VT CVWD VS QE D R E VQ FNWYVD GVE VH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTKNQVSLTCLV KGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP GK 289 IGG4 NS 37323 EVQLLESGGGLVQPGGSLRLSCAASGFTFDNY AMHWVRQAPGKGLEWVSAISARAGITYYADSV KGRFTISRDNSICNTLYLQMNSLRAEDTAVYY CARRIGYSYGTAPPFDVWGQGTTVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTKTYTCNV WESNGQPENNY KTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS PGK 290 IGG4 NS 38389 MSWIRQAPGKGLEWVSYIASSGSVIYYADSVK GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCA RHGTPRAFDIWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPE FLGGPSVFLFPPKPKDTLMISRTPEV T S VWDVS QE D R E VQ FNWYVDGVE VHNAKT K R REEQFNST YRWSVLTVLHQDWLNGKE YKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTICNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSPGK 291 IGG4 NS 38358 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSS AMAWVRQAPGKGLEWVSTISGSGITTWYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKGSRHLNAFNRWGQGTTVTVSSASTKGPSVF

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PLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTP E VT C VWD VS QE D P E VQ FNW YVD GVE VHNAKT KPREEQFNSTYRWSVLTVLH QDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSPGK 292 IGG4 NS 33303 P SSSLGTKTYTCNVDHKPSNTICVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RT P E VT C V WDV SQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTICNQVSL TCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP GK 293 IG G4 NS 33342 QLQLQESGPGLVKPSETLSLTCTVSGGSISSS SYYWGWIRQPPGKGLEWIGSISYSGSTYYNPS LKSRVTISVDTSKNQFSLKLSSVTAADTAVYY CARTELGKMHFDYWGQGTLVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSL GTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDI AVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 294 IG G4 NS 33329 SL GTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTICNQVSLTCLVKGFYPSDI AVEWESNG

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QPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSPGK 295 IGG4 NS 33351 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDY YMSWIRQAPGKGLEWVSYISSSGSTIYYADSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSSLGTHNWFDPWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGTK TYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR T P E VT C WVD VS QE D P E VQ FNW YVDGVE VHNA KTKPREEQFNST YRWSVLTVLHQDWLNGKE Y KCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLV KGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK 296 IGG4 NS 33357 QVQLQESGPGLVKPSETLSLTCAVSGYSISSG YYWGWIRQPPGKGLEWIGSIYHSGSTYYNPSL KSRVTISVDTSKNQFSLKLSSVTAADTAVYYC AREGALSYSWLAAFDIWGQGTMVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSL GTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMI S RT P E VT C WVD VS QE D P E VQ FNWYVD GVE VH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTKNQVSL TCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP GK 297 298 299 300 L.C. 33343 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 301 L.C. 37268 EIVLTQSPGTLLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS

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QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 302 L.C. 37269 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 303 L.C. 37271 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 304 L.C. 37272 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 305 L.C. 37277 EIVLTQSPGTLLSLSPGERATLSCGASQSVSSD YLAWYQQKPGQAPRLLIYGAYSLATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQWAVHSP YTFGGGTICVEIKRTVAAPSVFIFPPSDEQLK SGTASWCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC 306 L.C. 38373 EIVLTQSPGTLSLSPGERATLSCQASQAVSSN YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTH QGLSSPVTKSFNRGEC 307 L.C. 38375 V YACEVTHQGLSSPVTKSFNRGEC 308 L.C. 38379 EIVLTQSPGTLLSLSPGERATLSCRASQSVSST YLAWYQQKPGQAPRLLIYGASSREAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQTVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS

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GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 309 L.C. 38381 EIVLTQSPGTLSLSPGERATLSCQASQAVSSN YLAWYQQKPGQAPRLLIYGASNRAAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAIHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 310 L.C. 38383 EIVLTQSPGTLSLSPGERATLSCQASQSVSSS YLAWYQQKPGQAPRLLIYGASNRAAGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTH QGLSSPVTKSFNRGEC 311 L.C. 38386 EIVLTQSPGTLLSLSPGERATLSCKASQAVSSS YLAWYQQKPGQAPRLLIYGASSRQDGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQWHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACE VTHQGLSSPVTKSFNRGEC 312 L.C. 37273 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQAVHSP YTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 313 L.C. 33361 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSSYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 314 L.C. 35624 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSSYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 315 L.C. 38410 EIVLTQSPGTLLSLSPGERATLSCEASQSVSSS YLAWYQQKPGQAPRLLIYGASNRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP

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PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 316 L.C. 38418 EIVLTQSPGTLSLSPGERATLSCEASQSVSAS YLAWYQQKPGQAPRLLIYDASSRASGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQFSSYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 317 L.C. 38420 EIVLTQSPGTLSLSPGERATLSCEASQSVSSA YLAWYQQKPGQAPRLLIYDASTRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVSSYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACE VTHQGLSSPVTKSFNRGEC 318 L.C. 38421 EIVLTQSPGTLSLSPGERAALSCRVSQSVSDA YLAWYQQKPGQAPRLLIYDASSRASGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVSSYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV Y ACEVTHQGLSSPVTKSFNRGEC 319 L.C. 38422 EIVLTQSPGTLSLSPGERATLSCEVSQSVSAS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 320 L.C. 38424 EIVLTQSPGTLSLSPGERATLSCRASQSVSSA YLAWYQQKPGQAPRLLIYGASDRANGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEV THQGLSSPVTKSFNRGEC 321 L.C. 38425 EIVLTQSPGTLSLSPGERATLSCRASNAVSSS YLAWYQQKPGQAPRLLIYGASDRANGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQHSIYP PTFGGGTICVEIKRTVAAPSVFIFPPSDEQLK SGTASWCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHK V YACEVTHQGLSSPVTKSFNRGEC 322 L.C. 38426 EIVLTQSPGTLSLSPGERATLSCRASNAVSSS YLAWYQQKPGQAPRLLIYGASYRATGIPDRFS

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GSGSGTDFTLTISRLEPEDFAVYYCQQHSLYP PTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 323 L.C. 37323 DIQMTQSPSTLSASVGDRVTITCRASQSINSW LAWYQQKPGKAPKLLISDASSLESGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQQYDSHIT FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASWCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSICDSTYSLSSTLTLSKADYEKHKV Y ACEVTHQGLSSPVTKSFNRGEC 324 L.C. 38389 DIQMTQSPSSVSASVGDRVTITCAASQGISSD LAWYQQKPGKAPKLLIYSASSTQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAYLYPI TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASWCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHK VY ACEVTHQGLSSPVTKSFNRGEC 325 L.C. 38358 GVQMTQSPSSLSASVGDRVTITCRASQDISTY LNWYQQKPGKAPKLLIYDAFNLETGVPSRFSG SGSGTDFTFTISSLQPEDIATYYCQQLPFLPI TFGGGTICVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHK V YACEVTHQGLSSPVTKSFNRGEC 326 L.C. 33303 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHS NGYNYLDWYLQKPGQS PQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQA LGGPWTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSICDSTYSLSSTLTLSK ADY EKHICVYACEVTHQGLSSPVTKSFNRGEC 327 L.C. 33342 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASRRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYVSDP ITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACE VTHQGLSSPVTKSFNRGEC 328 L.C. 33299 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS YLAWYQQKPGQAPRLLIYGASRRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQVGSSP ITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAICVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACE VTHQGLSSPVTKSFNRGEC

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329 L.C. 33351 DIQMTQSPSSLSASVGDRVTITCRASQSISSY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQSHLVPR TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASWCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHK VY ACEVTHQGLSSPVTKSFNRGEC 330 L.C. 33357 EIVMTQSPATLSVSPGERATLSCRASQSVSSN LAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQANHHPP FTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACE VTHQGLSSPVTKSFNRGEC 331 332 333 334 Fc for IGG1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTQT YICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPP KPKDTLMISRTPEVTCVWDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNST YRWSVLTVL HQ DWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK 335 Fc region for IGG4 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTKT YTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVWDVSQEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTYRWSVLTVLHQ D WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSPGK 336 Kappa region for LC RTVAAPSVFIFPPSDEQLKSGTASWCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC 337 hHLA-Gl MWMAPRTLFLLLSGALTLTETWAGSHSMRYF SAAVSRPGRGEPRFIAMGYVDDTQFVRFDSDS ACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQ TDRMNLQTLRGYYNQSEASSHTLQWMIGCDLG

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SDGRLLRGYEQYAYDGKDYLALNEDLRSWTAA DTAAQISKRKCEAANVAEQRRAYLEGTCVEWL HRYLENGKEMLQRADPPKTHVTHHPVFDYEAT LRCWALGFYPAEIILTWQRDGEDQTQDVELVE TRPAGDGTFQKWAAWVPSGEEQRYTCHVQHE GL P E P LML RWKQ S S L P TIPI MG IVAGL WL AA WT GAAVAAVLWRKKS S D 338 hHLA-G5 MWMAPRTLFLLLSGALTLTETWAGSHSMRYF SAAVSRPGRGEPRFIAMGYVDDTQFVRFDSDS ACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQ TDRMNLQTLRGYYNQSEASSHTLQWMIGCDLG SDGRLLRGYEQYAYDGKDYLALNEDLRSWTAA DTAAQISKRKCEAANVAEQRRAYLEGTCVEWL HRYLENGK EMLQRADPPKTHVTHHPVFDYEAT LRCWALGFYPAEIILTWQRDGEDQTQDVELVE TRPAGDGTFQKWAAWVPSGEEQRYTCHVQHE GLPEPLMLRWSKEGDGGIMSVRESRSLSEDL 339 Cynomolgus macaque, HLA-AG MAVMAPRTLLLVLSGVLALTQPRAGSHSMRYF YTAVSRPGRGQPRFIAVGYVDDTQFVRFDSDA ESPRMEPRAPWVEQEGPEYWDRETQNMKTATQ TYQANLRTLLRYYNQSEAGSHTFQKMYGCDLG PDGRLLRGYEQFAYDGRDYIILNEDLRSWTAA DMAAQNT Q RKWEAAGAAEQH RT YL E GE CL EWL RRYLENGKETLQRADPPKTNVTHHPVSDYEAT LRCWALGFYPAEITLTWQRDGEEQTEDTELVE TRPTGDGTFQKWAAWVPSGEEQRYTCHVQHE GLPKPLTLRWEPSSQSTILIVGIIAGLVLLGT WT GAWAAVMWRRKS 340 Rhesus monkey HLAAG MAVMAPRTLLLVLSGVLALTQTRAGSHSMRYF YTSMSRPGRGQPRFIAVGYVDDTQFVRFDSDA ESPRMEPRAPWVEQEGPEYWDRETQNMKTATQ TYRENLRTLLRYYNQSEAGSHTIQKMYGCDLG PDGRLLRGYEQFAYDGRDYIALNEDLRSWTAA DMAAQ FT Q RKWEAAGAAEQH RT YL E GE CL EWL RRYLENGKETLQRADPPKTNVTHHPVSDYEAT LRCWALGFYPAEITLTWQRDGEEQTEDTELVE TRPTGDGTFQKWAAWVPSGEEQRYTCHVQHE GLPEPLTLRWEPSSQSTILIVGIIAGLVLLGT WT GAWAAVMWRRKS SDR 341 ECD hHLA-G with signal peptide MWMAPRTLFLLLSGALTLTETWAGSHSMRYF S AAVSRPGRGEPRFIAMGYVDDTQFVRFDSDSA C PRMEPRAPWVEQEGPEYWEEETRNTKAHAQTD R MNLQTLRGYYNQSEASSHTLQWMIGCDLGSDG R LLRGYEQYAYDGKDYLALNEDLRSWTAADTAA Q IS KRKCEAANVAEQRRAYLE GT CVEWLHRYL E N

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Claims (13)

GKEMLQRADPPKTHVTHHPVFDYEATLRCWAL G FYPAEIILTWQRDGEDQTQDVELVETRPAGDG T FQKWAAWVPSGEEQRYTCHVQHEGLPEPLML R W 342 ECD hHLA-G without signal peptide GSHSMRYFSAAVSRPGRGEPRFIAMGYVDDTQ FVRFDSDSACPRMEPRAPWVEQEGPEYWEEET RNTKAHAQTDRMNLQTLRGYYNQSEASSHTLQ WMIGCDLGSDGRLLRGYEQYAYDGKDYLALNE DLRSWTAADTAAQISKRKCEAANVAEQRRAYL EGTCVEWLHRYLENGKEMLQRADPPKTHVTHH PVFDYEATLRCWALGFYPAEIILTWQRDGEDQ TQDVELVETRPAGDGTFQKWAAVWPSGEEQR YTCHVQHEGLPEPLMLRW Equivalents. The description above may cover several separate inventions of independent utility. Although each of these inventions has been disclosed in its preferred form (or forms), the specific embodiments disclosed and illustrated herein are not to be construed as limiting as numerous variations are possible. The subject matter of the present inventions includes all new and non-obvious combinations and subcombinations of various elements, features, functions and/or properties described herein. The following claims contain certain specific combinations and subcombinations that are considered novel and non-obvious. Inventions embodied in other combinations and subcombinations of features, functions, elements and/or properties may be within the scope claimed herein; in applications claiming priority based on this application; or in related applications. Such claims, whether they are directed to another invention or to the same invention, or whether they are broader, narrower, equal or different in scope from the original claims, are also considered to be included in the subject matter of the invention, described in this document. CLAIM 1. An antibody that specifically binds to human HLA-G (hHLA-G), comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a) VH contains: i) complementarity determining region (CDR) 1 VH-VHCDR1 containing the amino acid sequence presented in SEQ ID NO: 7; VHCDR2 containing the amino acid sequence presented in SEQ ID NO: 44; and VHCDR3, containing the amino acid sequence presented in SEQ ID NO: 93, and these CDRs are defined by Chothia; or ii) VHCDR1 containing the amino acid sequence presented in SEQ ID NO: 25; VHCDR2 containing the amino acid sequence presented in SEQ ID NO: 65; and VHCDR3, containing the amino acid sequence presented in SEQ ID NO: 93, and these CDRs are defined by Kabat; And b) VL contains: i) VLCDR1 containing the amino acid sequence presented in SEQ ID NO: 118; VLCDR2 containing the amino acid sequence presented in SEQ ID NO: 138; and VLCDR3, containing the amino acid sequence presented in SEQ ID NO: 155, and these CDRs are determined by Chothia and Kabat. 2. The antibody of claim 1, comprising a VH sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 192 and a VL sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 220. 3. An antibody according to claim 1 or 2, comprising: i) a heavy chain of the sequence SEQ ID NO: 254 and a light chain of the sequence SEQ ID NO: 322 or ii) a heavy chain of the sequence SEQ ID NO: 288 and a light chain of the sequence SEQ ID NO: 322. 4. Antibody according to any one of claims 1-3, which is a monoclonal antibody. 5. A pharmaceutical composition containing an antibody according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient. - 153 045983 6. A pharmaceutically acceptable composition according to claim 5, further comprising at least one of the following: a) antibodies against ILT2; b) antibodies against ILT4; c) antibodies against KIR2DL4; d) antibodies against HLA-E; e) antibodies against NKG2A; f) antibodies against HLA-F; g) antibodies against PD-L1; h) antibodies against PD-1; i) antibodies against CD38; j) antibodies against CD39; k) antibodies against CD73; l) antibodies against the A2A receptor; m) antibodies against the A2B receptor; n) antibodies against the dual A2A/A2B receptor or a combination thereof; o) antibodies against CD47; p) antibodies against CTLA-4; q) antibodies against TIM-3; r) antibodies against TIGIT; s) antibodies against VISTA; t) antibodies against CD94; u) low molecular weight inhibitor; v) a bispecific T cell recruiter, an agent for CART therapy, CAR NK cell therapy, CAR macrophage therapy, engineered cell therapy and/or adoptive T cell therapy; w) oncolytic virus; x) a chemotherapeutic agent; y) a therapeutic agent with ADCC function, which uses competent effector antibodies, such as anti-CD19, anti-CD20, anti-eGF, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA, anti-GD2 and/or anti-CCR4 antibodies; y1) antibodies to an immunoinhibitory receptor or ligand and/or y2) antibodies to an immunostimulatory receptor or ligand. 7. Isolated nucleic acid encoding the antibody according to claims 1-4. 8. An expression vector containing the nucleic acid according to claim 7. 9. A prokaryotic or eukaryotic host cell containing the vector according to claim 8. 10. A kit for therapeutic use, comprising an antibody according to any one of claims 1 to 4 and a solvent for reconstituting the anti-HLA-G antibody. 11. A kit for diagnostic use, containing an antibody according to any one of claims 1 to 4 and a solvent for reconstituting the anti-HLA-G antibody. 12. A method of treating a subject suffering from a disease in which up-regulation of HLA-G expression is present, comprising the step of administering to the subject a pharmaceutical composition containing an effective amount of an antibody according to any one of claims 1 to 4. 13. The method of claim 12, further comprising administering one or more of the following: a) antibodies against ILT2; b) antibodies against ILT4; c) antibodies against KIR2DL4; d) antibodies against HLA-E; e) antibodies against NKG2A; f) antibodies against HLA-F; g) antibodies against PD-L1; h) antibodies against PD-1; i) antibodies against CD38; j) antibodies against CD39; k) antibodies against CD73; l) antibodies against the A2A receptor; m) antibodies against the A2B receptor; n) antibodies against the dual A2A/A2B receptor or a combination thereof; o) antibodies against CD47; p) antibodies against CTLA-4; - 154 -