Ilt2 binding agents and uses thereof

Abstract

The present disclosure provides ILT2 binding agents (e.g., antibodies, including monospecific and multispecific antibodies such as bispecific antibodies) and uses thereof.

Description

ILT2 BINDING AGENTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 608,778, filed December 11, 2023 and U.S. Provisional Patent Application No. 63 / 579,866, filed August 31, 2023, the disclosure of each of which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14529-163 -228_SEQ_LISTING. xml”, was created on August 25, 2024, and is 136,926 bytes in size.1. FIELD

[0003] The present disclosure relates generally to binding agents, such as antibodies (including fragments thereof) that bind to ILT2 including human ILT2, and methods of use thereof.2. BACKGROUND

[0004] Ig-like transcript 2 (ILT2) is a cell surface receptor expressed on a wide range of immune cells and recognizes a broad spectrum of human leukocyte antigen (HLA) molecules (see, e.g., Shiroishi et al. Proc. Natl. Acad. Sci. USA 100(15):8856-8861 (2003)). Thus, ILT2 is a potential target for removing suppressions of immune cells and enhancing anti-tumor responses by immune cells. There remains a need in the art for binding agents targeting ILT2 for enhancing immune responses and treating diseases or disorders such as cancer. The binding agents, compositions and methods provided herein satisfy this need and provide related advantages.3. SUMMARY

[0005] The present disclosure provides ILT2 binding agents, including human ILT2 binding agents. Such agents include antibodies that bind to ILT2, for example, monospecific or multispecific (e.g., bispecific) antibodies that bind to ILT2. Such binding agents, in some embodiments, bind to the same epitope of ILT2 (e.g., human ILT2) as an antibody comprising the CDRs described herein (e.g., Tables 1-4). Such binding agents, in some embodiments, bind to the same epitope of ILT2 (e.g., human ILT2) as an antibodycomprising a heavy chain variable region and a light chain variable region described herein (e.g., Tables 1-4).

[0006] The present disclosure also provides nucleic acids encoding an ILT2 binding agent provided herein (e.g., an antibody or fragment thereof, such as an antigen-binding fragment), vectors comprising one or more of such nucleic acids, and cells comprising the nucleic acid, the vector, or both (such as cells expressing the binding agent).

[0007] The present disclosure also provides compositions comprising an ILT2 binding agent. Such compositions, in some embodiments, include antibodies that bind to ILT2, for example, monospecific or multispecific (e.g., bispecific) antibodies that bind to ILT2. Such compositions, in some embodiments, include antibodies that bind to essentially the same epitope of ILT2 (e.g., human ILT2) as an antibody comprising the CDRs described herein (e.g., Tables 1-4). Such compositions, in some embodiments, include antibodies that bind to essentially the same epitope of ILT2 (e.g., human ILT2) as an antibody comprising a heavy chain variable region and a light chain variable region described herein (e.g., Tables 1-4).

[0008] The present disclosure also provides compositions comprising the nucleic acids encoding an ILT2 binding agent provided herein (e.g., an antibody or fragment thereof, such as an antigen-binding fragment), vectors comprising one or more nucleic acids, or cells comprising the nucleic acid, the vector, or both (such as cells expressing the binding agent).

[0009] The present disclosure further provides various uses of the present binding agents and compositions, including, for example, methods for inhibiting interaction between (i) any of HLA-G, HLA-A, HLA-B, and HLA-C and (ii) ILT2 (such as those expressed on an immune cell), and methods of preventing suppression of an immune cell or activating a response mediated by an immune cell. Other aspects provided herein include methods for treating a disease or disorder in a subject with an ILT2 binding agent or a composition provided herein. Such compositions include antibodies that bind to ILT2, for example, monospecific or multispecific (e.g., bispecific) antibodies that bind to ILT2 (e.g., human ILT2).4. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGs. 1A-1E provide exemplary ILT2 HEK cell binding results of Ab101 (FIG. 1A), Ab121 (FIG. 1B), Ab125 (FIG. 1C), Benchmark Antibody 1 (FIG. 1D), and Benchmark Antibody 2 (FIG. 1E), as further illustrated in Example 6.

[0011] FIGs. 2A-2G provide exemplary MEC1 cell binding results of Ab101 (FIG. 2A), Ab121 (FIG. 2B), Ab125 (FIG. 2C), Benchmark Antibody 1 (FIG. 2D), BenchmarkAntibody 2 (FIG. 2E), Ab101 variants (FIG. 2F), and Ab121 / Ab125 variants (FIG. 2G), as further illustrated in Example 6.

[0012] FIGs. 3A-3G provide exemplary JVM-2 cell binding results of Ab101 (FIG. 3A), Ab121 (FIG. 3B), Ab125 (FIG. 3C), Benchmark Antibody 1 (FIG. 3D), Benchmark Antibody 2 (FIG. 3E), Ab101 variants (FIG. 3F), and Ab121 / Ab125 variants (FIG. 3G), as further illustrated in Example 6.

[0013] FIGs. 4A-4E provide exemplary cytokine secretion results of Ab101, Ab121, Ab 125, their variants, Benchmark Antibody 1 (also referred to as “BM Ab 1”), Benchmark Antibody 2 engineered from IgG4 to comprise an IgG1 sFc (also referred to as “Benchmark Antibody 2 engineered w / IgG1 sFc” or “BM Ab 2 (IgG1 sFc)”), and KLH isotype antibody engineered to have a sFc (also referred to as “KLH Isotype Control (sFc)” or “KLH (sFc)”), as further illustrated in Example 7. FIG. 4A plots the obtained IFNy concentrations of groups treated with Ab101, Ab121, Ab125, or the controls. FIG. 4B shows IFNy concentration folds at 1.6 nM, while FIG. 4C compares IFNy concentration folds with reference to the KLH control. FIG. 4D plots the obtained IFNy concentrations of groups treated with Ab101, its variants, or controls. FIG. 4E plots the obtained IFNy concentrations of groups treated with Ab121, Ab125, their variant, or controls.

[0014] FIGs. 5A-5E provide exemplary cytotoxicity results of Ab101, Ab121, Ab125, their variants, Benchmark Antibody 1 (also referred to as “BM Ab 1”), Benchmark Antibody 2, Benchmark Antibody 2 engineered from IgG4 to comprise an IgG1 sFc (also referred to as “BM Ab 2 (IgG1 sFc)”), and KLH isotype antibody engineered to have a sFc (also referred to as “KLH (sFc)”), as further illustrated in Example 8. FIG. 5A shows a dose-dependent response. FIG. 5B plots the obtained cytotoxicity percentages using three different concentrations (40.0 nM, 8.0 nM, and 1.6 nM) of Ab101, Ab121, Ab125, and controls. FIG. 5C compares the cytotoxicity percentages at 1.6 nM of Ab101, Ab121, Ab125, and controls. FIG. 5D plots the obtained cytotoxicity percentages using three different concentrations (40.0 nM, 8.0 nM, and 1.6 nM) of Ab101, Ab101-02, Ab101-12, Ab101-11, and controls. FIG. 5E plots the obtained cytotoxicity percentages using three different concentrations (40.0 nM, 8.0 nM, and 1.6 nM) of Ab121, Ab125, Ab12x-15, Ab12x-33, and controls.

[0015] FIG. 6 compares the IFNy folds vs. the cytotoxicity folds of the antibodies generated in Example 1 and selected according to Examples 2-6, including Ab101, Ab 121, Ab 125, Benchmark Antibody 1 (also referred to as “BM Ab 1”), Benchmark Antibody 2 engineered from IgG4 to comprise an IgG1 sFc (also referred to as “BM Ab 2 (IgG1 sFc)”),and KLH isotype antibody engineered to have a sFc (also referred to as “KLH (sFc)”) as further illustrated in Example 8.

[0016] FIGs. 7A-7H provide exemplary IFNy secretion results (FIGs. 7A-7D) and cytotoxicity results (FIGs. 7E-7H) of Ab 125, antibody variants and indicated controls, such as Benchmark Antibody 2, Benchmark Antibody 3, and KLH isotype antibody, as further illustrated in Example 9. FIG. 7A and FIG. 7E focus on Ab125. FIG. 7B and FIG. 7F focus on Ab 101-11. FIG. 7C and FIG. 7G focus on Ab12x-33. FIG. 7D and FIG. 7H show all controls.

[0017] FIGs. 8A-8E provide exemplary T cell results of Ab101, Ab121, Ab125, their variants, Benchmark Antibody 1, Benchmark Antibody 2, Benchmark Antibody 3, and isotype control, as further illustrated in Examples 10-12. FIG. 8A shows exemplary results obtained using 2 ng / mL anti-human CD3, Jurkat ILT2 non-B2M KO reporter cells, and HLA-G HEK cells, while FIG. 8B shows exemplary results obtained using 10 ng / mL antihuman CD3 and Jurkat ILT2 non-B2M KO reporter cells, and HLA-G HEK cells. FIG. 8C and FIG. 8D show exemplary results obtained using Jurkat ILT2 B2M KO reporter cells and LCL-HLA-G cells. FIG. 8C focuses on Ab101 and its variants, while FIG. 8D focuses on Ab121, Ab125, and their variants. FIG. 8E shows exemplary results obtained using Jurkat ILT2 non-B2M KO reporter cells and LCL-HLA-G cells.5. DETAILED DESCRIPTION

[0018] The present disclosure is based, at least in part, on novel ILT2 binding agents and their properties. Such agents include antibodies (e.g., monospecific or multispecific, including bispecific) that bind to ILT2, including antibodies that bind to human ILT2. In certain aspects, such binding agents are useful in compositions and in methods for inhibiting the interaction between (i) any of HLA-G, HL A-A, HLA-B, and HLA-C and (ii) ILT2 (for example, an ILT2 or a complex comprising the same expressed on an immune cell), thereby preventing suppression of the immune cell or activating an anti-tumor response mediated by the immune cell. In addition, ILT2 binding agents described herein, such as ILT2 binding antibodies (e.g., monospecific or multispecific antibodies, including bispecific antibodies), are useful for the killing and / or removal of tumor cells. ILT2 binding agents described herein, such as ILT2 binding antibodies (e.g., monospecific or multispecific antibodies, including bispecific antibodies), are useful in compositions and in methods for treating a disease or disorder such as cancer.

[0019] As it would be understood, the section or subsection headings as used herein is for organizational purposes only and are not to be construed as limiting and / or separating the subject matter described.5.1. Definitions

[0020] Techniques and procedures described or referenced herein include those that are generally well understood and / or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et cd., Molecular Cloning: A Laboratory Manual (3d ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Diibel eds., 2d ed. 2010). Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0021] The term “ILT2” refers to a polypeptide (“polypeptide” and “protein” are used interchangeably herein) or any native ILT2 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkey (cyno)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. ILT2 is also known as, for example, leukocyte Ig-like receptor 1, leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), CD85J, leukocyte immunoglobulin-like receptor 1 (LIR1), paired immunoglobulin-like receptor B (PIRB), and myeloid inhibitory receptor 7 (MIR7). ILT2 belongs to the subfamily B class of LIR receptors. ILT2 contains an extracellular domain comprising four Ig-like C2 type domains, a transmembrane domain, and a cytoplasmic domain comprising four immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (see, e.g., Borges et al., 1997, J. Immunol., 159:5192-5196). The four Ig-like extracellular domains may be referred to herein as DI, D2, D3, and D4. DI is situated at the N-terminal portion of the protein, then D2, D3, with D4 situated closest to the transmembrane region. ILT2 is broadly expressed on monocytes, B cells, dendritic cells (DCs), macrophages, myeloid-derived suppressor cells, and subsets of natural killer (NK) and T cells. Various ligands are known to interact with ILT2, including classical HLA class I molecules (e.g, HLA-A, HLA-B, and HLA-C) andnon-classical HLA class I molecules (e.g., HLA-E, HLA-F, and HLA-G). ILT2 is a protein encoded by the LILRB1 gene. The term ILT2 encompasses “full-length” ILT2, as well as any form of ILT2 or any fragment thereof, for example those resulted from processing in a cell. In some embodiments, an exemplary amino acid sequence of a full-length ILT2 is provided below (see, e.g., UniProt access no. Q8NHL6-1). In some embodiments, the ILT2 comprises a signal sequence. In some embodiments, the ILT2 does not include a signal sequence. In some embodiments, the term ILT2 refers to a fragment of the full-length ILT2, which comprises an ILT2 extracellular domain. In some embodiments, the term ILT2 refers to a fragment of the full-length ILT2, which comprises DI and D2. The term ILT2 also encompasses naturally occurring variants of ILT2, such as SNP variants, splice variants and allelic variants. An exemplary amino acid sequence of a full-length human ILT2 (including the signal peptide in bold and italic font) is provided below:MTP / ZTEL / CZGZ5ZGPPTHE(MGHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEY RLYREKKTALWITRIPQELVKKGQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLEL VVTGAYIKPTLSAQPSPVVNSGGNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPH ARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSV QPGPIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPV SRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTL LCQSQGWMQTFLLTKEGAADDPWRLRSTYQSQKYQAEFPMGPVTSAHAGTYRCYG SQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRH LGVVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRG LQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPR REMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATE PPPSQEGPSPAVPSIYATLAIH (SEQ ID NO: 105). An exemplary amino acid sequence of extracellular domain (ECD) of human ILT2 (ILT2 ECD) is provided below:GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKK GQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSG GNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWY RCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETLTLQCGSDAGYN RFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSA PSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDP WRLRSTYQSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPS GGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV(SEQ ID NO:89). An exemplaryamino acid sequence of a human ILT2 comprising DI and D2 but having its D3 and D4 truncated (ILT2 D1-D2) is provided below:GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKK GQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSG GNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWY RCYAYDSNSPYEWSLPSDLLELLVLG (SEQ ID NO:90).

[0022] In some embodiments, the term ILT2 as used herein refers to an ILT2 epitope.

[0023] As used herein, the term “binding agent” or a grammatical equivalent thereof refers to a molecule (e.g., antibody) with one or more antigen-binding sites that binds an antigen. In some embodiments, an ILT2 binding agent as described herein is an antibody (including an antibody fragment, such as an antigen-binding fragment or an epitope-binding fragment) or other peptide-based molecule as well as a conjugate of an antibody, antibody fragment, or peptide-based molecule (e.g., an antibody-drug conjugate) that binds to ILT2, such as human ILT2.

[0024] The terms “antibody,” “immunoglobulin,” and “Ig” are used interchangeably herein, and are used in the broadest sense and specifically cover, for example polyclonal antibodies, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full-length monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, recombinantly produced antibodies, single domain (e.g., VHH) antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human versions of antibodies having full-length heavy and / or light chains. VHH as used herein refers to a domain antibody derived from a variable region of a heavy chain only antibody. Exemplary single domain antibodies include, but are not limited to, antibodies naturally devoid of light chains such as those from Camelidae species (e.g., llama), single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine. VHH can also be derived from other species besides Camelidae that may produce heavy chain antibodies naturally devoid of light chain. Antibodies also include antibody fragments (and / or polypeptides that comprise antibody fragments) that retain ILT2 binding characteristics. Non-limiting examples of antibody fragments include antigen-binding regions and / or effector regions of the antibody, e.g., Fab, Fab’, F(ab')2, Fv, scFv, (scFv)2,single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide-linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non-covalently coupled). In general terms, a variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (VH) and / or light (VL) variable domains. For example, antibodies also include tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer. Thus, for example, the V region domain may be dimeric and contain VHH-VHH, VH-VH, VH-VL, or VL-VL dimers that bind ILT2. If desired, the VH and VL may be covalently coupled either directly or through a linker to form a single chain Fv (scFv). For ease of reference, scFv proteins are referred to herein as included in the category “antibody fragments.” Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed “minimal recognition units” or “hypervariable regions”) can be obtained by constructing polynucleotides that encode one or more CDRs of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et aL, Methods: A Companion to Methods in Enzymology, 2: 106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies,” in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley- Liss, Inc. (1995)). Antibody fragments may be incorporated, for example, into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9): 1126-1136, 2005). In some embodiments, antibodies comprising a VH and / or VL further contain a light chain and / or a heavy chain constant region, such as one or more constant regions, including one or more IgG1, IgG2, IgG3 and / or IgG4 constant regions. In some embodiments, antibodies can include epitope-binding fragments of any of the above. The antibodies described herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2) of immunoglobulin molecule.

[0025] The term “monospecific” when used in reference to a binding agent (e.g., an antibody) as used herein denotes a binding agent that has one or more binding sites each of which binds to the same epitope of the same antigen.

[0026] The term “multispecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent is able to specifically bind to at least two distinct epitopes, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) or each formed by a pair of VHH domains binding to different antigens or to different epitopes on the same antigen. Such a bispecific binding agent (e.g., an antibody) may have a 1+1 format (comprising one binding site for a first antigen or epitope and one binding site for a second antigen or epitope). Other bispecific binding agent (e.g., an antibody) formats may be 2+1 or 1+2 formats (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 format (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). When a bispecific binding agent (e.g., an antibody) comprises two antigen-binding sites, each may bind to a different epitope. Such a bispecific binding agent (e.g., an antibody) may bind to two different epitopes on the same antigen (e.g., epitopes on ILT2).

[0027] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In some embodiments, two nucleic acids or polypeptides are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues in length or any integral value there between. In some embodiments, identity exists over a longerregion than 60-80 residues, such as at least about 80-100 residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as the coding region of a target protein or an antibody. In some embodiments, identity exists over a region of the nucleotide sequences that is at least about 10 bases, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 bases, such as at least about 80-1000 bases or more, and in some embodiments the sequences are substantially identical over the full-length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.

[0028] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics. Families of amino acid residues having similar side chains have been generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservative substitution. Generally, conservative substitutions in the sequences of the polypeptides, soluble proteins, and / or antibodies of the disclosure do not abrogate the binding of the polypeptide, soluble protein, or antibody containing the amino acid sequence, to the target binding site. Methods of identifying amino acid conservative substitutions which do not eliminate binding are well-known in the art.

[0029] The term “polypeptide” refers to polymers of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can include (e.g., be interrupted by) non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as linkage to or conjugation with (directly or indirectly) a moiety such as a labeling component or a drug (e.g., toxin). Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure can be based upon antibodies orother members of the immunoglobulin superfamily, in some embodiments, the polypeptides can occur as single chains or dimers of single chains.

[0030] As used herein, an “antigen” is a moiety or molecule that contains an epitope to which a binding agent (e.g., an antibody) can bind. As such, an antigen can be bound by an antibody. In some embodiments, the antigen, to which a binding agent (e.g., an antibody) described herein binds, is ILT2 (e.g., human ILT2), or a fragment thereof, including a fragment that comprises one or more domains of ILT2.

[0031] As used herein, an “epitope” is a term in the art and refers to a localized region of an antigen to which an antibody can bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope), e.g., human ILT2. It will be appreciated by one of skill in the art that, in general, a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. For example, in some embodiments, an antibody binds to a group of amino acids regardless of whether they are folded in a natural three-dimensional protein structure. In other embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.

[0032] An antibody binds “an epitope” or “essentially the same epitope” or “the same epitope” as a reference antibody, when the two antibodies recognize identical, overlapping or adjacent epitopes in a three-dimensional space. The most widely used and rapid methods for determining whether two antibodies bind to identical, overlapping or adjacent epitopes in a three-dimensional space are competition assays, which can be configured in a number of different formats, for example, using either labeled antigen or labeled antibody. In some assays, the antigen is immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent or enzyme labels.

[0033] “Epitope binning” is the process of grouping antibodies based on the epitopes they recognize. More particularly, epitope binning comprises methods and systems for discriminating the epitope recognition properties of different antibodies, using competition assays combined with computational processes for clustering antibodies based on their epitope recognition properties and identifying antibodies having distinct binding specificities.

[0034] As used herein, the terms “specifically binds,” “specifically recognizes,”“immunospecifically binds,” “selectively binds,” “immunospecifically recognizes” and “immunospecific” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope) as such binding is understood by one skilled in the art. In some embodiments, “specifically binds” means, for instance that a polypeptide or molecule interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIACORE™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), the OctetQK384 system (ForteBio, Menlo Park, CA), or other assays known in the art. In some embodiments, an antibody or antigen-binding domain binds to or specifically binds to an antigen when it binds to the antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIAs) and enzyme linked immunosorbent assays (ELISAs). Typically a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity. In some embodiments, the extent of binding of an antibody or antigen-binding domain to a “non-targef ’ protein is less than about 10% of the binding of the antibody or antigen-binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIAs. In some embodiments, molecules that specifically bind to an antigen bind to the antigen with a Ka that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Ka when the molecules bind to another antigen. In some embodiments, molecules that specifically bind to an antigen do not cross react with other proteins. In another specific embodiment, molecules that specifically bind to an antigen do not cross react with other non-ILT2 proteins. In some embodiments “specifically binds” means, for instance, that a polypeptide or molecule binds a protein or target with a KD of about 0.1mM or less, but more usually less than about 1 μM. In some embodiments, “specifically binds” means that a polypeptide or molecule binds a target with a KD of at least about 0.1 μM or less, at least about 0.01 μM or less, or at least about InM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, because of homology within certain regions of polypeptide sequences of different proteins, specific binding can include a polypeptide or molecule thatrecognizes more than one protein or target. It is understood that, in some embodiments, a polypeptide or molecule that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target. Thus, a polypeptide or molecule can, in some embodiments, specifically bind more than one target. In some embodiments, multiple targets can be bound by the same antigen-binding site on the polypeptide or molecule. For example, an antibody can, in certain instances, comprise two identical antigen- binding sites, each of which specifically binds the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities. Generally, but not necessarily, reference to “binding” means “specific binding”.

[0035] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding agent such as an antibody) and its binding partner (e.g., an antigen such as ILT2). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. In one embodiment, the “KD” or “KD value” may be measured by biolayer interferometry (BLI) using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA). Alternatively, the KD may also be measured in a radiolabeled antigen-binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen (Chen, et al.. (1999) J. Mol Biol 293:865- 881) or using surface plasmon resonance (SPR) assays by BIACORE™, using, for example, a BIACORE™-2000 or a BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ). An “on- rate” or “rate of association” or “association rate” or “kon,” as well as an “off-rate” or “rate of dissociation” or “dissociation rate” or “koir,” can also be determined with the same SPR or BLI techniques described above using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA) or a BIACORE™-2000 or a BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ), respectively.

[0036] The term “compete” or any grammatical variation thereof when used in the context of ILT2 binding agents (e.g., antibodies) means binding agents that compete for the same epitope or binding site on a target, which includes competition between such binding agents as determined by an assay in which the binding agent under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand, or reference antigen- binding protein, such as a reference antibody) to a common antigen (e.g., ILT2). Numerous types of competitive binding assays can be used to determine if a test binding agent competes with a reference molecule for binding to ILT2 (e.g., human ILT2). Examples of assays that can be employed include solid phase direct or indirect radioimmunoassay (RIA); solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., (1983) Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol. 137:3614-3619 or Cheung, et al., (1990) Virology 176:546-552); solid phase direct labeled assay; solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (see, e.g., Morel et al., (1988) Molec. Immunol. 25:7-15); and direct labeled RIA (Moldenhauer et al., (1990) Scand. J. Immunol. 32:77-82). Typically, such an assay involves the use of a purified antigen (e.g., ILT2, such as human ILT2) bound to a solid surface or cells bearing either of an unlabelled test antigen- binding protein (e.g., test ILT2 antibody) or a labeled reference antigen-binding protein (e.g., reference ILT2 antibody). Competitive inhibition may be measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen-binding protein. Usually, the test antigen-binding protein is present in excess. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and / or antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference for antibodies steric hindrance to occur (e.g., similar epitope or overlapping epitope). Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 20%, for example, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instance, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more.

[0037] As used herein, the term “constant region” or “constant domain” is a well-known antibody term of art and refers to an antibody portion, for example, a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to an antigen but which can exhibit various effector functions, such as interaction with an Fcreceptor. The term includes the portion of an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0038] Antibody “effector functions” refer to those biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibodydependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0039] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226 (according to the EU numbering system), or from Pro230 (according to the EU numbering system), to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. An exemplary Fc region sequence is provided below (CH2 domain = bold text; CH3 domain = underline text):

[0040] A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis (such as antibody-dependent cellular phagocytosis, z.e., ADCP); down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or domain) and can be assessed using various assays as disclosed.

[0041] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature, and not manipulated, modified, and / or changed (e.g., isolated, purified, selected, including or combining with other sequences suchas variable region sequences) by a human. Native sequence human Fc regions include a native sequence human IgG1 Fc region (non- A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.

[0042] A “variant Fc region” comprises an amino acid sequence that differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g., substituting, addition, or deletion), preferably one or more amino acid substitution(s). In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region described herein can possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, or at least about 90% homology therewith, for example, at least about 95% homology therewith. The variant Fc region herein described herein may have a loss of an effector function (e.g., silent Fc).

[0043] In some embodiments, a variant Fc region comprises an alanine (Ala, A) residue at position Leu234 (L234) according to the EU numbering system, an alanine (Ala, A) residue at position Leu235 (L235) according to the EU numbering system, and a lysine (Lys, K) residue at position Pro329 (P329) according to the EU numbering system (also referred to herein as “LALAPK” or “L234A / L235A / P329K”). In further embodiments, the variant Fc region of L234A / L235A / P329K is a silent Fc (also referred to herein as sFc).

[0044] An exemplary variant Fc region (“silent Fc”) sequence is provided below (CH2 domain = bold text with amino acid changes underlined; CH3 domain = underline text):

[0045] Additionally or alternatively, a variant Fc region has a reduced potential immunogenicity. In further embodiments, a variant Fc region comprises a glutamic acid (Glu, E) residue at position Asp356 (D356) according to the EU numbering system, a glutamic acid (Glu, E) residue at position Glu357 (E357) according to the EU numbering system, and amethionine (Met, M) residue position Leu358 (L358) according to the EU numbering system (also referred to herein as “EEM” or “D356E / E357E / L358M”).

[0046] As used herein, the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portion includes one or more constant regions. The “heavy chain” can refer to any distinct types, e.g., for example, alpha (a), delta (5), epsilon (a), gamma (y) and mu (p), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3 and IgG4.

[0047] As used herein, the term “light chain” when used in reference to an antibody can refer to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy -terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, e.g., kappa (K) or lambda (X) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art.

[0048] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen- binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding fragment, domain, or region its specificity and affinity for the antigen (e.g., the CDRs). “Antigen-binding fragment” as used herein includes “antibody fragment,” which comprises a portion of an antibody including one or more CDRs, such as the antigen-binding or variable region of the antibody.

[0049] Antibodies described herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, Fab fragments, F(ab’) fragments, disulfide-linked Fvs (sdFv), anti -idiotypic (anti- id) antibodies, and epitope-binding fragments of any of the above.

[0050] In some embodiments, antibodies described herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, including molecules that contain one or more antigen-binding sites that bind to an ILT2 antigen.

[0051] Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgAl or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In some embodiments, antibodies described herein are IgG antibodies (e.g., human IgG), or a class (e.g., human IgG1, IgG2, IgG3 or IgG4) or a subclass thereof.

[0052] In some embodiments, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs. In further embodiments, the amino acid sequences of the H chains are identical and the amino acid sequences of the L chains are identical. In other embodiments, the amino acid sequences of the H chains are different from each other. Additionally or alternatively, the amino acid sequences of the L chains are different from each other. For example, an antibody comprises a first H / L chain pair and a second H / L chain pair, wherein the first H / L chain pair binds to an ILT2 antigen and the second H / L chain pair binds to another ILT2 antigen or a non-ILT2 antigen. In some embodiments, an antibody is a 2-chain antibody unit comprising a VHH-VHH pair. In further embodiments, the amino acid sequences of the VHH are identical. In other embodiments, the amino acid sequence of the VHH are different from each other. For example, an antibody comprises a first VHH and a second VHH, wherein the first VHH binds to an ILT2 antigen and the second VHH binds to another ILT2 antigen or a non-ILT2 antigen. In some embodiments, the H and / or L chains comprise constant regions, for example, human constant regions. In some embodiments, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In some embodiments, the H chain constant region of such antibodies comprises a gamma heavy chain constant region, for example, a human gamma heavy chain constant region. In some embodiments, such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g., IgG1, IgG2, IgG3, and / or IgG4 constant regions).

[0053] An antibody or fragment thereof may preferentially bind to ILT2, such as human ILT2, meaning that the antibody or fragment thereof binds ILT2 with greater affinity than it binds to a control protein (e.g., hen egg white lysozyme, LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, or LILRB5) and / or binds human ILT2 with greater affinity than it binds to an unrelated control protein (e.g., hen egg white lysozyme, human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, or LILRB5). For example, the antibody or fragment thereof may specifically recognize and bind ILT2 or a portion thereof. “Specific binding” means that the antibody or fragment thereof binds to ILT2 with an affinity that is at least 5,10, 15, 20, 25, 50, 100, 250, 500, 1000, or 10,000 times greater than the affinity for an unrelated control protein (e.g., hen egg white lysozyme, LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, or LILRB5). In some embodiments, the antibody or fragment thereof may bind ILT2 substantially exclusively (e.g, is able to distinguish ILT2 from other known polypeptides, for example, by virtue of measurable differences in binding affinity).

[0054] The term “variable region” or “variable domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain, has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH .” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g, relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” or alternatively called “complementarity determining regions (CDRs).” The variable regions of heavy and light chains each comprise four frameworks (FR1, FR2, FR3 and FR4), largely adopting a P sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the P sheet structure. The hypervariable regions in each chain are held together in close proximity by the frameworks and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g, Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, (1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. The variability in sequence is concentrated in the CDRs while the less variable portions in the variable region are referred to as framework regions (FR). The CDRs of the light and heavy chains are primarily responsible for theinteraction of the antibody with its antigen. In specific embodiments, the variable region is a human variable region.

[0055] The term “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions: three in the VH (Hl or VH CDR1, H2 or VH CDR2, and H3 or VH CDR3), and three in the VL (LI or VL CDR1, L2 or VL CDR2, and L3 or VL CDR3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below.

[0056] A universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT®) Information System (Lefranc et al., Dev. Comp. Immunol. 27(l):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger andPluckthun, J. Mol. Biol. 309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lefranc et al., supra) and is also illustrated below. Various systems known in the art or described herein represent different ways of delineating CDRs, and when they are used to define the same antibody, they are often considered equivalent. An Exemplary system, shown herein, combines Kabat and Chothia. The residues from each of these hypervariable regions or CDRs are exemplified in the table below.Exemplary CDRs According to Various Numbering Systems

[0057] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 or 26- 35A (Hl), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. As used herein, the terms “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” are used interchangeably.

[0058] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. A cell that produces a binding molecule of the present disclosure may include a parent hybridoma cell, as well as bacterial and eukaryotic host cells into which nucleic acids encoding the antibodies have been introduced. Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5’ to the 5’ end of the RNA transcript are referred toas “upstream sequences”; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 3 ’ to the 3 ’ end of the RNA transcript are referred to as “downstream sequences.”

[0059] The term “vector” refers to a substance that is used to carry or include a nucleic acid sequence, including for example, in order to introduce a nucleic acid sequence into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes and artificial chromosomes, which can include selection sequences or markers operable for stable integration into a host cell’s chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can include constitutive and / or inducible promoters, transcription enhancers, transcription terminators, and the like which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both an antibody heavy and light chain or an antibody VH and VL) both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, or immunoblotting for expression of gene products, or other suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecules are expressed in a sufficient amount to produce a desired product (e.g., an ILT2 binding agent as described herein), and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0060] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0061] “Excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipientsinclude, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freunds’ adjuvant (complete or incomplete)) or vehicle. In some embodiments, excipients are pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro, Remington’s Pharmaceutical Sciences (18th ed. 1990). In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005;Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In some embodiments, a pharmaceutically acceptable excipient is an aqueous pH buffered solution.In some embodiments, excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly forinjectable solutions. An excipient can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, including formulations, can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Compositions, including pharmaceutical compounds, may contain a prophylactically or therapeutically effective amount of an ILT2 binding agent (e.g., an antibody), for example, in isolated or purified form, together with a suitable amount of excipient so as to provide the form for proper administration to the subject (e.g., patient). The formulation should suit the mode of administration.

[0062] An “effective amount” is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate the symptoms and / or underlying cause, prevent or delay the occurrence of symptoms and / or their underlying cause, and / or improve or remediate the damage that results from or is associated with a disease, disorder, or condition. In some embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount.

[0063] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., an antibody described herein or any other agent described herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g, a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance / molecule / agent of the present disclosure (e.g, an ILT2 antibody) may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule / agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term“therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0064] The term “treating” or any grammatical variation thereof refers to reducing and / or ameliorating the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein). In some embodiments, the term “treating,” or “treatment” excludes a prophylactic treatment.

[0065] A “prophylactically effective amount” is an amount of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of a disease, disorder or condition, or reducing the likelihood of the onset (or reoccurrence) of a disease, disorder, or condition or associated symptom(s).

[0066] The full therapeutic or prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations.

[0067] The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less variation of a given value or range.

[0068] As used herein, comparative terms as used herein, such as reduce, decrease, increase, or any grammatical variation thereof, can refer to certain variation from the reference. In some embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 fold, or about 3 fold, or about 4 fold, or about 5 fold, or about 10 fold, or about 20 fold, or about 30 fold, or about 40 fold, or about 100 fold or higher than the reference. In some embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.

[0069] As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.

[0070] In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first antibody” and “second antibody” are used to distinguish two antibodies.

[0071] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0072] The term “between” as used in a phrase as such “between A and B” or “between A-B” refers to a range including both A and B or any subranges thereof.

[0073] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0074] The term “optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances wherein the circumstance occurs, and the instances wherein the circumstance does not occur.5.2. ILT2 Binding Agents

[0075] In some embodiments, the present disclosure provides ILT2 binding agents that can be used herein as an agent for enhancing immune responses and / or therapeutic agents. Such agents include antibodies (e.g., monospecific or multispecific, including bispecific) that bind to ILT2. Exemplary antibodies include polyclonal, monoclonal, humanized, human, bispecific, and heteroconjugate antibodies, as well as variants thereof having increased or decreased affinity or other properties.

[0076] In some embodiments, described herein are ILT2 binding agents (e.g., antibodies) that bind to ILT2, including an ILT2 polypeptide, an ILT2 polypeptide fragment, an ILT2 peptide or an ILT2 epitope. In some embodiments, the ILT2 binding agents are human or humanized antibodies (e.g., comprising human constant regions) that bind ILT2, including an ILT2 polypeptide, an ILT2 polypeptide fragment, an ILT2 peptide or an ILT2 epitope. In some embodiments, an ILT2 binding agent (e.g., an antibody), such as a human ILT2 bindingagent, can bind to ILT2 expressed on the surface of a mammalian (e.g., human) cell, including an ILT2 expressing immune cell (e.g., an NK cell, a T cell, a B cell, a monocyte, a macrophage, a dendritic cell, or a myeloid-derived suppressor cell). In some embodiments, an ILT2 binding agent (e.g., an antibody) binds an ILT2 extracellular epitope exposed on a cell such as an immune cell. In some embodiments, described herein is an ILT2 binding agent (e.g., an antibody) that binds to ILT2, such as human ILT2 or a portion thereof. In some embodiments, ILT2 is a human ILT2. In some embodiments, an ILT2 binding agent is a human ILT2 binding agent (e.g., an antibody that binds to human ILT2). In some embodiments, ILT2 binding agents (e.g., antibodies) bind to both human and cyno ILT2. In other embodiments, ILT2 binding agents (e.g., antibodies) bind to human ILT2 but not to cyno ILT2.

[0077] In some embodiments, the ILT2 binding agent (e.g., an antibody) provided herein binds to ILT2 (e.g., human ILT2) with a dissociation constant (KD) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g. 10-8M or less, e.g. from 10-8M to 10-10M, e.g., from 10-8M to 10-9M or from 10-9M to 10-10M, e.g., from 0.2x 10-9M to 2x 10-9M). A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure, including by RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by OCTET®, using, for example, an OCTET®Red96 system, or by BIACORE ™, using, for example, a BIACORE™-2000 or a BIACORE™-3000. An “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the OCTET®Red96, the BIACORE™-2000, the BIACORE™-3000 system, the BIACORE™-8K, or the BIACORE™-8K+ system.

[0078] In some embodiments, the ILT2 binding agent (e.g., an antibody) provided herein does not bind to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5). In other embodiments, the ILT2 binding agent (e.g., an antibody) provided herein binds to ILT2 (e.g., human ILT2) with higher affinity than to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB 5). In some embodiments, the binding affinity of the ILT2 binding agent (e.g., an antibody)provided herein to ILT2 (e.g., human ILT2) is at least 2 fold of that to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5). In some embodiments, the binding affinity of the ILT2 binding agent (e.g., an antibody) provided herein to ILT2 (e.g., human ILT2) is at least 5 fold of that to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5). In some embodiments, the binding affinity of the ILT2 binding agent (e.g., an antibody) provided herein to ILT2 (e.g., human ILT2) is at least 10 fold of that to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB 5). In some embodiments, the binding affinity of the ILT2 binding agent (e.g., an antibody) provided herein to ILT2 (e.g., human ILT2) is at least 100 fold of that to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5). In some embodiments, the binding affinity of the ILT2 binding agent (e.g., an antibody) provided herein to ILT2 (e.g., human ILT2) is at least 1000 fold of that to LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB5 (e.g., human LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB2 / ILT4, LILRB3, LILRB4, and / or LILRB 5).

[0079] In some embodiments, provided herein are ILT2 binding agents which are:(a) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL0;(b) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VLl;(c) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL2;(d) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL0;(e) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VLl;(f) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL2;(g) an antibody comprising a VH designated 121-VH0 and a VL designated 121-VL0;(h) an antibody comprising a VH designated 121-VH0 and a VL designated 125-VL0;(i) an antibody comprising a VH designated 121-VH0 and a VL designated 12x-VL3;(j) an antibody comprising a VH designated 125-VH0 and a VL designated 121-VL0;(k) an antibody comprising a VH designated 125-VH0 and a VL designated 125-VL0;(l) an antibody comprising a VH designated 125-VH0 and a VL designated 12x-VL3;(m) an antibody comprising a VH designated 12x-VH3 and a VL designated 121-VL0;(n) an antibody comprising a VH designated 12x-VH3 and a VL designated 125-VL0; and(o) an antibody comprising a VH designated 12x-VH3 and a VL designated 12x-VL3; respectively, as shown in Tables 1-4.

[0080] In some embodiments, the ILT2 binding agents (e.g., antibodies) described herein comprise a VH region, VL region, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of any one of the antibodies described herein, such as an amino acid sequence of a VH region, VL region, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 depicted in Tables 1-4. Accordingly, in some embodiments, an ILT2 binding agent (e.g., an antibody) described herein comprises: (A) (1) any one, any two, and / or all three heavy chain CDRs from a VH designated 101-VH0, or 101-VH1; and / or (2) any one, any two, and / or all three light chain CDRs from a VL designated 101-VL0, 101- VL1, or 101-VL2; or (B) (1) any one, any two, and / or all three heavy chain CDRs from a VH designated 121-VH0, 125-VH0, or 12x-VH3, and / or (2) any one, any two, and / or all three light chain CDRs from a VL designated 121-VL0, 125-VL0, or 12x-VL3; as shown in Tables 1-4. In some embodiments, an ILT2 binding agent (e.g., an antibody) described herein comprises any one, any two, and / or all three heavy chain CDRs and / or any one, any two, and / or all three light chain CDRs from:(a) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL0;(b) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL1;(c) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL2;(d) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL0;(e) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL1;(f) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL2;(g) an antibody comprising a VH designated 121-VH0 and a VL designated 121-VL0;(h) an antibody comprising a VH designated 121-VH0 and a VL designated 125-VL0;(i) an antibody comprising a VH designated 121-VH0 and a VL designated 12x-VL3;(j) an antibody comprising a VH designated 125-VH0 and a VL designated 121-VL0;(k) an antibody comprising a VH designated 125-VH0 and a VL designated 125-VL0;(l) an antibody comprising a VH designated 125-VH0 and a VL designated 12x-VL3;(m) an antibody comprising a VH designated 12x-VH3 and a VL designated 121-VL0;(n) an antibody comprising a VH designated 12x-VH3 and a VL designated 125-VL0; or(o) an antibody comprising a VH designated 12x-VH3 and a VL designated 12x-VL3(see Tables 1-4).

[0081] In some embodiments, an ILT2 binding agent (e.g., an antibody) described herein comprises any one, any two, and / or all three heavy chain CDRs and any one, any two, and / or all three light chain CDRs from:(a) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL0;(b) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL1;(c) an antibody comprising a VH designated 101-VH0 and a VL designated 101-VL2;(d) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL0;(e) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL1;(f) an antibody comprising a VH designated 101-VH1 and a VL designated 101-VL2;(g) an antibody comprising a VH designated 121-VH0 and a VL designated 121-VL0;(h) an antibody comprising a VH designated 121-VH0 and a VL designated 125-VL0;(i) an antibody comprising a VH designated 121-VH0 and a VL designated 12x-VL3;(j) an antibody comprising a VH designated 125-VH0 and a VL designated 121-VL0;(k) an antibody comprising a VH designated 125-VH0 and a VL designated 125-VL0;(l) an antibody comprising a VH designated 125-VH0 and a VL designated 12x-VL3;(m) an antibody comprising a VH designated 12x-VH3 and a VL designated 121-VL0;(n) an antibody comprising a VH designated 12x-VH3 and a VL designated 125-VL0; or(o) an antibody comprising a VH designated 12x-VH3 and a VL designated 12x-VL3 (seeTables 1-4)

[0082] In some embodiments, an ILT2 binding agent (e.g., an antibody) comprises a VH region, which comprises a VH CDR1, a VH CDR2, and / or a VH CDR3, and / or a VL region, which comprises a VL CDR1, a VL CDR2, and / or a VL CDR3, of any one of the VH and VLs described herein (as the case may be) (see, e.g., any one of Tables 1-4). Accordingly, in some embodiments, an ILT2 binding agent (e.g., an antibody) described herein comprises any one, any two, and / or all three heavy chain CDRs and / or any one, any two, and / or all threelight chain CDRs from Table 1 or Table 2. In some embodiments, an ILT2 binding agent (e.g., an antibody) described herein comprises any one, any two, and / or all three heavy chain CDRs and / or any one, any two, and / or all three light chain CDRs from Table 3 or Table 4.

[0083] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19, or SEQ ID NO:20 and / or (ii) a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0084] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64, SEQ ID NO:65, or SEQ ID NO:68 and / or (ii) a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84, SEQ ID NO:85, or SEQ ID NO:88.

[0085] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia. Various exemplary CDR numbering systems are described and illustrated above in Section 5.1.

[0086] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 4, 7, 8, 11, and 15; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 5, 9, 12, 14, 16,and 17; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 6, 10, and 13; and / or (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 25, 27, and 29; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 26, and 30; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 28, and 31.

[0087] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0088] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NON, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0089] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NON; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0090] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR2 comprising the amino acid sequence of SEQ ID NOV, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:28.

[0091] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 31.

[0092] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 14, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0093] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0094] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0095] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0096] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 4, 7, 8, 11, and 15; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 9, 12, 14, 16, 17, and 18; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 6, 10, and 13; and / or (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 25, 27, and 29; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 26, and 30; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 28, and 31.

[0097] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0098] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0099] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0100] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR2 comprising the amino acid sequence of SEQ ID NOV, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:28.

[0101] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 31.

[0102] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 14, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0103] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0104] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

[0105] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0106] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0107] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0108] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0109] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0110] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0111] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0112] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0113] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0114] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0115] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according toAbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0116] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

[0117] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0118] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0119] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0120] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81.

[0121] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0122] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0123] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0124] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0125] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0126] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0127] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0128] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0129] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0130] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0131] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0132] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0133] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0134] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0135] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0136] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0137] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0138] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0139] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0140] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0141] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0142] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0143] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0144] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0145] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In someembodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0146] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

[0147] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0148] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0149] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0150] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81.

[0151] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0152] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0153] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0154] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0155] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0156] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting ofSEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0157] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0158] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0159] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0160] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0161] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0162] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0163] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0164] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0165] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, theCDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0166] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0167] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0168] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0169] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0170] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0171] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0172] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0173] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0174] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0175] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0176] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

[0177] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0178] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0179] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0180] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81.

[0181] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0182] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0183] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0184] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

[0185] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and / or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and / or a VL CDR1, a VL CDR2, and / or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to IMGT numbering. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a combination of Kabat and Chothia.

[0186] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises (a) a VH region comprising a VH CDR1 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and (b) a VL region comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

[0187] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0188] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0189] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0190] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising theamino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

[0191] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78.

[0192] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0193] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0194] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

[0195] In some embodiments, the antibody further comprises one or more framework regions of SEQ ID NOs: 19, 20, 32, 33, 34, 64, 65, 68, 84, 85, and / or 88. In some embodiments, the antibody or fragment thereof further comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence as set forthin any one of SEQ ID NOs: 19, 20, 32, 33, 34, 64, 65, 68, 84, 85, and 88. In some embodiments, the antibody provided herein is a humanized antibody. Framework regions described herein are determined based upon the boundaries of the CDR numbering system. In other words, if the CDRs are determined by, e.g., Kabat, IMGT, or Chothia, then the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. For example, FR1 is defined as the amino acid residues N-terminal to the CDR1 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system, FR2 is defined as the amino acid residues between CDR1 and CDR2 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system, FR3 is defined as the amino acid residues between CDR2 and CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system, and FR4 is defined as the amino acid residues C-terminal to the CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system.

[0196] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise a VH region or VH domain. Additionally or alternatively, in some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise a VL region or VL domain. In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein have a combination of (i) a VH domain or VH region; and (ii) a VL domain or VL region.

[0197] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:32.

[0198] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VLcomprising the amino acid sequence of SEQ ID NO:33. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:33.

[0199] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:34.

[0200] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:32.

[0201] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:33. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:33.

[0202] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:34.

[0203] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64. In someembodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0204] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0205] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0206] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0207] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0208] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0209] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0210] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0211] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) comprises a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0212] In certain embodiments, the ILT2 binding agent (e.g., an antibody of a fragment thereof) provided herein comprises amino acid sequences with certain percent identity (such as at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or as at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at leastabout 96%, or at least about 97%, or at least about 98%, or at least about 99%, or higher) relative to any antibody or fragment thereof provided herein, for example, a CDR, VH or VL in Tables 1-4, or any full-length antibody chain as disclosed herein. In some embodiments, the ILT2 binding agent (e.g., an antibody of a fragment thereof) provided herein comprises CDRs of any antibody or fragment thereof provided herein, for example in Tables 1-4. In further embodiments, the ILT2 binding agent provided herein comprises amino acid sequences with certain percent identity (such as at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or as at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or higher) relative to any antibody or fragment thereof provided herein, for example, a VH or VL in Tables 1-4, or any full-length antibody chain as disclosed herein.

[0213] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268 (1990), modified as in Karlin and Altschul, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., J. Mol. Biol. 215:403 (1990). BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, word length=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein.BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, word length=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25:3389 3402 (1997). In some embodiments, the percent identity between two sequences is calculated by dividing the number of residue(s) varied (excluding or including conservative amino acid substitution(s) or degenerate nucleotide substitution(s)) between the two sequences in the alignment with the residue number of any one of the following: (i) full length of the shorter sequence, (ii) full length of the longer sequence, (iii) mean length of the two sequences, (iv) total length of the non-gap portion of the alignment, (v) length of the alignment excluding overhangs, or (vi) length of the alignment including overhangs. Overhangs as used herein with respect to asequence alignment refer to either or both ends of the alignment where residues of one sequence are considered as aligning to no residues (e.g., gap) in the other sequence. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CAB IOS 4: 11-17 (1998). Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0214] In some embodiments, the binding agent (e.g., an antibody) provided herein contains substitutions (e.g, conservative substitutions), insertions, or deletions relative to the reference sequence, but the binding agent comprising that sequence retains the ability to bind to ILT2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in a reference amino acid sequence. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (e.g, in the FRs and / or constant regions).

[0215] In some embodiments, the position of one or more CDRs along the VH (e.g, CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) region of an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein may vary by one, two, three, four, five, or six amino acid positions so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). For example, in some embodiments, the position defining a CDR of any of Table 1, 2, 3, or 4 may vary by shifting the N-terminal and / or C-terminal boundary of the CDR by one, two, three, four, five, or six amino acids, relative to the current CDR position, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Additionally or alternatively, in some embodiments, the length of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3)and / or VL (e.g., CDR1, CDR2, or CDR3) region of an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein may vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). For example, in some embodiments, a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described by SEQ ID NOS: 1-18, 22-31, 35-63, or 69-83, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In other embodiments, a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described by SEQ ID NOS: 1-18, 22-31, 35-63, or 69-83, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In some embodiments, the amino terminus of a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-18, 22-31, 35-63, or 69-83, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Additionally or alternatively, in some embodiments, the carboxy terminus of a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-18, 22-31, 35-63, or 69-83, so long as binding to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Any method known in the art can be used to ascertain whether binding to ILT2 (e.g., human ILT2) is maintained, for example, the binding assays and conditions described in the “Examples” section described herein.

[0216] In other embodiments, the ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, presented herein that bind to ILT2, further comprise conservative sequence modifications. With respect to polypeptides that are ILT2 binding agents (e.g., antibodies), such as human ILT2 binding agents, conservative sequence modifications include conservative amino acid substitutions that include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain.Families of amino acid residues having similar side chains have been defined in the art. Thus, in some embodiments, a predicted nonessential amino acid residue in an ILT2 is replaced with another amino acid residue from the same side chain family. Methods of identifying amino acid conservative substitutions which do not eliminate antigen binding and nucleotides encoding thereof are well-known in the art (see, e.g., Brummell et al., Biochem. 32: 1 ISO- 1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). In some embodiments, the conservative sequence modifications described herein modify the amino acid sequences of the ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, by 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 98%, or 99%. In some embodiments, the amino acid sequence modifications refer to at most 1, 2, 3, 4, 5, or 6 amino acid substitutions to the CDRs, such as those described in any one of Tables 1-4. Thus, for example, each such CDR may contain up to 5 conservative amino acid substitutions, for example up to (not more than) 4 conservative amino acid substitutions, for example up to (not more than) 3 conservative amino acid substitutions, for example up to (not more than) 2 conservative amino acid substitutions, or no more than 1 conservative amino acid substitution. In some embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, contains one or more, including six, CDRs having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the CDRs of an antibody provided herein (see, e.g., those having a VH and a VL shown in Tables 1, 2, 3, or 4). In some embodiments, the conservative sequence modification(s) occur in regions outside the CDRs (e.g., in the FRs and / or constant regions).

[0217] In some embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, contains a VH and a VL comprising CDRs identical to those of an antibody provided herein (see, e.g., those having a VH and a VL shown in Tables 1, 2, 3, or 4). In some embodiments, the amino acid sequence modifications do not include any modification within an SDR. In some embodiments, the amino acid sequence modifications do not include any modification within a CDR (such as CDR1, CDR2, CDR3, or any combination thereof). Additionally or alternatively, the amino acid sequence modifications are in the framework, constant region, and / or fragment crystallizable region (Fc).

[0218] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 19, and / or a VLdomain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:32, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0219] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 19, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:33, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0220] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 19, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:34, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0221] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:32, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantiallymaintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0222] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:33, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0223] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:34, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0224] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:64, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 84, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0225] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:64, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:85, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0226] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:64, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:88, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0227] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:65, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 84, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0228] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:65, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99% sequence identity to the amino acid sequence of SEQ ID NO:85, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0229] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:65, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:88, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0230] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:68, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 84, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0231] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:68, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:85, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0232] In some embodiments, the antibody or fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:68, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:88, and the binding of the antibody or fragment thereof to ILT2 (e.g., human ILT2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0233] In some embodiments, functional epitopes can be mapped, e.g., by combinatorial alanine scanning or hydrogen / deuterium exchange mass spectrometry (HDX-MS), to identify amino acids in the ILT2 protein that are necessary for interaction with ILT2 binding agents (such as antibodies) provided herein. In some embodiments, conformational and crystal structure of ILT2 binding agents (such as antibodies) bound to ILT2 may be employed to identify the epitopes. In some embodiments, the present disclosure provides an antibody that specifically binds to the same epitope as any of the ILT2 binding agents (such as antibodies or fragments thereof) provided herein.

[0234] For example, in some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0235] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:20,and a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0236] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0237] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO: 85.

[0238] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO: 88.

[0239] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0240] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO: 85.

[0241] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO: 88.

[0242] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0243] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO: 85.

[0244] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2,and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) binds to the same epitope as an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO: 88.

[0245] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with any one of the anti-ILT2 antibodies or fragments thereof described herein.

[0246] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0247] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:20, and a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0248] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitivelywith an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0249] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0250] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:64, and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0251] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0252] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0253] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0254] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO:84.

[0255] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO:85.

[0256] In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88. In some embodiments, the ILT2 binding agent provided herein (e.g., an antibody) specifically binds to ILT2 competitively with an anti-ILT2 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:68, and a VL comprising the amino acid sequence of SEQ ID NO:88.

[0257] In some embodiments, the binding agents are superior developability based on a known assay in the art, for example, various chromatographic methods, including sizeexclusion chromatography (SEC), strong-cation exchange chromatography (SCX), hydrophobic interaction chromatography (HIC), standup monolayer adsorption chromatography (SMAC), measurement of UNCLE Poly dispersity Index (PDI), measurement of hydrodynamic diameter, measurement of melting temperature (Tm), measurement of aggregation temperature (Tagg), non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE); reducing SDS-PAGE, and native (nondenaturing) polyacrylamide gel electrophoresis (native PAGE). In some embodiments, the binding agents have superior developability based on measurement of monomer percentage, solubility, and / or antibody aggregation or precipitation.

[0258] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise a heavy chain having a combination of (i) a VH described herein, such as in Tables 1 or 3; and (ii) one or more heavy chain constant domains (e.g., CHI, Hinge, CH2, and CH3). An exemplary IgG heavy chain comprises any VH sequence as described herein and the following CHI, Hinge, CH2, and CH3 amino acid sequence:Another exemplary IgG heavy chain comprises any VH sequence as described herein and the following CHI, Hinge, CH2, and CH3 amino acid sequence:. In further embodiments, the carboxyl terminus (C terminus) of the VH isconjugated directly or indirectly to the amino terminus (N terminus) of the one or more heavy chain constant domains.

[0259] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein further comprise an Fc region. In further embodiments, an ILT2 binding agent disclosed herein comprises an amino acid sequence as set forth in SEQ ID NO: 106. In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein further comprise a variant Fc region. In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein further comprise a variant Fc region having a loss of an effector function. In further embodiments, an ILT2 binding agent disclosed herein comprises a silent Fc. In yet further embodiments, an ILT2 binding agent disclosed herein comprises a variant Fc region that comprises the L234A / L235A / P329K mutations. In some embodiments, an ILT2 binding agent disclosed herein further comprises an amino acid sequence as set forth in SEQ ID NO: 107. In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein further comprise a variant Fc region having a reduced potential immunogenicity. In yet further embodiments, an ILT2 binding agent disclosed herein comprises a variant Fc region that comprises the D356E / E357E / L358M mutations. In some embodiments, an ILT2 binding agent disclosed herein comprises a variant Fc region that comprises the D356E / E357E / L358M mutations and the L234A / L235A / P329K mutations.

[0260] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise a light chain having a combination of (i) a VL domain described herein, such as in Tables 2 or 4; and (ii) a light chain constant domain (CL). An exemplary light chain (e.g., for pairing with an IgG heavy chain) comprises any VL sequence described herein and the following CL amino acid sequence: RTVAAPSVFIFPPSDSQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 94), or RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 109).In further embodiments, the C terminus of the VL is conjugated directly or indirectly to the N terminus of the CL.

[0261] In some embodiments, the binding agent provided herein inhibits the HLA- G / ILT2 binding. In some embodiments, the binding agent provided herein inhibits the HLA- A / ILT2 binding. In some embodiments, the binding agent provided herein inhibits the HLA- B / ILT2 binding. In some embodiments, the binding agent provided herein inhibits the HLA- C / ILT2 binding. Such inhibition can be measured, for example, as detailed in the Examples.

[0262] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise(a) a heavy chain having a combination of (i) a VH described herein, such as in Table 1 or 3, and (ii) one or more heavy chain constant domains (e.g., CH1, Hinge, CH2, and CH3); and(b) a light chain having a combination of (i) a VL described herein, such as in Table 2 or 4, and (ii) a light chain constant domain in an IgG format (CL or CL1). An exemplary ILT2 binding agent (e.g., an antibody) comprises an IgG heavy chain comprising any VH sequence as described herein and the amino acid sequence of SEQ ID NO: 93 or 108, and a light chain comprising any VL sequence as described herein and the amino acid sequence of SEQ ID NO:94 or 109.

[0263] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in any one of Table 5-1, Table 5-2, Table 5-3, Table 5-4, Table 5- 5, and Table 5-6, and (b) a light chain shown in any one of Table 5-1, Table 5-2, Table 5-3, Table 5-4, Table 5-5, and Table 5-6.

[0264] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-1, and (b) a light chain shown in Table 5-1.

[0265] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-2, and (b) a light chain shown in Table 5-2.

[0266] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-3, and (b) a light chain shown in Table 5-3.

[0267] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-4, and (b) a light chain shown in Table 5-4.

[0268] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-5, and (b) a light chain shown in Table 5-5.

[0269] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 5-6, and (b) a light chain shown in Table 5-6.

[0270] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in any one of Table 6-1, Table 6-2, Table 6-3, Table 6-4, Table 6- 5, Table 6-6, Table 6-7, Table 6-8, and Table 6-9, and (b) a light chain shown in any one ofTable 6-1, Table 6-2, Table 6-3, Table 6-4, Table 6-5, Table 6-6, Table 6-7, Table 6-8, and Table 6-9.

[0271] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-1, and (b) a light chain shown in Table 6-1.

[0272] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-2, and (b) a light chain shown in Table 6-2.

[0273] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-3, and (b) a light chain shown in Table 6-3.

[0274] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-4, and (b) a light chain shown in Table 6-4.

[0275] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-5, and (b) a light chain shown in Table 6-5.

[0276] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-6, and (b) a light chain shown in Table 6-6.

[0277] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-7, and (b) a light chain shown in Table 6-7.

[0278] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-8, and (b) a light chain shown in Table 6-8.

[0279] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain shown in Table 6-9, and (b) a light chain shown in Table 6-9.

[0280] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110 or 21, and (b) a light chain comprising the amino acid sequence of any one of SEQ ID NO: 111, 66, and 67.

[0281] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 111.

[0282] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:66.

[0283] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:67.

[0284] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:21, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 111.

[0285] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:21, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:66.

[0286] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:21, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:67.

[0287] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of any one of SEQ ID NO:86, 112 and 114, and (b) a light chain comprising the amino acid sequence of any one of SEQ ID NO:87, 113 and 115.

[0288] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 113.

[0289] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 115.

[0290] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:87.

[0291] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 113.

[0292] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 115.

[0293] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:87.

[0294] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:86, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 113.

[0295] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:86, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 115.

[0296] In some embodiments, ILT2 binding agents (e.g., antibodies such as monospecific or bispecific antibodies), including human ILT2 binding agents, described herein comprise (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:86, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:87.

[0297] In some embodiments, provided herein is an ILT2 binding protein comprising any one of the anti-ILT2 antibodies described herein. In some embodiments, the ILT2 binding protein is an antibody comprising two heavy chains and two light chains. In some embodiments, the ILT2 binding protein is an antibody comprising two heavy chains comprising a same VH region and two light chains comprising a same VL region.

[0298] In some embodiments, the ILT2 binding protein is a monoclonal antibody, including a mouse, chimeric, humanized or human antibody. In some embodiments, the anti- ILT2 antibody is an antibody fragment, e.g., an scFv. In some embodiments, the ILT2 binding protein is a fusion protein comprising the anti-ILT2 antibody provided herein. In other embodiments, the ILT2 binding protein is a multispecific antibody comprising the anti- ILT2 antibody or fragment thereof provided herein.

[0299] Other exemplary ILT2 binding molecules are described in more detail in the following sections. In some embodiments, the anti-ILT2 antibody or antigen-binding protein according to any of the above embodiments may incorporate any of the features, singly or in combination, as described in Sections 5.2.1 to 5.2.4 below.Table 1: Antibody Clone Ab101 VH and VariantsTable 2: Antibody Clone Ab101 VL and VariantsTable 3: Antibody Clone Ab121 / Ab125 VH and VariantsTable 3 (continued)Table 4: Antibody Clone Ab121 / Ab125 VL and VariantsTable 5-1: Full-Length Heavy and Light Chain Sequences of Antibody Clone Ab101Table 5-2: Full-Length Heavy and Light Chain Sequences of Variant 101-VH0 / 101-VL1 of Antibody Clone Ab101 (Ab101-01)Table 5-3: Full-Length Heavy and Light Chain Sequences of Variant 101-VH0 / 101-VL2 of Antibody Clone Ab101 (Ab101-02)Table 5-4: Full-Length Heavy and Light Chain Sequences of Variant 101-VH1 / 101-VL0 of Antibody Clone Ab101 (Ab101-10)Table 5-5: Full-Length Heavy and Light Chain Sequences of Variant 101-VH1 / 101-VL1 of Antibody Clone Ab101 (Ab101-ll)Table 5-6: Full-Length Heavy and Light Chain Sequences of Variant 101-VH1 / 101-VL2 of Antibody Clone Ab101 (Ab101-12)Table 6-1: Full-Length Heavy and Light Chain Sequences of Antibody Clone Ab121Table 6-2: Full-Length Heavy and Light Chain Sequences of Antibody Clone Ab125Table 6-3: Full-Length Heavy and Light Chain Sequences of Variant 121-VH0 / 125-VL0 (Ab12x-15)Table 6-4: Full-Length Heavy and Light Chain Sequences of Variant 121-VH0 / 12x-VL3 (Ab12x-13)Table 6-5: Full-Length Heavy and Light Chain Sequences of Variant 125-VH0 / 121-VL0 (Ab12x-51)Table 6-6: Full-Length Heavy and Light Chain Sequences of Variant 125-VH0 / 12x-VL3 (Ab12x-53)Table 6-7: Full-Length Heavy and Light Chain Sequences of Variant 12x-VH3 / 121-VL0 (Ab12x-31)Table 6-8: Full-Length Heavy and Light Chain Sequences of Variant 12x-VH3 / 125-VL0 (Ab12x-35)Table 6-9: Full-Length Heavy and Light Chain Sequences of Variant 12x-VH3 / 12x-VL3 (Ab12x-33)5.2.1. Antibody Fragments

[0300] Even though the term “antibody” is sometimes used in a phrase of “antibody or fragment thereof’ herein, it should be understood the term “antibody” as used herein also includes various antibody fragments, such as an antigen-binding fragment or epitope-binding fragment. Thus, when the term “antibody” is used alone without being followed by “fragment thereof’ or similar terms, it should be understood the term “antibody” includes an antibody fragment, such as an antigen-binding fragment or epitope-binding fragment. Antibodies provided herein include, but are not limited to, immunoglobulin molecules and immunologically active portions of immunoglobulin molecules.

[0301] Variants and derivatives of antibodies include antibody functional fragments that retain the ability to bind to an antigen. Antibody fragments include but are not limited to those described in Section 5.1 above. Exemplary functional fragments include Fab fragments (e.g., an antibody fragment that contains the antigen-binding domain and comprises a light chain and part of a heavy chain bridged by a disulfide bond); Fab’ (e.g., an antibody fragment containing a single antigen-binding domain comprising an Fab and an additional portion of the heavy chain through the hinge region); F(ab')2(e.g., two Fab’ molecules joined by interchain disulfide bonds in the hinge regions of the heavy chains; the Fab’ molecules may be directed toward the same or different epitopes); a bispecific Fab (e.g., a Fab molecule having two antigen-binding domains, each of which may be directed to a different epitope); a single chain comprising a variable region, also known as, scFv (e.g., the variable, antigen- binding determinative region of a single light and heavy chain of an antibody linked together by a chain of, e.g., 10-25 amino acids); a disulfide-linked Fv, or dsFv (e.g., the variable, antigen-binding determinative region of a single light and heavy chain of an antibody linked together by a disulfide bond); a bispecific scFv (e.g., an scFv or a dsFv molecule having two antigen-binding domains, each of which may be directed to a different epitope); a diabody (e.g., a dimerized scFv formed when the VH domain of a first scFv assembles with the VL domain of a second scFv and the VL domain of the first scFv assembles with the VH domain of the second scFv; the two antigen-binding regions of the diabody may be directed towards the same or different epitopes); a triabody (e.g., a trimerized scFv, formed in a manner similar to a diabody, but in which three antigen-binding domains are created in a single complex; the three antigen-binding domains may be directed towards the same or different epitopes); and a tetrabody (e.g., a tetramerized scFv, formed in a manner similar to a diabody, but in which four antigen-binding domains are created in a single complex; the four antigen- binding domains may be directed towards the same or different epitopes).

[0302] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al.. 1992, J. Biochem. Biophys. Methods 24: 107-17; and Brennan et aL, 1985, Science 229:81-83). However, these fragments can now be produced directly by recombinant host cells. For example, Fab, Fv, and scFv antibody fragments can all be expressed in and secreted from E. coli, yeast or insect cells, thus allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2fragments (Carter et al., 1992, Bio / Technology 10:163-67). According to another approach, F(ab')2fragments can be isolated directly from recombinant host cell culture. Fab and F(ab')2fragments with increased in vivo half-life comprising salvage receptor binding epitope residues are described in, for example, U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner. In certain embodiments, an antibody is a single chain Fv fragment (scFv) (see, e.g., WO 93 / 16185; U.S. Pat. Nos. 5,571,894 and 5,587,458). Fv and scFv have intact combining sites that are devoid of constant regions; thus, they may be suitable for reduced nonspecific binding during in vivo use. scFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an scFv (See, e.g., Borrebaeck ed., supra). The antibody fragment may also be a “linear antibody,” for example, as described in the references cited above. Such linear antibodies may be monospecific or multi-specific, such as bispecific.5.2.2. Humanized Antibodies

[0303] The present disclosure provides humanized antibodies that bind ILT2, including human ILT2. Humanized antibodies of the present disclosure may comprise one or more CDRs from a VH and / or VL disclosed herein, such as those as shown in Tables 1-4. Various methods for humanizing non-human antibodies are known in the art. For example, a humanized antibody can have one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanized antibodies that bind ILT2 may be produced using techniques known to those skilled in the art (Zhang et al., Molecular Immunology, 42(12): 1445-1451, 2005; Hwang et al., Methods, 36(1): 35-42, 2005; Dall’Acqua et al., Methods, 36(1): 43-60, 2005; Clark, Immunology Today, 21(8): 397-402, 2000, and U.S. Pat. Nos. 6,180,370; 6,054,927; 5,869,619; 5,861,155; 5,712,120; and 4,816,567).

[0304] In some cases, the humanized antibodies are constructed by CDR grafting, in which the amino acid sequences of the six CDRs of a VH and a VL of the parent non-human antibody (e.g., rodent) are grafted onto a human antibody framework. For example, Padlan et al. (FASEB J. 9: 133-139, 1995) determined that only about one third of the residues in the CDRs actually contact the antigen, and termed these the “specificity determining residues,” or SDRs. In the technique of SDR grafting, only the SDR residues are grafted onto the human antibody framework (see, e.g., Kashmiri et al.. Methods 36: 25-34, 2005).

[0305] The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies can be important to reduce antigenicity. For example, according to the so-called “best-fit” method, the sequence of the variable domain of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable-domain sequences. The human sequence which is closest to that of the rodent may be selected as the human framework for the humanized antibody (Sims et al., (1993) J. Immunol. 151 :2296; Chothia e / a / . (1987) J. Mol. Biol. 196:901). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (Carter et al., (1992) Proc. Natl. Acad. Sci. USA, 89:4285; Presta e / o / . (1993) J. Immunol., 151 :2623). In some cases, the framework is derived from the consensus sequences of the most abundant human subclasses, VL6 subgroup I (VL6I) and VH subgroup III (VHIII). In another method, human germline genes are used at the source of the framework regions.

[0306] In an alternative paradigm based on comparison of CDRs, called Superhumanization, framework homology is irrelevant. The method consists of comparison of the non-human sequence with the functional human germline gene repertoire. Those genes encoding the same or closely related canonical structures to the murine sequences are then selected. Next, within the genes sharing the canonical structures with the non-human antibody, those with highest homology within the CDRs are chosen as framework donors. Finally, the non-human CDRs are grafted onto these frameworks (see, e.g., Tan et al, J. Immunol. 169: 1119-1125, 2002).

[0307] It is further generally desirable that antibodies be humanized with retention of their affinity for the antigen and other favorable biological properties. To achieve this goal, according to one method, humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulinmodels are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. These include, for example, WAM (Whitelegg and Rees, Protein Eng. 13: 819-824, 2000), Modeller (Sali and Blundell, J. Mol. Biol. 234: 779-815, 1993), and Swiss PDB Viewer (Guex and Peitsch, Electrophoresis 18: 2714-2713, 1997). Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, framework residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the hypervariable region residues are directly and most substantially involved in influencing antigen binding.

[0308] Another method for antibody humanization is based on a metric of antibody humanness termed Human String Content (HSC). This method compares the mouse sequence with the repertoire of human germline genes and the differences are scored as HSC. The target sequence is then humanized by maximizing its HSC rather than using a global identity measure to generate multiple diverse humanized variants. See, e.g., Lazar et al., Mol. Immunol. 44: 1986-1998, 2007.

[0309] In addition to the methods described above, empirical methods may be used to generate and select humanized antibodies. These methods include those that are based upon the generation of large libraries of humanized variants and selection of the best clones using enrichment technologies or high throughput screening techniques. Antibody variants may be isolated from phage, ribosome and yeast display libraries as well as by bacterial colony screening (see, e.g., Hoogenboom, Nat. Biotechnol. 23: 1105-1116, 2005; Dufner et al., Trends Biotechnol. 24: 523-529, 2006; Feldhaus et al., Nat. BiotechnoL 21 : 163-70, 2003; Schlapschy et al., Protein Eng. Des. SeL 17: 847-60, 2004).

[0310] In the framework library approach, a collection of residue variants are introduced at specific positions in the framework followed by selection of the library to select the framework that best supports the grafted CDR. The residues to be substituted may include some or all of the “Vernier” residues identified as potentially contributing to CDR structure (see, e.g., Foote and Winter, J. Mol. Biol. 224: 487-499, 1992), or from the more limited set of target residues identified by Baca et al. (J. Biol. Chem. 272: 10678-10684, 1997).

[0311] In framework shuffling, whole frameworks are combined with the non-human CDRs instead of creating combinatorial libraries of selected residue variants (see, e.g.,Dall’ Acqua et al., Methods 36: 43-60, 2005). The libraries may be screened for binding in a two-step selection process, first humanizing VL, followed by VH. Alternatively, a one-step framework shuffling process may be used. Such a process has been shown to be more efficient than the two-step screening, as the resulting antibodies exhibited improved biochemical and physico-chemical properties including enhanced expression, increased affinity and thermal stability (see, e.g., Damschroder et al., Mol. Immunol. 44: 3049-60, 2007).

[0312] The “humaneering” method is based on experimental identification of essential minimum specificity determinants (MSDs) and is based on sequential replacement of non- human fragments into libraries of human frameworks and assessment of binding. It begins with regions of the CDR3 of non-human VH and VL chains and progressively replaces other regions of the non-human antibody into the human frameworks, including the CDR1 and CDR2 of both VH and VL. This methodology typically results in epitope retention and identification of antibodies from multiple sub-classes with distinct human V-segment CDRs. Humaneering allows for isolation of antibodies that are 91-96 % homologous to human germline gene antibodies. See, e.g., Alfenito, Cambridge Healthtech Institute’s Third Annual PEGS, The Protein Engineering Summit, 2007.

[0313] The "human engineering" method involves altering a non-human antibody or antibody fragment, such as a mouse or chimeric antibody or antibody fragment, by making specific changes to the amino acid sequence of the antibody so as to produce a modified antibody with reduced immunogenicity in a human that nonetheless retains the desirable binding properties of the original non-human antibodies. Generally, the technique involves classifying amino acid residues of a non-human (e.g., mouse) antibody as “low risk”, “moderate risk”, or “high risk” residues. The classification is performed using a global risk / reward calculation that evaluates the predicted benefits of making a particular substitution (e.g., for immunogenicity in humans) against the risk that the substitution will affect the resulting antibody’s folding and / or are substituted with human residues. The particular human amino acid residue to be substituted at a given position (e.g., low or moderate risk) of a non-human (e.g., mouse) antibody sequence can be selected by aligning an amino acid sequence from the non-human antibody’s variable regions with the corresponding region of a specific or consensus human antibody sequence. The amino acid residues at low or moderate risk positions in the non-human sequence can be substituted for the corresponding residues in the human antibody sequence according to the alignment. Techniques for making human engineered proteins are described in greater detail inStudnicka et aL, Protein Engineering, 7: 805-814 (1994), U.S. Pat. Nos. 5,766,886, 5,770,196, 5,821,123, and 5,869,619, and WO 93 / 11794.5.2.3. Antibody Variants

[0314] Modifications of the antibodies that bind to ILT2 described herein are contemplated. For example, it may be desirable to optimize the binding affinity and / or other biological properties of the antibody, including but not limited to specificity, thermostability, expression level, effector functions, glycosylation, reduced immunogenicity, or solubility. Thus, it is contemplated that variants of the antibodies that bind to ILT2 described herein can be prepared and are included in the present disclosure. In some embodiments, antibody variants are antibodies with amino acid sequence variations as compared with the original antibody, for example, substitution, deletion, or insertion of one or more amino acid(s), as described above. For example, variations may be a substitution, deletion, or insertion of one or more codons encoding the antibody or polypeptide that results in a change in the amino acid sequence (e.g., a conservative substitution) as compared with the original antibody or polypeptide. Sites of interest for substitutional mutagenesis include the CDRs, FRs and / or constant regions. For example, antibody variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA, and / or by synthesis of the desired antibody or polypeptide. Those skilled in the art who appreciate that amino acid changes may alter post- translational processes of the antibody.Chemical Modifications

[0315] Other exemplary modifications include chemical modifications, for example, by the covalent attachment of any type of molecule to the antibody. Antibody derivatives may include antibodies that have been chemically modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, or conjugation to one or more immunoglobulin domains (e.g., Fc or a portion of an Fc). Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. Additionally, the antibody may contain one or more non-classical amino acids.

[0316] In some embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion ofglycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0317] When the antibody provided herein is fused to an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in the binding molecules provided herein may be made in order to create variants with certain improved properties.

[0318] In other embodiments, when the antibody provided herein is fused to an Fc region, antibody variants provided herein may have a carbohydrate structure that lacks fucose attached (directly or indirectly) to said Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65%, or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., U.S. Pat. Publ. Nos. 2003 / 0157108 and 2004 / 0093621. Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: U.S. Pat. Publ. No. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. Pat. Publ. No. 2003 / 0115614; U.S. Pat. Publ. No. 2002 / 0164328; U.S. Pat. Publ. No. 2004 / 0093621; U.S. Pat. Publ. No.2004 / 0132140; U.S. Pat. Publ. No. 2004 / 0110704; U.S. Pat. Publ. No. 2004 / 0110282; U.S. Pat. Publ. No. 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki et al. J. Mol. Biol. 336: 1239- 1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lecl3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Pat. Publ. No. 2003 / 0157108; and WO 2004 / 056312, and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003 / 085107).

[0319] The binding molecules comprising an antibody provided herein are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region is bisected by GlcNAc. Such variants may have reduced fucosylation and / or improved ADCC function. Examples of such variants are described, e.g., in WO 2003 / 011878 (Jean-Mairet et al.}, U.S. Pat. No. 6,602,684 (Umana et al. ), and U.S. Pat. Publ. No. 2005 / 0123546 (Umana et al.). Variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such variants may have improved CDC function. Such variants are described, e.g., in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.

[0320] In molecules that comprise the present antibody and an Fc region, one or more amino acid modifications may be introduced into the Fc region, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.

[0321] In some embodiments, the present application contemplates variants that possess some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the binding molecule in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the binding molecule lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166: 1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96® non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, oradditionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat ’I Acad. Sci. USA 95:652-656 (1998). Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano- Santoro et al., J. Immunol. Methods 202: 163 (1996); Cragg, M.S. et al., Blood 101 : 1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al, Int’l. Immunol. 18(12): 1759-1769 (2006)).

[0322] Binding molecules with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581).

[0323] Certain variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)

[0324] In some embodiments, a variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues). In some embodiments, alterations are made in the Fc region that result in altered (e.g., either improved or diminished) Clq binding and / or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[0325] Binding molecules with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al.). Those molecules comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371,826). See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821; and WO 94 / 29351 concerning other examples of Fc region variants.

[0326] In some embodiments, it may be desirable to create cysteine engineered antibodies, in which one or more residues of an antibody are substituted with cysteine residues. In some embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein.

[0327] Other known covalent modifications of antibodies are included within the scope of the present disclosure. Covalent modifications include reacting targeted amino acid residues of an antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the antibody. Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (see, e.g., Creighton, Proteins: Structure and Molecular Properties 79-86 (1983)), acetylation of the N-terminal amine, and amidation of any C- terminal carboxyl group.

[0328] The antibody that binds to ILT2 of the present disclosure may also be modified to form chimeric molecules comprising the antibody that binds to ILT2 fused or conjugated to another, heterologous polypeptide or amino acid sequence or a small molecule compound, for example, an immune activator (such as a cytokine), an epitope tag (see, e.g., Terpe, Appl. Microbiol. Biotechnol. 60:523-33 (2003)) or the Fc region of an IgG molecule (see, e.g., Aruffo, Antibody Fusion Proteins 221-42 (Chamow and Ashkenazi eds., 1999)).

[0329] Also provided herein are fusion proteins comprising the antibody that binds to ILT2 of the disclosure and a heterologous polypeptide. In some embodiments, the heterologous polypeptide to which the antibody is genetically fused or chemically conjugated is useful for targeting the antibody to cells having cell surface-expressed ILT2. Genetically fused or chemically conjugated antibodies are described in more detail in sections below.In vitro Affinity Maturation

[0330] In some embodiments, antibody variants having an improved property such as affinity, stability, or expression level as compared to a parent antibody may be prepared by in vitro affinity maturation. Like the natural prototype, in vitro affinity maturation is based on the principles of mutation and selection. Libraries of antibodies are displayed on the surfaceof an organism (e.g., phage, bacteria, yeast, or mammalian cell) or in association (e.g., covalently or non-covalently) with their encoding mRNA or DNA. Affinity selection of the displayed antibodies allows isolation of organisms or complexes carrying the genetic information encoding the antibodies. Two or three rounds of mutation and selection using display methods such as phage display usually results in antibody fragments with affinities in the low nanomolar range. Affinity matured antibodies can have nanomolar or even picomolar affinities for the target antigen.

[0331] Phage display is a widespread method for display and selection of antibodies. The antibodies are displayed on the surface of Fd or M13 bacteriophages as fusions to the bacteriophage coat protein. Selection involves exposure to antigen to allow phage-displayed antibodies to bind their targets, a process referred to as “panning.” Phage bound to antigen are recovered and used to infect bacteria to produce phage for further rounds of selection. For review, see, for example, Hoogenboom, Methods. Mol. Biol. 178: 1-37 (2002); and Bradbury and Marks, J. Immunol. Methods 290:29-49 (2004).

[0332] In a yeast display system (see, e.g, Boder et al., Nat. Biotech. 15:553-57 (1997); and Chao et al., Nat. Protocols 1 :755-68 (2006)), the antibody may be fused to the adhesion subunit of the yeast agglutinin protein Aga2p, which attaches to the yeast cell wall through disulfide bonds to Agalp. Display of a protein via Aga2p projects the protein away from the cell surface, minimizing potential interactions with other molecules on the yeast cell wall. Magnetic separation and flow cytometry are used to screen the library to select for antibodies with improved affinity or stability. Binding to a soluble antigen of interest is determined by labeling yeast with biotinylated antigen and a secondary reagent such as streptavidin conjugated to a fluorophore. Variations in surface expression of the antibody can be measured through immunofluorescence labeling of either the hemagglutinin or c-Myc epitope tag flanking the single-chain antibody (e.g., scFv). Expression has been shown to correlate with the stability of the displayed protein, and thus antibodies can be selected for improved stability as well as affinity (see, e.g., Shusta et al., J. Mol. Biol. 292:949-56 (1999)). An additional advantage of yeast display is that displayed proteins are folded in the endoplasmic reticulum of the eukaryotic yeast cells, taking advantage of endoplasmic reticulum chaperones and quality-control machinery. Once maturation is complete, antibody affinity can be conveniently “titrated” while displayed on the surface of the yeast, eliminating the need for expression and purification of each clone. A theoretical limitation of yeast surface display is the potentially smaller functional library size than that of other display methods; however, a recent approach uses the yeast cells’ mating system to create combinatorialdiversity estimated to be 1014in size (see, e.g., U.S. Pat. Publ. No. 2003 / 0186374; and Blaise et al., Gene 342:211-18 (2004)).

[0333] In ribosome display, antibody-ribosome-mRNA (ARM) complexes are generated for selection in a cell-free system. The DNA library coding for a particular library of antibodies is genetically fused to a spacer sequence lacking a stop codon. This spacer sequence, when translated, is still attached to the peptidyl tRNA and occupies the ribosomal tunnel, and thus allows the protein of interest to protrude out of the ribosome and fold. The resulting complex of mRNA, ribosome, and protein can bind to surface-bound ligand, allowing simultaneous isolation of the antibody and its encoding mRNA through affinity capture with the ligand. The ribosome-bound mRNA is then reverse transcribed back into cDNA, which can then undergo mutagenesis and be used in the next round of selection (see, e.g., Fukuda et al., Nucleic Acids Res. 34:el27 (2006)). In mRNA display, a covalent bond between antibody and mRNA is established using puromycin as an adaptor molecule (Wilson et al., Proc. Natl. Acad. Sci. USA 98:3750-55 (2001)).

[0334] As these methods are performed entirely in vitro, they provide two main advantages over other selection technologies. First, the diversity of the library is not limited by the transformation efficiency of bacterial cells, but only by the number of ribosomes and different mRNA molecules present in the test tube. Second, random mutations can be introduced easily after each selection round, for example, by non-proofreading polymerases, as no library must be transformed after any diversification step. In some embodiments, mammalian display systems may be used.

[0335] Diversity may also be introduced into the CDRs of the antibody libraries in a targeted manner or via random introduction. The former approach includes sequentially targeting all the CDRs of an antibody via a high or low level of mutagenesis or targeting isolated hot spots of somatic hypermutations (see, e.g., Ho et al., J. Biol. Chem. 280:607-17 (2005)) or residues suspected of affecting affinity on experimental basis or structural reasons. Diversity may also be introduced by replacement of regions that are naturally diverse via DNA shuffling or similar techniques (see, e.g., Lu et al., J. Biol. Chem. 278:43496-507 (2003); U.S. Pat. Nos. 5,565,332 and 6,989,250). Alternative techniques target hypervariable loops extending into framework-region residues (see, e.g., Bond et al., J. Mol. Biol. 348:699- 709 (2005)) employ loop deletions and insertions in CDRs or use hybridization-based diversification (see, e.g., U.S. Pat. Publ. No. 2004 / 0005709). Additional methods of generating diversity in CDRs are disclosed, for example, in U.S. Pat. No. 7,985,840. Further methods that can be used to generate antibody libraries and / or antibody affinity maturationare disclosed, e.g., in U.S. Pat. Nos. 8,685,897 and 8,603,930, and U.S. Publ. Nos. 2014 / 0170705, 2014 / 0094392, 2012 / 0028301, 2011 / 0183855, and 2009 / 0075378, each of which is incorporated herein by reference.

[0336] Screening of the libraries can be accomplished by various techniques known in the art. For example, antibodies can be immobilized onto solid supports, columns, pins, or cellulose / poly (vinylidene fluoride) membranes / other filters, expressed on host cells affixed to adsorption plates or used in cell sorting, or conjugated to biotin for capture with streptavidin-coated beads or used in any other method for panning display libraries.

[0337] For reviews of in vitro affinity maturation methods, see, e.g., Hoogenboom, Nature Biotechnology 23 : 1105-16 (2005); Quiroz and Sinclair, Revista Ingeneria Biomedia 4:39-51 (2010); and references therein.

[0338] An antibody internalization assay may be used to determine receptor-mediated endocytosis when binding to an antibody. In some embodiments, the efficacy of certain antibody-based therapeutics depends on antibody internalization process. In some embodiments, an antibody internalization assay examines the rate and extent of antibody internalization in order to evaluate the antibody’s ability of delivering treatments to sites or cells of interest. A non-limiting exemplary assay is briefly described below. Target cells of interest are seeded at an appropriate seeding density (e.g., in a 96-well U-bottom plate), and a tested antibody is labelled with a signal reporting reagent, for example, fluorescent compounds, Horseradish peroxidase (HRP) reagent, radiolabeled compounds, or biotin. Then the tested antibody and the target cells are incubated at an appropriate molar ratio. Following the incubation, unbound antibodies are removed by wash. The cells can be left on ice or incubated at 37°C for a period of time to facilitate internalization. The cells may then be incubated for a period of time in the presence of a stop reagent to inhibit internalization. Subsequently, the cells are washed and incubated with the signal developing reagent. The final signal can be studied using plate reader or imaging instrument and an analytical software. For example, mean fluorescence intensity (MFI) of the cells can be measured using a flow cytometer, and MFI reduction can represent antibody internalization, antibody dissociation or a combination of both. Cell imaging can be scanned and acquired to analyze the signal intensity, size and shape. Alternatively, the cells are lysed, releasing internalized antibody. This antibody is then captured in a microtiter well plate coated with specific antigen against which the antibody was raised. Bound antibody in the well is detected using an alkaline phosphatase or HRP-conjugated secondary antibody and a chromogenic substrate. Alternative detectable labels for the antibody and means for detecting internalized labeledantibody will be obvious to those skilled in the art upon this disclosure. Any methods known in the art to determine antibody internalization can be used in the present disclosure.5.2.4. Other Binding Agents Comprising the Antibodies

[0339] In some embodiments, the antibody or fragment thereof provided herein is a part of a larger binding agent. Non-limiting exemplary binding agents comprising the antibody or fragment provided herein are described below.

[0340] The present disclosure provides ILT2 binding agents (e.g., antibodies) with a masking moiety and / or cleavable moiety in which one or more of the ILT2 binding domains of the ILT2 binding agent (e.g., antibody) are masked (e.g., via a masking moiety) and / or activatable (e.g., via a cleavable moiety). Technologies for masking of an ILT2 binding agent (e.g., an antibody) are well known in the art, including SAFEbody masking technology (see, e.g., U.S. Pat. Publ. No. 2019 / 0241886) and Probody masking technology (see, e.g., U.S. Pat. Publ. No. 2015 / 0079088). Such technologies can be used to generate an ILT2 binding agent (e.g., an antibody) that is masked and / or activatable. Such masked and / or activatable ILT2 binding agents (e.g, antibodies) are also useful for the preparation of conjugates, including immunoconjugates, antibody-drug conjugates (ADCs), masked ADCs and activatable ADCs (AADCs), comprising any one of the ILT2 binding agents (e.g., antibodies), such as human ILT2 binding agents, of the present disclosure, including those directly or indirectly linked another agent such as a drug and / or an immune activator (such as a cytokine). For example, ILT2 binding agents (e.g., antibodies), such as human ILT2 binding agents, of the present disclosure may be covalently bound by a synthetic linker to one or more agents such as drugs and / or immune activators (such as cytokines).

[0341] If desired, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, is linked or conjugated (directly or indirectly) to a moiety with effector function, such as cytotoxic activity (e.g., a chemotherapeutic moiety or a radioisotope), immune recruitment or modulating activity. Moieties that are linked or conjugated (directly or indirectly) include drugs that are cytotoxic (e.g., toxins such as aurostatins) or non- cytotoxic, e.g., signal transduction modulators such as kinases or masking moieties that mask one or more binding domains of an ILT2 binding agent (e.g., antibody), or cleavable moieties that allow for activating an ILT2 binding agent by cleaving off a cleavable moiety to unmask one or more binding domains of an ILT2 binding agent (e.g., antibody) in the tumor microenvironment in the form of masked conjugates. Moieties that promote immune recruitment can include other antigen-binding agents, such as viral proteins that bind selectively to cells of the innate and / or adaptive immune system. Alternatively or in addition,an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, is optionally linked or conjugated (directly or indirectly) to a moiety that facilitates isolation from a mixture (e.g., a tag) or a moiety with reporter activity (e.g., a detection label or reporter protein). It will be appreciated that the features of an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein extend also to a polypeptide comprising an ILT2 binding agent fragment.

[0342] In some embodiments, ILT2 binding agents (e.g., antibodies), including ILT2 binding agents, described herein which bind to human ILT2, may be linked or conjugated (directly or indirectly) to a polypeptide, which can result in the generation of an activatable antibody. In some embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, is linked or conjugated (directly or indirectly) to an additional agent. In some embodiments, the additional agent is a drug, resulting in an ADC or an AADC when the antibody of the ADC comprises a masking moiety and a cleavable moiety.

[0343] In some embodiments, ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, described herein are conjugated or recombinantly linked (directly or indirectly) to a therapeutic agent (e.g., a cytotoxic agent or a cytokine) or to a diagnostic or detectable agent. The conjugated or recombinantly linked antibodies, including masked or activatable conjugates, can be useful, for example, for treating or preventing a disease, disorder or condition such as an ILT2-mediated disease, disorder or condition. The conjugated or recombinantly linked ILT2 binding agents (e.g., antibodies), including masked or activatable conjugates, can be useful, for example, for monitoring or prognosing the onset, development, progression, and / or severity of an ILT2-mediated disease, disorder or condition.

[0344] Such diagnosis and detection can be accomplished, for example, by coupling an ILT2 binding agent (e.g., an antibody) to detectable substances including, for example: enzymes, including, but not limited to, horseradish peroxidase, alkaline phosphatase, betagalactosidase, or acetylcholinesterase; prosthetic groups, including, but not limited to, streptavidin / biotin or avidin / biotin; fluorescent materials, including, but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; luminescent materials, including, but not limited to, luminol; bioluminescent materials, including, but not limited to, luciferase, luciferin, or aequorin; chemiluminescent material, including, but not limited to, an acridinium based compound or a HALOTAG; radioactive materials, including, but not limited to, iodine (131I,125I,123I, and121I), carbon (14C), sulfur (35S), tritium (3H), indium (115In,113In,112In, andH 1In), technetium (99Tc), thallium (201Ti), gallium (68Ga and67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F),153Sm,177Lu,159Gd,149Pm,140La,175Yb,166HO,90Y,47SC,186Re,188Re,142Pr,105Rh,97Ru,68Ge,57Co,65Zn,85Sr,32P,153Gd,169Yb,51Cr,54Mn,75Se,113Sn, or117Sn; positron emitting metals using various positron emission tomographies; and non-radioactive paramagnetic metal ions.

[0345] Also described herein are ILT2 binding agents (e.g., antibodies) that are recombinantly linked or conjugated (covalent or non-covalent conjugations, directly or indirectly) to a heterologous protein or polypeptide or fragment thereof, for example, to a polypeptide (e.g., of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acids) to generate fusion proteins, as well as uses thereof. In particular, described herein are fusion proteins comprising an antigen-binding fragment of an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein (e.g., comprising CDR1, CDR2, and / or CDR3 of VH and / or VL) and a heterologous protein, polypeptide, or peptide. In some embodiments, the heterologous protein, polypeptide, or peptide that an ILT2 binding agent (e.g., an antibody) is linked to is useful for targeting the ILT2 binding agent to a particular cell (e.g., an ILT2-expressing cell, including an immune cell). Other non-limiting heterologous protein, polypeptide, or peptide that an ILT2 binding agent (e.g., an antibody) is linked to can be useful as an internalization signal or engaging a tumor cell with an immune cell.

[0346] Moreover, ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, described herein can be linked (directly or indirectly) to marker or “tag” sequences, such as a peptide, to facilitate purification. In some embodiments, the marker or tag amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (see, e.g., QIAGEN, Inc.), among others, many of which are commercially available. For example, as described in Gentz et al., 1989, Proc. Natl. Acad. Sci. USA 86:821-24, hexa-histidine provides for convenient purification of a fusion protein. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin (“HA”) tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767-78), and the “FLAG” tag.

[0347] Methods for linking or conjugating (directly or indirectly) moieties (including polypeptides) to antibodies are well known in the art, any one of which can be used to make an antibody-drug conjugate or fusion protein described herein.

[0348] In some embodiments, an ILT2 binding agent (e.g., an antibody) described herein is a fusion protein. The term “fusion protein” as used herein refers to a polypeptide thatcomprises an amino acid sequence of a binding agent (e.g., an antibody) and an amino acid sequence of a heterologous polypeptide or protein (e.g., a polypeptide or protein not normally a part of the antibody). In certain embodiments, the fusion protein retains the biological activity of an ILT2 binding agent. In certain embodiments, the fusion protein comprises an ILT2 antibody VH region, VL region, VH CDR (one, two or three VH CDRs), and / or VL CDR (one, two or three VL CDRs), wherein the fusion protein binds to an ILT2 epitope, an ILT2 fragment and / or an ILT2 polypeptide. In some embodiments, a fusion protein comprises a VH or heavy chain of an ILT2 antibody, a VL or light chain of an ILT2 antibody, separated by a linker, such as a cleavable linker.

[0349] Fusion proteins may be generated, for example, through the techniques of geneshuffling, motif-shuffling, exon-shuffling, and / or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to alter the activities of ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, as described herein, including, for example, ILT2 binding agents with higher affinities and lower dissociation rates (see, e.g., U.S. Pat. Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458; Patten et al., 1997, Curr. Opinion Biotechnol. 8:724-33; Harayama, 1998, Trends Biotechnol. 16(2):76-82; Hansson et al., 1999, J. Mol. Biol. 287:265-76; and Lorenzo and Blasco, 1998, Biotechniques 24(2):308-13). In some embodiments, ILT2 binding agents, including human ILT2 binding agents, may be altered by being subjected to random mutagenesis by error- prone PCR, random nucleotide insertion, or other methods prior to recombination. A polynucleotide encoding an ILT2 binding agent described herein may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[0350] ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, described herein may also be attached to solid supports, which are useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

[0351] ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, described herein can also be linked or conjugated (directly or indirectly) to a second antibody to form an antibody heteroconjugate.

[0352] The linker may be a “cleavable moiety” facilitating release of the linked or conjugated agent in a cell, but non-cleavable linkers are also contemplated herein. Linkers for use in conjugates (e.g., ADCs or AADCs) of the present disclosure include, without limitation, acid labile linkers (e.g., hydrazone linkers), disulfide-containing linkers,peptidase-sensitive linkers (e.g., peptide linkers comprising amino acids, for example, valine and / or citrulline such as citrulline-valine or phenylalanine-lysine), photolabile linkers, dimethyl linkers, thioether linkers, or hydrophilic linkers designed to evade multidrug transporter-mediated resistance.

[0353] Conjugates of an antibody and agent, including wherein the agent is a drug for the preparation of ADC or an AADC, may be made using a variety of bifunctional protein coupling agents such as N-(P-maleimidopropyloxy)succinimide ester (BMPS); N-e- malemidocaproyl-oxysuccinimide ester (ECMS); N-y-malemidocaproyl-oxysuccinimide ester (GMBS); 1,6-hexane-bis-vinylsulfone (HBVS); succinimidyl 4(-N- maleimidomethyl)cyclohexane-1-carboxy-(6-amidocaproate)) (LC-SMCC); m- maleimidobenzoyl-N-hydroxy succinimide ester (MBS); 4-(4-N-maleimidophenyl)butyric acid hydrazide (MPBH); succinimidil 3 -(bromoacetamido) propionate (SBAP); succinimidyl iodoacetate (SIA); succinimidyl (4-iodoacetyl)aminobenzoate (SIAB); succinimidyl-4-(N- maleimidomethyl)cyclohexane-1-carboxylate (SMCC); succinimidyl 4-(p-maleimido- phenyl)butyrate (SMPB); succinimidyl-6-(P-maleimidopropionamido)hexanoate (SMPH); N- (s-maleimidocaproyloxy)sulfosuccinimide ester (sulfo-ECMS); N-(y- maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS); N-(K- maleimidoundecanoyloxy)sulfosuccinimide ester (sulfo-KMUS); m-maleimidobenzoyl-N- hydroxy sulfosuccinimide ester (sulfo-MBS); sulfosuccinimidyl(4-iodo-acetyl)aminobenzoate (sulfo-SIAB); sulfosuccinimidyl 4-(N-maleimido-methyl)cyclohexane-1-carboxylate (sulfo- SMCC); sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (sulfo-SMPB); and succinimidyl- (4-vinylsulfone)benzoate) (SVSB).

[0354] The present disclosure further contemplates conjugates of antibodies and agents, including wherein the agent is a drug for the preparation of ADC or AADC, may be prepared using any suitable methods as disclosed in the art (see, e.g., Bioconjugate Techniques (Hermanson ed., 2d ed. 2008)).

[0355] Conventional conjugation strategies for antibodies and agents, including wherein the agent is a drug for the preparation of ADC or AADC, have been based on random conjugation chemistries involving the 8-amino group of Lys residues or the thiol group of Cys residues, which results in heterogeneous conjugates. Recently developed techniques allow site-specific conjugation to antibodies, resulting in homogeneous loading and avoiding conjugate subpopulations with altered antigen-binding or pharmacokinetics. These include engineering of “thiomabs” comprising cysteine substitutions at positions on the heavy and light chains that provide reactive thiol groups and do not disrupt immunoglobulin folding andassembly or alter antigen binding (see, e.g., Junutula et aL, 2008, J. Immunol. Meth. 332: 41- 52; and Junutula et al., 2008, Nature Biotechnol. 26:925-32). In another method, selenocysteine is co-translationally inserted into an antibody sequence by recoding the stop codon UGA from termination to selenocysteine insertion, allowing site specific covalent conjugation at the nucleophilic selenol group of selenocysteine in the presence of the other natural amino acids (see, e.g., Hofer et al., 2008, Proc. Natl. Acad. Sci. USA 105: 12451-56; and Hofer et al., 2009, Biochemistry 48(50): 12047-57).

[0356] In some embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein is conjugated to an agent, for example, an immune activator or a cytotoxic agent. In some embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, disclosed herein can be optionally conjugated with one or more cytotoxic agent(s) disclosed herein or known in the art in order to generate an ADC or AADC. In some embodiments, the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin, doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents. In some embodiments, the cytotoxic agent is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. In some embodiments, the cytotoxic agent is a radioisotope to produce a radioconjugate or a radioconjugated agent. A variety of radionuclides are available for the production of radioconjugated agents including, but not limited to,90Y,125I,131I,123I,n iIn,131In,105Rh,153Sm,67Cu,67Ga,166Ho,177Lu,186Re,188Re, and212Bi. Conjugates of a polypeptide or molecule and one or more small molecule toxins, such as a calicheamicin, maytansinoids, a trichothene, and CC1065, and the derivatives of these toxins that have toxin activity, can also be used. Conjugates of a polypeptide or molecule and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2- pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene).

[0357] In other embodiments, an ILT2 binding agent (e.g., an antibody), including a human ILT2 binding agent, described herein is conjugated to a drug such as a signal transduction modulator, a pro-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an alkylating agent, an anti- angiogenic agent, an anti-metabolite, a boron-containing agent, a chemoprotective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, such as camptothecin or an analog thereof, and a tyrosine kinase inhibitor. In some embodiments, the mitotic inhibitor is a dolastatin, an auristatin, a maytansinoid, and a plant alkaloid. In some embodiments, the drug is a dolastatin, an auristatin, a maytansinoid, and a plant alkaloid. An example of an auristatin is monomethylaurisatin F (MMAF) or monomethy auristatin E (MMAE). Examples of maytansinoids include, but are not limited to, DM1, DM2, DM3, and DM4. In some embodiments, the anti-tumor antibiotic is selected from the group consisting of an actinomycine, an anthracycline, a calicheamicin, and a duocarmycin. An example of an actinomycine is a pyrrolobenzodiazepine (PBD). An example of an anthracycline is a PNU- anthracycline such as PNU-159682 or derivative.

[0358] ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, described herein may be monospecific, bispecific, trispecific or of greater multispecificity. Such agents may include monospecific or multispecific antibodies. Multispecific antibodies, such as bispecific antibodies, are monoclonal antibodies that have binding specificities for at least two different targets (e.g., antigens) or two different epitopes on the same target (e.g., a bispecific antibody directed to ILT2 with a first binding domain for a first epitope of an ILT2, and a second binding domain for a second epitope of ILT2). In some embodiments, the monospecific and multispecific (e.g., bispecific) antibodies can be constructed based on the sequences of the antibodies described herein, e.g., the CDR sequences listed in Tables 1-4. In some embodiments, the multispecific antibodies described herein are bispecific antibodies. In some embodiments, bispecific antibodies are mouse, chimeric, human or humanized antibodies.

[0359] In some embodiments, one of the binding specificities of the multispecific antibody is for ILT2 and the other is for any other target (e.g., antigen). In some embodiments, a multispecific (e.g., bispecific) antibody can comprise more than one target (e.g., antigen) binding domain, in which different binding domains are specific for differenttargets (e.g. , a first binding domain that binds to ILT2 and a second binding domain that binds another target (e.g., antigen). In some embodiments, the second target is an immune checkpoint regulator (e.g., a negative checkpoint regulator). In some embodiments, the second target is expressed on an immune cell. In some embodiments, the second target is expressed on a tumor or cancer cell.

[0360] In some embodiments, multispecific (e.g., bispecific) antibody molecules can bind than one (e.g., two or more) epitopes on the same target (e.g., antigen).

[0361] Methods for making multispecific antibodies are known in the art, such as, by co- expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (see, e.g., Milstein and Cuello, 1983, Nature 305:537-40). For further details of generating multispecific antibodies (e.g., bispecific antibodies), see, for example, Bispecific Antibodies (Kontermann ed., 2011).

[0362] Exemplary structures of multispecific antibodies are known in the art and are further described in Weidle et al., 2013, Cancer Genomics & Proteomics 10: 1-18; Brinkman et al., 2017, MABS, 9:2, 182-212; Godar et al., 2018, Expert Opinion on Therapeutic Patents, 28:3, 251-276; and Spiess et al., 2015, Mol. Immunol. 67 95-106.

[0363] For example, bispecific antibody molecules can be classified into different structural groups: (i) bispecific immunoglobulin G (BsIgG); (ii) IgG appended with an additional antigen-binding moiety; (iii) bispecific antibody fragments; (iv) bispecific fusion proteins; and (v) bispecific antibody conjugates. As a non-limiting example, BsIgG formats can include crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, knobs-in- holes common LC, knobs-in-holes assembly, charge pair, Fab-arm exchange, SEEDbody, triomab, LUZ-Y, Fcab, rA-body, and / or orthogonal Fab.

[0364] In some embodiments, BsIgG comprises heavy chains that are engineered for heterodimerization. For example, heavy chains can be engineered for heterodimerization using a “knobs-into-holes” strategy, a SEED platform, a common heavy chain (e.g., in rA- bodies), and use of heterodimeric Fc regions. Strategies are known in the art to avoid heavy chain pairing of homodimers in BsIgG, including knobs-into-holes, duobody, azymetric, charge pair, HA-TF, SEEDbody, and differential protein A affinity.

[0365] Another bispecific antibody format is IgG appended with an additional antigen- binding moiety. For example, monospecific IgG can be engineered to have bispecificity by appending an additional antigen-binding unit onto the monospecific IgG, e.g., at the N- or C- terminus of either the heavy or light chain. Exemplary additional antigen-binding units include single domain antibodies (e.g., variable heavy chain or variable light chain),engineered protein scaffolds, and paired antibody variable domains (e.g., single chain variable fragments or variable fragments). Non-limiting examples of appended IgG formats include dual variable domain IgG (DVD-Ig), IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv- (L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv- IgG, IgG-2scFv, scFv4-Ig, zybody, and DVI-IgG (four- in-one). See Spiess et al. Mol. Immunol. 67(2015):95-106. In some embodiments, an exemplary antibody format is a B- Body format for monospecific or multispecific (e.g., bispecific antibodies) as described in e.g. WO 2018 / 075692 and U.S. Pat. Publ. No. 2018 / 0118811.

[0366] Bispecific (Bs) antibody (BsAb) fragments are a format of bispecific antibody molecules that lack some or all of the antibody constant domains. For example, some BsAb lack an Fc region. In embodiments, bispecific antibody fragments include heavy and light chain regions that are connected by a peptide linker that permits efficient expression of the BsAb in a single host cell. Non-limiting examples of bispecific antibody fragments include, but are not limited to, nanobody, nanobody- HAS, BiTE, Diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab')2, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HC Ab, scDiabody-Fc, Diabody-Fc, tandem scFv-Fc, and intrabody.

[0367] Bispecific fusion proteins include antibody fragments linked to other proteins. For example, bispecific fusion proteins can be linked to other proteins to add additional specificity and / or functionality. In some embodiments, the dock-and-lock (DNL) method can be used to generate bispecific antibody molecules with higher valency. For example, bispecific antibody fusions to albumin binding proteins or human serum albumin can be extend the serum half-life of antibody fragments. In embodiments, chemical conjugation, e.g., chemical conjugation of antibodies and / or antibody fragments, can be used to create BsAb molecules. An exemplary bispecific antibody conjugate includes the CovX-body format, in which a low molecular weight drug is conjugated site-specifically to a single reactive lysine in each Fab arm or an antibody or fragment thereof. In some embodiments, the conjugation improves the serum half-life.

[0368] Methods of production of multispecific antibodies, including bispecific antibodies, are known in the art. For example, multispecific antibodies, including bispecific antibodies, can be produced by separate expression of the component antibodies in different host cells and subsequent purification / assembly or by expression of the component antibodies in a single host cell. Purification of multispecific (e.g., bispecific) antibody molecules can be performed by various methods known in the art, including affinity chromatography.

[0369] In some embodiments, ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, disclosed herein can be provided in any antibody format disclosed herein or known in the art. As a non-limiting example, in some embodiments, the ILT2 binding agents (e.g., antibodies), including human ILT2 binding agents, can be selected from Fabs-in-tandem-lg (FIT-lg); DVD-lg; hybrid hybridoma (quadroma or tetradoma); anticalin platform (Pieris); diabodies; single chain diabodies; tandem single chain Fv fragments; TandAbs, Trispecific Abs (Affimed); Darts dual affinity retargeting (Macrogenics); Bispecific Xmabs (Xencor); Bispecific T cell engagers (Bites; Amgen; 55kDa); Triplebodies; Tribody = Fab-scFv Fusion Protein multifunctional recombinant antibody derivates (CreativeBiolabs); Duobody platform (Genmab); dock and lock platform; knobs-into-holes (KIH) platform; Humanized bispecific IgG antibody (REGN1979) (Regeneron); Mab2 bispecific antibodies (F-Star); DVD-lg = dual variable domain immunoglobulin (Abbott); kappa-lambda bodies; TBTI = tetravalent bispecific tandem Ig; and CrossMab (Roche).

[0370] In some embodiments, a multispecific (e.g., bispecific) antibody disclosed herein comprises an ILT2 binding domain and one or more additional binding domains that bind to one or more targets that are not ILT2. In some embodiments, a multispecific (e.g., bispecific) antibody disclosed herein comprises an ILT2 binding domain that comprises the VH and / or VL amino acid sequences as disclosed herein, such as those of Table 1, Table 2, Table 3 or Table 4

[0371] In some embodiments, described herein is a multispecific (e.g., bispecific) antibody comprising a binding domain which binds to ILT2 that comprises VH and VL CDRs disclosed herein, such as those as set forth in Table 1, Table 2, Table 3 or Table 4.

[0372] In another aspect, the antibody or antigen-binding fragment thereof provided herein can be part of an engineered cell surface receptor such as a chimeric antigen receptor (CAR). Typically, a CAR comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain.

[0373] In some embodiments, provided herein is a CAR comprising an extracellular domain that comprises one or more antibody or fragment thereof provided herein. In some embodiments, the extracellular domain of a CAR provided herein comprises VH and VL CDRs disclosed herein, such as those as set forth in Table 1, Table 2, Table 3 or Table 4.

[0374] The CARs of the present disclosure comprise a transmembrane domain that can be directly or indirectly fused to the extracellular antigen-binding domain. The transmembrane domain may be derived either from a natural or from a synthetic source. As used herein, a “transmembrane domain” refers to any protein structure that is thermodynamically stable in acell membrane, preferably a eukaryotic cell membrane. Transmembrane domains compatible for use in the CARs described herein may be obtained from a naturally occurring protein. Alternatively, it can be a synthetic, non-naturally occurring protein segment, e.g., a hydrophobic protein segment that is thermodynamically stable in a cell membrane. Transmembrane domains are classified based on the three dimensional structure of the transmembrane domain. For example, transmembrane domains may form an alpha helix, a complex of more than one alpha helix, a beta-barrel, or any other stable structure capable of spanning the phospholipid bilayer of a cell.

[0375] The CARs of the present disclosure comprise an intracellular signaling domain. The intracellular signaling domain is responsible for activation of at least one of the normal effector functions of the immune effector cell expressing the CARs. The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Thus the term “cytoplasmic signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire cytoplasmic signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the cytoplasmic signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term cytoplasmic signaling domain is thus meant to include any truncated portion of the cytoplasmic signaling domain sufficient to transduce the effector function signal.

[0376] In some embodiments, the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell. In some embodiments, the CAR comprises an intracellular signaling domain consisting essentially of a primary intracellular signaling domain of an immune effector cell. “Primary intracellular signaling domain” refers to cytoplasmic signaling sequence that acts in a stimulatory manner to induce immune effector functions.

[0377] Many immune effector cells require co-stimulation, in addition to stimulation of an antigen-specific signal, to promote cell proliferation, differentiation and survival, as well as to activate effector functions of the cell. In some embodiments, the CAR comprises at least one co-stimulatory signaling domain. The term “co-stimulatory signaling domain,” as used herein, refers to at least a portion of a protein that mediates signal transduction within a cell to induce an immune response such as an effector function.

[0378] The CARs of the present disclosure may comprise a hinge domain that is located between the extracellular antigen-binding domain and the transmembrane domain. A hinge domain is an amino acid segment that is generally found between two domains of a protein and may allow for flexibility of the protein and movement of one or both of the domains relative to one another. Any amino acid sequence that provides such flexibility and movement of the extracellular antigen-binding domain relative to the transmembrane domain of the effector molecule can be used.

[0379] The CARs of the present disclosure may comprise a signal peptide (also known as a signal sequence) at the N-terminus of the polypeptide. In general, signal peptides are peptide sequences that target a polypeptide to the desired site in a cell.

[0380] Other engineered transmembrane receptors comprising the antibody or fragment provided herein are also included in the present disclosure.5.3. Nucleic Acids, Vectors and Cells

[0381] Additionally provided are a nucleic acid encoding an ILT2 binding agent (e.g., antibody or antibody fragment) or a fusion polypeptide as disclosed herein, a nucleic acid complementary thereto; a vector comprising a nucleic acid as disclosed herein; and a cell comprising any one or more of: an ILT2 binding agent as disclosed herein, a nucleic acid as disclosed herein, or a vector as disclosed herein. In some embodiments, the cell expresses the ILT2 binding agent. In some embodiments, the cell replicates the nucleic acid or the vector. In some embodiments, provided are the materials for generating ILT2 binding agents, e.g., human ILT2 binding agents, and fragments thereof. For example, an isolated cell may produce an ILT2 binding agent (e.g., antibody or antibody fragment). In this regard, a cell (e.g., an isolated cell) may produce an antibody or fragment thereof comprising a VH and a VL as disclosed herein. In some embodiments, polynucleotides described herein may comprise one or more nucleic acid sequences encoding an ILT2 binding agent (e.g., antibody or antibody fragment). In some embodiments, the polynucleotide is an isolated and / or recombinant polynucleotide. In various aspects, the isolated polynucleotide comprises a nucleotide sequence that encodes a VH and / or a VL, wherein the VH and the VL comprise complementarity determining regions (CDRs) identical to CDRs as disclosed herein.

[0382] As used herein, the term “complementary” refers to specific binding between polynucleotides based on the sequences of the polynucleotides. As used herein, a first polynucleotide and a second polynucleotide are complementary if they bind to each other in a hybridization assay under stringent conditions, e.g, if they produce a given or detectable level of signal in a hybridization assay. Portions of polynucleotides are complementary toeach other if they follow conventional base-pairing rules, e.g., A pairs with T (or U) and G pairs with C, although small regions (e.g., fewer than about 3 bases) of mismatch, insertion, or deleted sequence may be present. The term “stringent assay conditions” refers to conditions that are compatible to produce binding pairs of nucleic acids, e.g., probes and target mRNAs, of sufficient complementarity to provide for the desired level of specificity in the assay while being generally incompatible to the formation of binding pairs between binding members of insufficient complementarity to provide for the desired specificity. The term “stringent assay conditions” generally refers to the combination of hybridization and wash conditions.

[0383] In some embodiments, one or more vectors (e.g., expression vectors) may comprise one or more polynucleotides for expression of the one or more polynucleotides in a suitable host cell. Such vectors are useful, for example, for amplifying the polynucleotides in host cells to create useful quantities thereof, and for expressing binding agents, such as antibodies or antibody fragments, using recombinant techniques.

[0384] In some embodiments, one or more vectors are expression vectors wherein one or more polynucleotides are operatively linked to one or more polynucleotides comprising expression control sequences. Autonomously replicating recombinant expression constructs such as plasmid and viral DNA vectors incorporating one or more polynucleotides encoding antibody sequences that bind ILT2 are specifically contemplated. Expression control DNA sequences include promoters, enhancers, and operators, and are generally selected based on the expression systems in which the expression construct is to be utilized. Promoter and enhancer sequences are generally selected for the ability to increase gene expression, while operator sequences are generally selected for the ability to regulate gene expression.Expression constructs may also include sequences encoding one or more selectable markers that permit identification of host cells bearing the construct. Expression constructs may also include sequences that facilitate, and preferably promote, homologous recombination in a host cell. In some embodiments, expression constructs of the can also include sequences necessary for replication in a host cell.

[0385] Exemplary expression control sequences include promoter / enhancer sequences, e.g., cytomegalovirus promoter / enhancer (Lehner et al., J. Clin. Microbiol., 29: 2494-2502, 1991; Boshart et al., Cell, 41 : 521-530, 1985); Rous sarcoma virus promoter (Davis et al., Hum. Gene Ther., 4: 151, 1993); Tie promoter (Korhonen et al., Blood, 86(5): 1828-1835, 1995); simian virus 40 promoter; DRA (downregulated in adenoma; Alrefai et al., Am. J. Physiol. Gastrointest. Liver Physiol., 293: G923-G934, 2007); MCT1 (monocarboxylatetransporter 1; Cuff et al., Am. J. Physiol. Gastrointet. Liver Physiol., G977-G979. 2005); and Math1 (mouse atonal homolog 1; Shroyer et aL, Gastroenterology, 132: 2477-2478, 2007), for expression in mammalian cells, the promoter being operatively linked upstream (e.g., 5’) of a polypeptide coding sequence. In another variation, the promoter is an epithelial-specific promoter or endothelial-specific promoter. Polynucleotides may also optionally include a suitable polyadenylation sequence (e.g., the SV40 or human growth hormone gene polyadenylation sequence) operably linked downstream (e.g., 3’) of the polypeptide coding sequence.

[0386] If desired, the one or more polynucleotides also optionally comprise nucleotide sequences encoding secretory signal peptides fused in frame with the polypeptide sequences. The secretory signal peptides direct secretion of the antibody polypeptides by the cells that express the one or more polynucleotides, and are cleaved by the cell from the secreted polypeptides. The one or more polynucleotides may further optionally comprise sequences whose only intended function is to facilitate large scale production of the vector. One can manufacture and administer polynucleotides for gene therapy using procedures that have been described in the literature for a variety of transgenes. See, e.g., Isner et al., Circulation, 91 : 2687-2692, 1995; and Isner et al. , Human Gene Therapy, 7: 989-1011, 1996.

[0387] In some embodiments, polynucleotides may further comprise additional sequences to facilitate uptake by host cells and expression of the antibody or fragment thereof (and / or any other peptide). In some embodiments, a “naked” transgene encoding an antibody or fragment thereof described herein (e.g., a transgene without a viral, liposomal, or other vector to facilitate transfection) is employed.

[0388] The polynucleotides of the disclosure can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double-stranded or single-stranded, and if single stranded can be the coding strand or non-coding (anti-sense) strand. In some embodiments, the polynucleotide is in the form of cDNA. In some embodiments, the polynucleotide is a synthetic polynucleotide.

[0389] The present disclosure further relates to variants of the polynucleotides described herein, wherein the variant encodes, for example, fragments, analogs, and / or derivatives of the binding molecules of the disclosure. In certain embodiments, the present disclosure provides a polynucleotide comprising a polynucleotide having a nucleotide sequence at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, and in some embodiments, at least about 96%, 97%, 98% or 99% identical to a polynucleotide encoding the binding molecule of thedisclosure. As used herein, the phrase “a polynucleotide having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence is intended to mean that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence can include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence can be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence can be inserted into the reference sequence. These mutations of the reference sequence can occur at the 5' or 3' terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.

[0390] The polynucleotide variants can contain alterations in the coding regions, non- coding regions, or both. In some embodiments, a polynucleotide variant contains alterations which produce silent substitutions, additions, or deletions, but does not alter the properties or activities of the encoded polypeptide. In some embodiments, a polynucleotide variant comprises silent substitutions that results in no change to the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code). Polynucleotide variants can be produced for a variety of reasons, for example, to optimize codon expression for a particular host (i.e., change codons in the human mRNA to those preferred by a bacterial host such as E. coli). In some embodiments, a polynucleotide variant comprises at least one silent mutation in a non-coding or a coding region of the sequence.

[0391] In some embodiments, a polynucleotide variant is produced to modulate or alter expression (or expression levels) of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to increase expression of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to decrease expression of the encoded polypeptide. In some embodiments, a polynucleotide variant has increased expression of the encoded polypeptide as compared to a parental polynucleotide sequence. In some embodiments, a polynucleotide variant has decreased expression of the encoded polypeptide as compared to a parental polynucleotide sequence.

[0392] Any suitable vectors may be used to introduce one or more polynucleotides that encode an antibody or fragment thereof into the host. Exemplary vectors that have been described include replication deficient retroviral vectors, including but not limited tolentivirus vectors (Kim et al., J. Virol., 72(1): 811-816, 1998; Kingsman & Johnson, Scrip Magazine, October, 1998, p...

Claims

WHAT IS CLAIMED IS:

1. An antibody or fragment thereof that binds to ILT2, wherein the antibody or fragment thereof comprises:(A) (1) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19, or SEQ ID NO:20; and(2) a VL CDR1 , a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34; or(B) (1) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64, SEQ ID NO:65, or SEQ ID NO:68; and(2) a VL CDR1 , a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84, SEQ ID NO:85, or SEQ ID NO:88.

2. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof comprises any one or more of (i)-(xxxiv):(i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32;(ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:33;(iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:34;(iv) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32;(v) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:33;(vi) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:34;(vii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84;(viii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85;(ix) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88;(x) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84;(xi) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85;(xii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88;(xiii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:84;(xiv) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:85; and(xv) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:88.

3. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 4, 7, 8, 11, and 15;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 5, 9, 12, 14, 16, and 17; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 6, 10, and 13; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 25, 27, and 29;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 26, and 30; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 28, and 31.

4. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NON, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NON; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR2 comprising the amino acid sequence of SEQ ID NOV, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:28;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NOVO, and a VL CDR3 comprising the amino acid sequence of SEQ ID NOV 1;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 14, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

5. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 4, 7, 8, 11, and 15;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 9, 12, 14, 16, 17, and 18; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 6, 10, and 13; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 25, 27, and 29;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 26, and 30; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 28, and 31.

6. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NON, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR3 comprising the amino acid sequence of SEQ ID NON; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR2 comprising the amino acid sequence of SEQ ID NOV, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VL CDR2 comprisingthe amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:28;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 31;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 14, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24.

7. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

8. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VHCDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

9. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

10. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

11. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 39, 43, 46, 48, 50, and 51; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

12. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

13. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

14. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprisingthe amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

15. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

16. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VHCDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

17. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 42, 52, 55, 57, and 60;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 53, 54, 56, 58, 59, 61, and 62; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

18. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:61, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:62, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

19. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 73, and 77; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

20. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:73, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:77, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:70, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

21. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80, 81, and 83.

22. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprisingthe amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:81;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:80.

23. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises(a) a VH region comprising:(1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 38, 41, 42, 45, and 49;(2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 43, 46, 48, 50, 51, and 63; and(3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 40, 44, and 47; and(b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 72, 74, and 76;(2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 79, and 82; and(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 75, and 78.

24. The antibody or fragment thereof of claim 1 or 2, wherein the antibody or fragment thereof comprises any one or more of (i)-(viii):(i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:72, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VHCDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:43, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:44; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:74, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 75;(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:45, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:46, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:76, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:82, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:78;(vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(vii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:49, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71; and(viii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:69, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:79, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71.

25. The antibody or fragment thereof of any one of claims 1 to 24, wherein the antibody or fragment thereof further comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence.

26. The antibody or fragment thereof of any one of claims 1 to 25, wherein the antibody or fragment thereof further comprises human framework sequences, optionally a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence as set forth in any one of SEQ ID NOs: 19, 20, 32, 33, 34, 64, 65, 68, 84, 85, and 88.

27. The antibody or fragment thereof of any one of claims 1 to 26, wherein the antibody or fragment thereof comprises:(i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:32;(ii) a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:33;(iii) a VH comprising the amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO:34;(iv) a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:32;(v) a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:33;(vi) a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:34;(vii) a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:84;(viii) a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:85;(ix) a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:88;(x) a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:84;(xi) a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:85;(xii) a VH comprising the amino acid sequence of SEQ ID NO:65 and a VL comprising the amino acid sequence of SEQ ID NO:88;(xiii) a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:84;(xiv) a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:85; or(xv) a VH comprising the amino acid sequence of SEQ ID NO:68 and a VL comprising the amino acid sequence of SEQ ID NO:88.28 The antibody or fragment thereof of any one of claims 1-27, wherein the antibody is a monoclonal antibody.

29. The antibody or fragment thereof of any one of claims 1-28, further comprising one or more heavy chain constant regions as set forth in SEQ ID NO: 108 directly or indirectly conjugated to the C terminus of the VH.

30. The antibody or fragment thereof of any one of claims 1-29, further comprising a light chain constant regions as set forth in SEQ ID NO: 109 directly or indirectly conjugated to the C terminus of the VL.

31. The antibody or fragment thereof of any one of claims 1-30, comprising(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110 and a light chain comprising the amino acid sequence of SEQ ID NO: 111;(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 110 and a light chain comprising the amino acid sequence of SEQ ID NO: 67;(iv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 21 and a light chain comprising the amino acid sequence of SEQ ID NO: 111;(v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 21 and a light chain comprising the amino acid sequence of SEQ ID NO: 66;(vi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 21 and a light chain comprising the amino acid sequence of SEQ ID NO: 67;(vii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112 and a light chain comprising the amino acid sequence of SEQ ID NO: 113;(viii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112 and a light chain comprising the amino acid sequence of SEQ ID NO: 115;(ix) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112 and a light chain comprising the amino acid sequence of SEQ ID NO: 87;(x) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114 and a light chain comprising the amino acid sequence of SEQ ID NO: 113;(xi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114 and a light chain comprising the amino acid sequence of SEQ ID NO: 115;(xii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114 and a light chain comprising the amino acid sequence of SEQ ID NO: 87;(xiii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 113;(xiv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 115; or(xv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 87.

32. The antibody or fragment thereof of any one of claims 1-28, wherein the antibody is a humanized, human or chimeric antibody.

33. The antibody or fragment thereof of any one of claims 1-28 and 32, which is any one of a Fab, Fab’, F(ab')2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, or a multispecific antibody formed from antibody fragments.

34. The antibody or fragment thereof of any one of claims 1-33, which is conjugated or recombinantly fused to a diagnostic agent, detectable agent or therapeutic agent.

35. The antibody or fragment thereof of claim 34, wherein the therapeutic agent is a chemotherapeutic agent, cytotoxin, or drug.

36. The antibody or fragment thereof of any one of claims 1-35, wherein the antibody is a multispecific antibody.

37. The antibody or fragment of claim 36, wherein the multispecific antibody is a bispecific antibody.

38. A binding agent that binds to essentially the same epitope as an antibody or fragment thereof of any one of claims 1-37.

39. The binding agent of claim 38, which is an antibody or fragment thereof.

40. The binding agent of claim 39, wherein the antibody is a multispecific antibody.

41. A binding agent that competes for binding to human ILT2 with an antibody or fragment thereof of any one of claims 1-37.

42. The binding agent of claim 41, wherein the binding agent is an antibody or fragment thereof.

43. The binding agent of claim 42, wherein the antibody is a multispecific antibody.

44. A polynucleotide encoding the antibody or fragment thereof of any one of claims 1-33 and 36-37 or the binding agent of any one of claims 39-40 and 42-43.

45. One or more vectors comprising one or more polynucleotides of claim 44 or a complementary polynucleotide.

46. A cell comprising any one or more of the antibody or fragment thereof of any one of claims 1-37, the binding agent of any one of claims 38-43, the polynucleotide of claim 44, or the one or more vectors of claim 45.

47. A pharmaceutical composition that comprises a pharmaceutically acceptable excipient and any one or more of: the antibody or fragment thereof of any one of claims 1-37,the binding agent of any one of claims 38-43, the polynucleotide of claim 44, the one or more vectors of claim 45, or the cell of claim 46.

48. A method of inhibiting interaction between HLA-G and ILT2, comprising contacting the ILT2 with the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43 or the pharmaceutical composition of claim 47.

49. The method of claim 48, wherein the HLA-G is expressed on a cancer cell.

50. A method of inhibiting interaction between HLA-A and ILT2, comprising contacting the ILT2 with the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43 or the pharmaceutical composition of claim 47.

51. The method of claim 50, wherein the HLA-A is expressed on a cancer cell.

52. A method of inhibiting interaction between HLA-B and ILT2, comprising contacting the ILT2 with the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43 or the pharmaceutical composition of claim 47.

53. The method of claim 52, wherein the HLA-B is expressed on a cancer cell.

54. A method of inhibiting interaction between HLA-C and ILT2, comprising contacting the ILT2 with the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43 or the pharmaceutical composition of claim 47.

55. The method of claim 54, wherein the HLA-C is expressed on a cancer cell.

56. The method of any one of claims 48-55, wherein ILT2 is expressed on an immune cell.

57. A method of preventing suppression of an immune cell or activating a response mediated by an immune cell, comprising contacting the immune cell with the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43 or the pharmaceutical composition of claim 47.

58. The method of claim 57, wherein the immune cell expresses ILT2.

59. The method of claim 57 or 58, wherein the response mediated by the immune cell is an anti-tumor response.

60. A method for treating a disease or disorder in a subject comprising administering to the subject the antibody or fragment thereof of any one of claims 1-37 or the binding agent of any one of claims 38-43, or the pharmaceutical composition of claim 47.

61. The method of claim 60, wherein the disease or disorder is a cancer.

62. The method of claim 61, wherein the cancer expresses HLA-G.

63. The method of claim 61, wherein the cancer expresses HLA-A.

64. The method of claim 61, wherein the cancer expresses HLA-B.

65. The method of claim 61, wherein the cancer expresses HLA-C.

66. The method of claim 60, wherein the disease or disorder is an autoimmune and inflammatory disease.

67. The method of any one of claims 60 to 66, wherein the subject is a human subject.

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