Antibodies that bind specifically to PD-1 and their uses

Abstract

The present invention relates to antibodies specifically binding PD-1, polynucleotides encoding the antibodies or fragments, and methods of making and using the foregoing.

Description

ANTIBODIES SPECIFICALLY BINDING PD-1 AND THEIR USES SEQUENCE LISTINGThis application contains a Sequence Listing submitted via EFS-Web, the entire content incorporated herein by reference in its entirety. The ASCII text file, created on 28 October 2016, is named JBI5071WOPCT_ST25.txt and is 418 kilobytes in size. FIELD OF THE INVENTIONThe present invention relates antibodies specifically binding PD-1,polynucleotides encoding the antibodies or fragments, and methods of making and using the foregoing. BACKGROUND OF THE INVENTIONThe immune system is tightly controlled by a network of costimulatory and co- inhibitory ligands and receptors. These molecules provide secondary signals for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection and tumors, while limiting immunity to self (Wang et al., (Epub Mar.7, 2011) J Exp Med 208(3):577-92; Lepenies et al., (2008) Endocr Metab Immune Disord Drug Targets 8:279-288).Immune checkpoint therapy, targeting co-inhibitory pathways in T cells to promote antitumor immune responses, has led to advances in clinical care of cancer patients.PD-1 is a negative immune checkpoint molecule that suppresses CD4+ and CD8+ T cell functions in the tumor microenvironment (TME). PD-1 engagement with its ligands (PD-L1 and PD-L2) drives T cell anergy and exhaustion in tumors by inhibiting multiple pathways downstream of the T cell receptor signaling, resulting in decreased T cell survival, growth and proliferation, compromised effector function, and altered metabolism. Preclinical studies have demonstrated that the PD-1 pathway blockade can reverse T cell exhaustion and stimulate anti-tumor immunity.The PD-1 pathway hence contributes to downregulation of T cell functions in the (TME) and evasion of tumors via immune destruction. In the TME, exhausted T cells, in addition to expressing high levels of PD-1, express other inhibitory receptors including CTLA-4, TIM-3, LAG-3, CD244, TIGIT and CD160 (see e.g., Pauken & Wherry; 2015, Trends in Immunology 36(4): 265–276). TIM-3 is a transmembrane receptor that is expressed on Th1 (T helper 1) CD4+ cells and cytotoxic CD8+ T cells that secrete IFN-γ. TIM-3 is generally not expressed on naïve T cells but rather upregulated on activated, effector T cells. TIM-3 has a role in regulating immunity and tolerance in vivo (see Hastings et al., (2009) Eur J Immunol 39(9):2492-501).PD-1 antibodies have been described for example in: U.S. Patent Nos.5,897,862 and 7,488,802, and in Int. Patent Publ. Nos. WO2004 / 004771, WO2004 / 056875, WO2006 / 121168, WO2008 / 156712, WO2010 / 029435, WO2010 / 036959,WO2011 / 110604, WO2012 / 145493, WO2014 / 194302, WO2014 / 206107,WO2015 / 036394, WO2015 / 035606, WO2015 / 085847, WO2015 / 112900 andWO2015 / 112805.TIM-3 antibodies have been described for example in: Monney et al., Nature (2002) 415(6871):536-41, and in Int. Patent Publ. Nos. WO2011 / 155607,WO2013 / 006490 and WO2015 / 117002.Combinations with TIM-3 antibody and a PD-L1 antibody have been evaluated in for example in Int. Patent Publ. No. WO2011 / 159877.While anti-PD-1 / PD-L1 antibodies are demonstrating encouraging clinical responses in patients with multiple solid tumors, the response rates are still fairly low, about 15% - 20% in pretreated patients (Swaika et al., (2015) Mol Immunol. doi:10.1016 / j.molimm.2015.02.009).Therefore, there is a need for new therapeutics that inhibit the immunosuppressive activity of checkpoint inhibitors such as PD-1 and TIM-3, to be used for cancer immunotherapy and treatment of other conditions that would benefit from enhancement of an immune response, such as chronic infections. BRIEF SUMMARY OF THE INVENTIONThe invention provides an isolated antagonistic antibody specifically binding PD- 1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, or SEQ ID NOs: 82, 83 and 85, respectively.The invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively. The invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.The invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising certain HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences as described herein.The invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising certain VH and VL amino acid sequences as described herein.The invention also provides an immunoconjugate comprising the antibody or antigen-binding portion thereof of the invention linked to a therapeutic agent or to an imaging agent.The invention also provides a pharmaceutical composition comprising the antibody of the invention and a pharmaceutically accepted carrier.The invention also provides a polynucleotide encoding the antibody VH, the antibody VL or the antibody VH and the antibody VL of the invention.The invention also provides a vector comprising the polynucleotide encoding the antibody VH, the antibody VL or the antibody VH and the VL of the invention.The invention also provides a host cell comprising the vector of the invention. The invention also provides a method of producing the antibody of the invention, comprising culturing the host cell of the invention in conditions that the antibody is expressed, and recovering the antibody produced by the host cell.The invention also provides a method of treating a cancer in a subject, comprising administering a therapeutically effective amount of the isolated antibody of the invention to the subject in need thereof for a time sufficient to treat the cancer.The invention also provides a method of enhancing an immune response in a subject, comprising administering a therapeutically effective amount of the isolated antibody of the invention to the subject in need thereof for a time sufficient to enhance the immune response.The invention also provides an anti-idiotypic antibody binding to the antibody of the invention.The invention also provides a kit comprising the antibody of the invention. BRIEF DESCRIPTION OF THE DRAWINGSFigure 1A shows that TIM-3 surface expression is elevated in tumors after treatment with anti-PD-1 antibodies. Balb / c mice with established CT26 colon carcinoma tumors were treated biweekly with anti-PD-1 antibody or vehicle. Tumors were harvested at day 22 and TIM-3 expression was evaluated on tumor-infiltrating T cells using flow cytometry. MFI: mean fluorescent intensity. PBS: controlFigure 1B shows that TIM-3 surface expression is elevated on tumor infiltrated lymphocytes (TIL) after treatment with anti-PD-1 antibodies. Balb / c mice with established MC38 colon carcinoma tumors were treated biweekly with anti-PD-1 antibody or vehicle. Geometric mean fluorescent intensity (gMFI) of TIM-3 expression on total CD8 TIL population is shown in vehicle treated (PBS) or anti-PD-1 antibody treated (PD-1) animals. p=0.003 vehicle vs anti-PD-1 antibody treated groups.Figure 1C shows the relative frequency of TIM-3+ CD8 cells of total CD8+ TILs in MC38 tumors harvested from mice treated with vehicle (PBS) or anti-PD-1 antibody (PD-1). p=0.045 vehicle vs anti-PD-1 antibody treated groups.Figure 2A shows that CD137 surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.005 vehicle vs anti-PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 2B shows that the relative frequency of CD137+ CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.0475 vehicle vs anti- PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 3A shows that OX40 surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.0013 vehicle vs anti-PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 3B shows that the relative frequency of OX40+ CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.03 vehicle vs anti-PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments. Figure 4A shows that GITR surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.0004 vehicle vs anti-PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 4B shows that the relative frequency of GITR+ CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group. p=0.0015 vehicle vs anti- PD-1 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 5 shows that treatment with anti-TIM-3 antibodies after anti-PD-1 antibody treatment further induces antigen-specific immune response. The antibodies were tested in the CMV assay using PBMCs from CMV positive donors, in which antigen-specific immune responses were induced with pp65 peptide pools. The cells were treated for 5 days with anti-PD-1 antibody PD1B244, re-stimulated, and treated for 24 hours with anti-TIM-3 antibody TM3B105. Immune response was determined by measuring increases in IFN- ^ secretion. IgG2s Iso: IgG2sigma isotype control. CMV: sample treated with cytomegalovirus p65 peptides in the absence of antibodies.Figure 6 shows the HCDR1 sequences of select anti-PD-1 antibodies and the HCDR1 genus sequence.Figure 7 shows the HCDR2 sequences of select anti-PD-1 antibodies and the HCDR2 genus sequence.Figure 8 shows the HCDR3 sequences of select anti-PD-1 antibodies and the first HCDR3 genus sequence.Figure 9 shows the HCDR3 sequences of select anti-PD-1 antibodies and the second HCDR3 genus sequence.Figure 10 shows the LCDR1 sequences of select anti-PD-1 antibodies and the LCDR1 genus sequence.Figure 11 shows the LCDR2 sequences of select anti-PD-1 antibodies and the LCDR2 genus sequence.Figure 12 shows the LCDR3 sequences of select anti-PD-1 antibodies and the LCDR3 genus sequence.Figure 13 shows the HCDR1 sequences of select anti-TIM-3 antibodies and the HCDR1 genus sequence. The genus sequence was determined by generating molecular models for all Fv (VH / VL pairs) in MOE (CCG, Montreal) using a default protocol for antibody modeling. For CDRs that have different lengths, these structural models were aligned based upon the structurally conserved regions and the structurally equivalent CDRs positions were identified. Figure 14 shows the HCDR2 sequences of select anti-TIM-3 antibodies and the HCDR2 genus sequence. The HCDR2 genus sequence was generated as described for Figure 10. Figure 15 shows the HCDR3 sequences of select anti-TIM-3 antibodies and the first HCDR3 genus sequence. The HCDR3 genus sequence was generated as described for Figure 10. Figure 16 shows the LCDR1 sequences of select anti-TIM-3 antibodies and the LCDR1 genus sequence. The LCDR1 genus sequence was generated as described for Figure 10. Figure 17 shows the LCDR2 sequences of select anti-TIM-3 antibodies and the LCDR2 genus sequence. The LCDR2 genus sequence was generated as described for Figure 10. Figure 18 shows the LCDR3 sequences of select anti-TIM-3 antibodies and the LCDR3 genus sequence. The LCDR3 genus sequence was generated as described for Figure 10. Figure 19A shows that TIGIT surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group. p=0.0181 vehicle vs anti-TIM-3 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 19B shows that the relative frequency of TIGIT+ CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group. p=0.0475 vehicle vs anti-TIM-3 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 20A shows that TIGIT surface expression (gMFI) is elevated on TILs in CT26 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group. p<0.001 vehicle vs anti-TIM-3 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 20B shows that the relative frequency of TIGIT+ CD8 cells of total CD8+ TILs in is elevated in CT26 colon carcinoma tumors in animals treated with anti-TIM-3antibodies (TIM-3 group) when compared to vehicle treated (PBS) group. p=0.0105 vehicle vs anti-TIM-3 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.Figure 21 shows upregulation of TIM-3 expression on peripheral T cells in melanoma patients PBMCs from treatment naïve melanoma patients stimulated with melanoma antigen peptide pools (NY-ESO, gp100, MART-1) in the presence or absence of anti-PD-1 or anti-TIM-3 function blocking antibodies. Expression of TIM-3 was determined by flow cytometry on restimulated cells on day 6.Figure 22A shows that TM3B403 treatment increases frequency of activated NK cells in IL-2 stimulated human PBMCs. IgG2s: Isotype control. NK cell activation was assessed as percentage (%) of CD69 expressing cells in the stimulated PBMCs.Figure 22B shows that TM3B403 treatment increases frequency of activated NK cells in IL-2 stimulated human PBMCs. IgG2s: Isotype control. NK cell activation was assessed as percentage (%) of CD25 expressing cells in the stimulated PBMCs. DETAILED DESCRIPTION OF THE INVENTIONAll publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.As used in this specification and the appended claims, the singular forms“a,” “an,” and“the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to“a cell” includes a combination of two or more cells, and the like.“Specific binding” or“specifically binds” or“binds” refers to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1x10-8 M or less, for example about 1x10-9 M or less, about 1x10-10 M or less, about 1x10-11 M or less, or about 1x10-12 M or less, typically with the KD that is at least one hundred fold less than its KD for binding to a non- specific antigen (e.g., BSA, casein). The dissociation constant may be measured using standard procedures. Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset). While a monospecific antibody specifically binds one antigen or one epitope, a bispecific antibody specifically binds two distinct antigens or two distinct epitopes.“Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen-binding fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.“Full length antibodies” are comprised of two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds as well as multimers thereof (for example IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.“Complementarity determining regions (CDR)” are“antigen binding sites” in an antibody. CDRs may be defined using various terms: (i) Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kabat, (1970) J Exp Med 132:211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). (ii) “Hypervariable regions”,“HVR”, or“HV”, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3) refer to the regions of an antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk, (1987) Mol Biol 196:901-17). The International ImMunoGeneTics (IMGT) database(http: / / www_imgt_org) provides a standardized numbering and definition of antigen- binding sites. The correspondence between CDRs, HVs and IMGT delineations is described in Lefranc et al., (2003) Dev Comparat Immunol 27:55-77. The term“CDR”, “HCDR1”,“HCDR2”,“HCDR3”,“LCDR1”,“LCDR2” and“LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia or IMGT, unless otherwise explicitly stated in the specification. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4.Antibody light chains of any vertebrate species may assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.“Antibody fragments” or“antigen-binding portion” refers to a portion of an immunoglobulin molecule that retains the antigen binding properties of the parental full length antibody. Exemplary antigen-binding portions are heavy chain complementarity determining regions (HCDR) 1, 2 and 3, light chain complementarity determining regions (LCDR) 1, 2 and 3, a heavy chain variable region (VH), a light chain variable region (VL), Fab, F(ab')2, Fd and Fv fragments as well as domain antibodies (dAb) consisting of either one VH or VL domain. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047. “Monoclonal antibody” refers to an antibody population with single amino acid composition in each heavy and each light chain, except for possible well known alterations such as removal of C-terminal lysine from the antibody heavy chain. Monoclonal antibodies typically bind one antigenic epitope, except that multispecific monoclonal antibodies bind two or more distinct antigens or epitopes. Bispecific monoclonal antibodies bind two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, or monovalent, bivalent or multivalent. A multispecific antibody, such as a bispecific antibody or a trispecific antibody is included in the term monoclonal antibody."Isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody specifically binding PD-1 is substantially free of antibodies that specifically bind antigens other than PD-1). An isolated antibody specifically binding TIM-3 is substantially free of antibodies that specifically bind antigens other than TIM-3. In case of bispecific PD- 1 / TIM-3 antibodies, the bispecific antibody specifically binds both PD-1 and TIM-3, and is substantially free of antibodies that specifically bind antigens other that PD-1 and TIM- 3.“Isolated antibody” encompasses antibodies that are isolated to a higher purity, such as antibodies that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.“Humanized antibodies” refers to antibodies in which at least one CDR is derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include intentionally introduced mutations in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.“Human antibody” refers to an antibody having heavy and light chain variable regions in which both the framework and all 6 CDRs are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region also is derived from sequences of human origin.Human antibody comprises heavy or light chain variable regions that are“derived from” sequences of human origin if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci as described herein.“Human antibody” may contain amino acid differences when compared to the human germline immunoglobulin or rearranged immunoglobulin genes due to for example naturally occurring somatic mutations or intentional introduction of substitutions into the framework or antigen binding site, or both. Typically,“human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases,“human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009 / 085462.Human antibodies derived from human immunoglobulin sequences may be generated using systems such as phage display incorporating synthetic CDRs and / or synthetic frameworks, or may be subjected to in vitro mutagenesis to improve antibody properties, resulting in antibodies that are not expressed by the human antibody germline repertoire in vivo. “Recombinant” refers to antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means."Epitope" refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be composed of contiguous and / or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3- dimensional space through the folding of the protein molecule. Antibody“epitope” depends on the methodology used to identify the epitope.“Multispecific” refers to an antibody that specifically binds at least two distinct antigens or two distinct epitopes within the antigens, for example three, four or five distinct antigens or epitopes.“Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross- reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset), or may bind an epitope that is shared between two or more distinct antigens. “Variant” refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions or deletions.“Vector” refers to a polynucleotide capable of being duplicated within a biological system or that can be moved between such systems. Vector polynucleotides typically contain elements, such as origins of replication, polyadenylation signal or selection markers, that function to facilitate the duplication or maintenance of these polynucleotides in a biological system. Examples of such biological systems may include a cell, virus, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector. The polynucleotide comprising a vector may be DNA or RNA molecules or a hybrid of these.“Expression vector” refers to a vector that can be utilized in a biological system or in a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector. “Polynucleotide” refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide.“Polypeptide” or“protein” refers to a molecule that comprises at least two amino acid residues linked by a peptide bond to form a polypeptide. Small polypeptides of less than 50 amino acids may be referred to as“peptides”.PD-1 refers to human programmed cell death protein 1, PD-1. PD-1 is also known as CD279 or PDCD1. The amino acid sequence of the mature human PD-1 (without signal sequence) is shown in SEQ ID NO: 1. The extracellular domain spans residues 1- 150, the transmembrane domain spans residues 151-171 and the cytoplasmic domain spans residues 172-268 of SEQ ID NO: 1. Throughout the specification,“ the extracellular domain of human PD-1“huPD1-ECD” refers to protein having amino acid sequence of residues 1-149 of SEQ ID NO: 1, and shown in SEQ ID NO:2.“PD-1” in the specification refers to human mature PD-1, unless explicitly stated to the contrary.TIM-3 refers to human hepatitis A virus cellular receptor 2, also called HAVCR2. The amino acid sequence of the mature human TIM-3 (without signal sequence) is shown in SEQ ID NO: 138. The extracellular domain spans residues 1-181, the transmembrane domain spans residues 182-202 and the cytoplasmic domain spans residues 203-280 of SEQ ID NO: 138. Throughout the specification,“the extracellular domain of human TIM- 3“huTIM-3-ECD” refers to protein having amino acid sequence of residues 1-179 of SEQ ID NO: 138, and shown in SEQ ID NO: 89. TIM-3 in the specification refers to human mature TIM-3, unless explicitly stated to the contrary.“In combination with” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.“Overexpress”,“overexpressed” and“overexpressing” is used interchangeably and refers to a sample such as a cancer cell, malignant cell or cancer tissue that has measurably higher levels of PD-1, TIM-3, PD-L1, PD-L2 or TIM-3 ligand when compared to a reference sample. The overexpression may be caused by gene amplification or by increased transcription or translation. Expression and overexpression of protein in the sample may be measured using well know assays using for example ELISA,immunofluorescence, flow cytometry or radioimmunoassay on live or lysed cells.Expression and overexpression of a polynucleotide in the sample may be measured for example using fluorescent in situ hybridization, Southern blotting, or PCR techniques. A protein or a polynucleotide is overexpressed when the level of the protein or the polynucleotide in the sample at least 1.5-fold higher or statistically significant when compared to the reference sample. Selection of the reference sample is known.“Sample” refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids such as those associated with non-solid tumors, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, fine needle aspirations or surgically resected tumor tissue.A“cancer cell” or a“tumor cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation may arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation / cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo (Freshney, Culture of Animal Cells: A Manual of Basic Technique (3rd ed.1994)). “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment,“about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.“Bispecific PD-1 / TIM-3 antibody”,“PD-1 / TIM-3 antibody”,“bispecific anti-PD- 1 / TIM-3 antibody” or“anti-PD-1 / TIM-3 antibody” refers to a molecule comprising at least one binding domain specifically binding PD-1 and at least one binding domain specifically binding TIM-3. The domains specifically binding PD-1 and TIM-3 are typically VH / VL pairs. The bispecific anti-PD-1 / TIM-3 antibody may be monovalent in terms of its binding to either PD-1 or TIM-3. “Valent” refers to the presence of a specified number of binding sites specific for an antigen in a molecule. As such, the terms“monovalent”,“bivalent”,“tetravalent”, and “hexavalent” refer to the presence of one, two, four and six binding sites, respectively, specific for an antigen in a molecule.“An antigen specific CD4+ or CD8+ T cell” refers to a CD4+ or CD8+ T cell activated by a specific antigen, or immunostimulatory epitope thereof.“CD137” (also called tumor necrosis factor receptor superfamily member 9, TNFRSF9, 4-1BBL) refers to a human CD137 molecule having the amino acid sequence shown in SEQ ID NO: 281. SEQ ID NO: 281MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSA GGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQ ELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPAD LSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYI FKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL “TIGIT” (also called T-cell immunoreceptor with Ig and ITIM domains) refers to human TIGIT molecule having the amino acid sequence shown in SEQ ID NO: 301. SEQ ID NO: 301MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHI SPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEH GARFQIPLLGAMAATLVVICTAVIVVVALTRKKKALRIHSVEGDLRRKSAGQEEW SPSAPSPPGSCVQAEAAPAGLCGEQRGEDCAELHDYFNVLSYRSLGNCSFFTETG "Agonist" refers to a molecule that, when bound to a cellular protein, induces at least one reaction or activity that is induced by a natural ligand of the protein. The molecule is an agonist when the at least one reaction or activity is induced by at least about 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the at least one reaction or activity induced in the absence of the agonist (e.g., negative control), or when the induction is statistically significant when compared to the induction in the absence of the agonist. Agonist may be an antibody, a soluble ligand, or a small molecule. An exemplary agonist is an agonistic antibody that specifically binds a T cell activating molecule. "Antagonist" refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein. A molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist. Antagonist may be an antibody, a soluble ligand, a small molecule, a DNA or RNA such as siRNA. Exemplary antagonists are an antagonistic antibody specifically binding PD-1, an antagonistic antibody specifically binding TIM-3, an antagonistic bispecific PD-1 / TIM-3 antibody or an antagonistic antibody specifically binding a T cell inhibitory molecule. A typical reaction or activity that is induced by PD-1 binding to its receptor PD-L1 or PD-L2 may be reduced antigen-specific CD4+ or CD8+ cell proliferation or reduced interferon- ^ (IFN- ^) production by T cells, resulting in suppression of immune responses against for example tumor. A typical reaction or activity that is induced by TIM-3 binding to its receptor, such as galectin-9, may be reduced antigen specific CD4+ or CD8+ cell proliferation, reduced IFN- ^ production by T cells, or reduced CD137 surface expression on CD4+ or CD8+ cells, resulting in suppression of immune responses against for example tumor. Similarly, a typical reaction or activity that is induced by a T cell inhibitory molecule is immunosuppression. Hence, an antagonistic PD-1 antibody specifically binding PD-1, an antagonistic antibody specifically binding TIM-3, an antagonistic bispecific PD-1 / TIM-3 antibody, or an antagonistic antibody specifically binding a T cell inhibitory molecule induces immune responses by inhibiting the inhibitory pathways. “Subject” includes any human or nonhuman animal.“Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows chickens, amphibians, reptiles, etc. Except when noted, the terms“patient” or“subject” are used interchangeably.The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated.Conventional one and three-letter amino acid codes are used herein as shown in Table 1. Table 1.Compositions of matterThe present invention provides antagonistic antibodies specifically binding PD-1, antagonistic antibodies specifically binding TIM-3, and antagonistic bispecific PD-1 / TIM- 3 antibodies. The present invention provides polypeptides and polynucleotides encoding the antibodies of the invention or complementary nucleic acids thereof, vectors, host cells, and methods of making and using them. Antagonistic antibodies specifically binding PD-1 PD-1, upon ligand engagement, suppresses T cell functions through multiple mechanisms (Pauken & Wherry (2015) Trends in Immunology 36(4): 265–276). PD-1 engagement directly inhibits T cell receptor (TCR) signaling through co-localization with the TCR and subsequent induction of dephosphorylation of TCR proximal signaling molecules, inhibition of Ras / MEK / ERK pathway leading to inhibition of the cell cycle progression and T cell proliferation, inhibition of cell growth and survival and reprogramming of T cell metabolism through suppression of PI3K / AKT pathway, leading to the upregulation of the BATF transcription factor, and modulation of development, maintenance and function of regulatory T cells. PD-1 has also been proposed to increase T cell motility and to limit duration of interaction between T cells and target cells, thereby reducing the extent of T cell activation (Honda et al., (2014) Immunity 40(2):235-47).Tumors have co-opted the PD-1 pathway to downregulate T cell function in the tumor microenvironment (TME) and to evade immune destruction. In the TME, under conditions of persistent antigen and inflammation, T cells become exhausted, or dysfunctional, and progressively lose their effector function and proliferative capacity. Exhausted T cells express high levels of PD-1, often together with other inhibitory receptors such as TIM-3 or LAG-3 (Pauken & Wherry (2015) Trends in Immunology 36(4): 265–276). One of the PD-1 ligands, PD-L1, is also upregulated in various tumors. PD-L1 expression occurs on the cancer cells themselves and / or infiltrating immune cells, including tumor associated macrophages, dendritic cells, fibroblasts and activated T cells (Chen et al., 2012 Clin Cancer Res 18(24):6580-7). In this setting, PD-1 engagement is hypothesized to limit anti-tumor T cell responses and lead to immune evasion. Recent studies have shown that a higher frequency and level of PD-1 expression occurs on tumor infiltrating lymphocytes (TILs) in multiple solid tumors. Importantly, these PD-1+ TILs are functionally impaired, as evidenced by lower proliferation and effector functions (Pauken & Wherry; 2015, Trends in Immunology 36(4): 265–276) These data support the hypothesis that PD-1 mediates immune suppression in the TME.T cell exhaustion in tumors is reversible, at least partially, by PD-1 pathway blockade. Anti-PD-1 / PD-L1 antibodies have been shown to enhance T cell function and lead to improved anti-tumor immunity in a number of preclinical tumor models. PD- 1 / PD-L1 antibodies have also shown encouraging clinical responses in multiple solid tumors, with 20-40% overall response rate (ORR) in melanoma, 10-24% in non-small cell lung cancer (NSCLC), 12-31% in renal cell carcinoma (RCC), 24-52% in bladder cancer, and 20% in head and neck cancer (Swaika et al., (2015) Mol Immunol 67(2 Pt A):4-17). The invention provides an isolated antagonistic antibody specifically binding PD- 1 or an antigen-binding portion thereof comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, or SEQ ID NOs: 82, 83 and 85, respectively.The invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.The invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.The invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.SEQ ID NOs: 82, 83, 84, 85, 86, 87 and 88 represent the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 genus sequences of affinity-matured variants of antagonistic antibodies specifically binding PD-1 having similar HCDR1, HCDR2, LCDR1, LCDR2 and LCDR3 sequences, and two similar HCDR3 groups of sequences. Antibodies within the genus bind PD-1 with the KD of less than about 1x10-7 M, such as less than about 1x10-8 M, for example less than about 1x10-9 M, or for example less than about 1x10-10 M. Exemplary such antibodies are antibodies having the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of antibodies PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201 and PD1B244 as described herein. SEQ ID NO: 82X1YX2IX3,whereinX1 is S or D;X2 is V or A; andX3 is H or S. SEQ ID NO: 83GIIPIX4X5TANYAQKFQG, whereinX4 is Y or F; andX5 is G or D. SEQ ID NO: 84PGLAAAYDTGX6LDY, whereinX6 is N or S. SEQ ID NO: 85GX7X8X9X10TGX11LDY, whereinX7 is T or Y;X8 is L or V;X9 is D or R;X10 is R or A; andX11 is H or M. SEQ ID NO: 86RASQSVX12X13YLA, whereinX12 is S, R or D; and X13 is S or N. SEQ ID NO: 87DASX14RAT,whereinX14 is N, D, Y, S or T. SEQ ID NO: 88QQRX15X16WPLT, wherein X15 is S, N, G, E, D, W or A; andX16 is N, Y, E or A. In some embodiments, the isolated antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof has one, two, three, four or five of the following properties:a) enhances an activation of antigen specific CD4+ or CD8+ T cells in a dosedependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1;b) binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;c) binds human PD-1 with the KD of less than about 1 nM, wherein the KD ismeasured using ProteOn XPR36 system at +25ºC;d) binds cynomolgus PD-1 with the KD of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC, ore) binds cynomolgus PD-1 with the KD of less than about 1 nM,wherein the KD is measured using ProteOn XPR36 system at +25ºC.Exemplary such antibodies are PD-1 antibodies PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201 and PD1B244 as described herein.In some embodiments, the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4+ or CD8+ T cells in a dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 10 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC. In some embodiments, the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds cynomolgus PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds cynomolgus PD-1 with an equilibrium dissociation constant (KD) of less than about 10 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.Activation of antigen specific CD4+ or CD8+ T cells may be assessed by measuring increased T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay, increased interferon- ^ (IFN- ^) secretion in the MLR assay, increased TNF- ^ secretion in the MLR assay, increased IFN- ^ secretion in a cytomegalovirus antigen assay (CMV assay) or increased TNF- ^ secretion in the CMV assay using known protocols and those described in Example 1. Antibodies of the invention enhance the activation of antigen specific CD4+ or CD8+ T when the measured T cell functionality is increased by the antibodies of the invention in a dose-dependent manner.The affinity of an antibody to human or cynomolgus PD-1 may be determined experimentally using any suitable method. Such methods may utilize ProteOn XPR36, Biacore 3000 or KinExA instrumentation, ELISA or competitive binding assays known to those skilled in the art. The measured affinity of a particular antibody / PD-1 interaction may vary if measured under different conditions (e.g., osmolarity, pH). Thus, measurements of affinity and other binding parameters (e.g., KD, Kon, Koff) are typically made with standardized conditions and a standardized buffer, such as the buffer described herein. Skilled in the art will appreciate that the internal error for affinity measurements for example using Biacore 3000 or ProteOn (measured as standard deviation, SD) may typically be within 5-33% for measurements within the typical limits of detection.Therefore the term“about” in the context of KD reflects the typical standard deviation in the assay. For example, the typical SD for a KD of 1x10-9 M is up to +0.33x10-9 M.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2 and the HCDR3 contained within a heavy chain variable region (VH) of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47 or 48, wherein the HCDR1, the HCDR2 and the HCDR3 are defined by Chothia, Kabat, or IMGT.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the LCDR1, the LCDR2 and the LCDR3 contained within a light chain variable region (VL) of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62, wherein the LCDR1, the LCDR2 and the LCDR are defined by Chothia, Kabat, or IMGT.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprisesthe HCDR1 of SEQ ID NOs: 10, 11 or 12;the HCDR2 of SEQ ID NOs: 13, 14 or 15; andthe HCDR3 of SEQ ID NOs: 16, 17, 18 or 19.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprisesthe LCDR1 of SEQ ID NOs: 20, 21, 22, 23, 24 or 25;the LCDR2 of SEQ ID NOs: 26, 27, 28, 29 or 30; andthe LCDR3 of SEQ ID NOs: 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprisesthe HCDR1 of SEQ ID NOs: 10, 11 or 12;the HCDR2 of SEQ ID NOs: 13, 14 or 15;the HCDR3 of SEQ ID NOs: 16, 17, 18 or 19;the LCDR1 of SEQ ID NOs: 20, 21, 22, 23, 24 or 25;the LCDR2 of SEQ ID NOs: 26, 27, 28, 29 or 30; andthe LCDR3 of SEQ ID NOs: 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the HCDR1, the HCDR2 and the HCDR3 ofSEQ ID NOs: 10, 13 and 16, respectively;SEQ ID NOs: 10, 14 and 16, respectively;SEQ ID NOs: 10, 13 and 17, respectively;SEQ ID NOs: 10, 13 and 18, respectively;SEQ ID NOs: 11, 15 and 18, respectively;SEQ ID NOs: 10, 13 and 19, respectively; SEQ ID NOs: 10, 14 and 17, respectively; orSEQ ID NOs: 12, 13 and 19, respectively.In some embodiments, the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the LCDR1, the LCDR2 and the LCDR3 ofSEQ ID NOs: 20, 26 and 31, respectively;SEQ ID NOs: 21, 26 and 32, respectively;SEQ ID NOs: 22, 27 and 33, respectively;SEQ ID NOs: 22, 26 and 34, respectively;SEQ ID NOs: 23, 28 and 35, respectively;SEQ ID NOs: 20, 26 and 36, respectively;SEQ ID NOs: 21, 27 and 37, respectively;SEQ ID NOs: 23, 26 and 32, respectively;SEQ ID NOs: 22, 26 and 32, respectively;SEQ ID NOs: 24, 26 and 38, respectively;SEQ ID NOs: 20, 29 and 39, respectively;SEQ ID NOs: 20, 30 and 32, respectively;SEQ ID NOs: 25, 26 and 40, respectively; orSEQ ID NOs: 24, 26 and 32, respectively.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively.In some embodiments, the antibody or the antigen-binding portion thereof binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 500 pM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody or the antigen-binding portion thereof binds cynomolgous PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 500 pM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 196 and 197, respectively. In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 / ^ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG4 / ^ isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises a heavy chain (HC) of SEQ ID NO: 72 and a light chain (LC) of SEQ ID NO: 73.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG2 / ^ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating cancer.The antibody is suitable for use in therapy, for example in treating a solid tumor. The antibody is suitable for use in therapy, for example in treating a melanoma. The antibody is suitable for use in therapy, for example in treating a lung cancer. The antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).The antibody is suitable for use in therapy, for example in treating a squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.The antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).The antibody is suitable for use in therapy, for example in treating a mesothelioma.The antibody is suitable for use in therapy, for example in treating a nasopharyngeal carcinoma (NPC).The antibody is suitable for use in therapy, for example in treating a colorectal cancer.The antibody is suitable for use in therapy, for example in treating a prostate cancer.The antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.The antibody is suitable for use in therapy, for example in treating a stomach cancer.The antibody is suitable for use in therapy, for example in treating an ovarian cancer.The antibody is suitable for use in therapy, for example in treating a gastric cancer.The antibody is suitable for use in therapy, for example in treating a liver cancer. The antibody is suitable for use in therapy, for example in treating a pancreatic cancer.The antibody is suitable for use in therapy, for example in treating a thyroid cancer.The antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.The antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract. The antibody is suitable for use in therapy, for example in treating a breast cancer. The antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.The antibody is suitable for use in therapy, for example in treating a brain cancer. The antibody is suitable for use in therapy, for example in treating an urethral cancer.The antibody is suitable for use in therapy, for example in treating an endometriosis.The antibody is suitable for use in therapy, for example in treating a cervical cancer.The antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.The antibody is suitable for use in therapy, for example in treating ahematological malignancy.The antibody is suitable for use in therapy, for example in treating a non- Hodgkin’s lymphoma.The antibody is suitable for use in therapy, for example in treating a chronic lymphocytic leukemia.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine. The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively.In some embodiments, the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 198 and 199, respectively.In some embodiments, the antibody comprises the VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65.In some embodiments, the antibody or the antigen-binding portion thereof binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 100 pM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 / ^ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG4 ^ isotype, comprising the S228P substitution when compared to the wild type IgG4. In some embodiments, the antibody comprises the HC of SEQ ID NO: 74 and the LC of SEQ ID NO: 75.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG2 / ^ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The antibody is suitable for use in therapy, for example in treating a melanoma. The antibody is suitable for use in therapy, for example in treating a lung cancer. The antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).The antibody is suitable for use in therapy, for example in treating a squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.The antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC). The antibody is suitable for use in therapy, for example in treating amesothelioma.The antibody is suitable for use in therapy, for example in treating anasopharyngeal carcinoma (NPC).The antibody is suitable for use in therapy, for example in treating a colorectal cancer.The antibody is suitable for use in therapy, for example in treating a prostate cancer.The antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.The antibody is suitable for use in therapy, for example in treating a stomach cancer.The antibody is suitable for use in therapy, for example in treating an ovarian cancer.The antibody is suitable for use in therapy, for example in treating a gastric cancer.The antibody is suitable for use in therapy, for example in treating a liver cancer. The antibody is suitable for use in therapy, for example in treating a pancreatic cancer.The antibody is suitable for use in therapy, for example in treating a thyroid cancer.The antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.The antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.The antibody is suitable for use in therapy, for example in treating a breast cancer. The antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.The antibody is suitable for use in therapy, for example in treating a brain cancer. The antibody is suitable for use in therapy, for example in treating an urethral cancer.The antibody is suitable for use in therapy, for example in treating an endometriosis.The antibody is suitable for use in therapy, for example in treating a cervical cancer. The antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.The antibody is suitable for use in therapy, for example in treating ahematological malignancy.The antibody is suitable for use in therapy, for example in treating a non- Hodgkin’s lymphoma.The antibody is suitable for use in therapy, for example in treating a chronic lymphocytic leukemia.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 24, 26 and 38, respectively.In some embodiments, the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 20, 30 and 32, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 202 and 203, respectively.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4. In some embodiments, the antibody comprises the HC of SEQ ID NO: 76 and the LC of SEQ ID NO: 77.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 16, 20, 26 and 31, respectively.In some embodiments, the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 212 and the LC of SEQ ID NO: 213.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprisingthe HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 16, 21, 26 and 32, respectively.In some embodiments, the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 214 and the LC of SEQ ID NO: 215.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 22, 27 and 33, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 216 and the LC of SEQ ID NO: 217.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 22, 26 and 34, respectively.In some embodiments, the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 218 and the LC of SEQ ID NO: 219.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 23, 28 and 35, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype. In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 220 and the LC of SEQ ID NO: 221.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 20, 26 and 31, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 20, 26 and 36, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 222 and the LC of SEQ ID NO: 223.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 21, 26 and 32, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 224 and the LC of SEQ ID NO: 225.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 21, 27 and 37, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 226 and the LC of SEQ ID NO: 227.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 23, 26 and 32, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype. In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 22, 26 and 32, respectively.In some embodiments, the antibody comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the HC of SEQ ID NO: 228 and the LC of SEQ ID NO: 229.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 18, 20, 26 and 31, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 20, 26 and 31, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 19, 20, 26 and 31, respectively. In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 20, 26 and 31, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 28 and 35, respectively.In some embodiments, the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 22, 26 and 34, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4. In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 20, 29 and 39, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 25, 26 and 40, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype. In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 24, 26 and 32, respectively.In some embodiments, the antibody of the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype.In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.The VH, the VL, the HCDR and the LCDR sequences of exemplary antagonistic antibodies specifically binding PD-1 of the invention are shown in Table 2.Although the embodiments illustrated in the Examples comprise pairs of variable regions, one from a heavy chain and one from a light chain, a skilled artisan will recognize that alternative embodiments may comprise single heavy or light chain variable regions. The single variable region may be used to screen for variable domains capable of forming a two-domain specific antigen-binding fragment capable of, for example, binding to human PD-1. The screening may be accomplished by phage display screening methods using for example hierarchical dual combinatorial approach disclosed in Int. Patent Publ. No. WO1992 / 01047. In this approach, an individual colony containing either a VH or a VL chain clone is used to infect a complete library of clones encoding the other chain (VL or VH), and the resulting two-chain specific antigen-binding domain is selected in accordance with phage display techniques using known methods and those described herein. Therefore, the individual VH and VL polypeptide chains are useful in identifying additional antibodies specifically binding to human PD-1 using the methods disclosed in Int. Patent Publ. No. WO1992 / 01047.In some embodiments, the antagonistic antibody specifically binding PD-1 is a multispecific antibody.In some embodiments, the antagonistic antibody specifically binding PD-1 is a bispecific antibody.In some embodiments, antagonistic bispecific antibody specifically binding PD-1 binds PD-L1 (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), TIM-3 (SEQ ID NO: 138), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), OX-40 (SEQ ID NO: 279), GITR (SEQ ID NO: 271), CD27 (SEQ ID NO: 280), VISTA (SEQ ID NO: 286), CD137 (SEQ ID NO: 281), TIGIT (SEQ ID NO: 301) or CTLA-4 (SEQ ID NO: 292). Bispecific and multispecific antibodies may be generated using methods described herein. Table 2.Homologous antibodiesVariants of the antagonistic antibodies specifically binding PD-1 or the antigen- binding portion thereof of the invention comprising the VH, the VL or the VH and the VL amino acid sequences shown in Table 2, Table 21 and Table 22 are within the scope of the invention. For example, variants may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions in the VH and / or the VL as long as the homologous antibodies retain or have improved functional properties when compared to the parental antibodies. In some embodiments, the sequence identity may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% to a VH or the VL amino acid sequence of the invention. Optionally, any variation of the variant compared to the parental antibody is not within the CDRs of the variant.The invention also provides an antagonistic antibody specifically binding PD-1or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprisingthe VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49;the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50;the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51;the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52;the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53;the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49; the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54;the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50;the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55;the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56;the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57;the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49;the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49;the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49;the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49;the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53;the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52;the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58;the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59;the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60;the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61;the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62; orthe VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 64 or 65. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH and the VL of SEQ ID NOs:41 and 49, respectively;41 and 50, respectively;42 and 51, respectively;42 and 52, respectively;42 and 53, respectively;43 and 49, respectively;43 and 54, respectively;43 and 50, respectively;43 and 55, respectively;43 and 56, respectively;43 and 57, respectively;44 and 49, respectively;45 and 49, respectively;46 and 49, respectively;47 and 49, respectively;48 and 53, respectively;48 and 52, respectively;47 and 58, respectively;47 and 59, respectively; 45 and 60, respectively;45 and 61, respectively;45 and 62, respectively; or63 and 65, respectively. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The homologous antagonistic antibodies specifically binding PD-1 or the antigen- binding portions thereof of the invention have one, two, three, four or five of the following properties:a) enhance an activation of antigen specific CD4+ or CD8+ T cells in a dosedependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1;b) bind human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;c) bind human PD-1 with the KD of less than about 1 nM, wherein the KD ismeasured using ProteOn XPR36 system at +25ºC;d) bind cynomolgus PD-1 of SEQ ID NO: 3 with the KD of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC, or e) bind cynomolgus PD-1 of SEQ ID NO: 3 with the KD of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody enhances activation of antigen specific CD4+ or CD8+ T cells in a dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody enhances activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 10 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions ×100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two amino acid sequences may be determined using the algorithm of E. Meyers and W. Miller (Comput Appl Biosci 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch ( J Mol Biol 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / _www_gcg_com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Antibodies with conservative modificationsThe invention also provides antagonistic antibodies specifically binding PD-1 or antigen-binding portions thereof comprising the VH comprising the HCDR1, the HCDR2 and the HCDR3 sequences and the VL comprising the LCDR1, the LCDR2 and the LCDR3 sequences, wherein one or more of the CDR sequences comprise specified amino acid sequences based on the antibodies described herein (e.g., antibodies shown in Table 2, Table 21 and Table 22, or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the parental antagonistic antibodies specifically binding PD-1 of the invention.The antibodies with conservative modifications have one, two, three, four or five of the following properties:a) enhance an activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1;b) bind human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;c) bind human PD-1 with the KD of less than about 1 nM, wherein the KD ismeasured using ProteOn XPR36 system at +25ºC;d) bind cynomolgus PD-1of SEQ ID NO: 3 with the KD of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC, or e) bind cynomolgus PD-1of SEQ ID NO: 3 with the KD of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody enhances activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antibody enhances activation of antigen specific CD4+ or CD8+ T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 10 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 ofSEQ ID NOs: 10, 13, 16, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 16, 21, 26 and 32, respectively;SEQ ID NOs: 10, 14, 16, 22, 27 and 33, respectively;SEQ ID NOs: 10, 14, 16, 22, 26 and 34, respectively;SEQ ID NOs: 10, 14, 16, 23, 28 and 35, respectively;SEQ ID NOs: 10, 13, 17, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 17, 20, 26 and 36, respectively;SEQ ID NOs: 10, 13, 17, 21, 26 and 32, respectively;SEQ ID NOs: 10, 13, 17, 21, 27 and 37, respectively;SEQ ID NOs: 10, 13, 17, 23, 26 and 32, respectively;SEQ ID NOs: 10, 13, 17, 22, 26 and 32, respectively;SEQ ID NOs: 10, 13, 18, 20, 26 and 31, respectively;SEQ ID NOs: 11, 15, 18, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 19, 20, 26 and 31, respectively;SEQ ID NOs: 12, 13, 19, 20, 26 and 31, respectively;SEQ ID NOs: 10, 14, 17, 23, 28 and 35, respectively; SEQ ID NOs: 10, 14, 17, 22, 26 and 34, respectively;SEQ ID NOs: 12, 13, 19, 24, 26 and 38, respectively;SEQ ID NOs: 12, 13, 19, 20, 29 and 39, respectively;SEQ ID NOs: 11, 15, 18, 20, 30 and 32, respectively;SEQ ID NOs: 11, 15, 18, 25, 26 and 40, respectively;SEQ ID NOs: 11, 15, 18, 24, 26 and 32, respectively, and conservative modifications thereof.“Conservative modification” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequences. Conservative modifications include amino acid substitutions, additions and deletions. Conservative substitutions are those in which the amino acid is replaced with an amino acid residue having a similar side chain. The families of amino acid residues having similar side chains are well defined and include amino acids with acidic side chains (for example, aspartic acid, glutamic acid), basic side chains (for example, lysine, arginine, histidine), nonpolar side chains (for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (for example, glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (for example, phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine), amide (for example, asparagine, glutamine), beta-branched side chains (for example, threonine, valine, isoleucine) and sulfur-containing side chains (cysteine, methionine). Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis (MacLennan et al., Acta Physiol. Scand. Suppl.643:55-67, 1998; Sasaki et al., Adv. Biophys.35:1-24, 1998). Amino acid substitutions to the antibodies of the invention may be made by well-known methods for example by PCR mutagenesis (US Pat. No.4,683,195). Alternatively, libraries of variants may be generated using known methods, for example using random (NNK) or non-random codons, for example DVK codons, which encode 11 amino acids (Ala, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp). The resulting antibody variants may be tested for their characteristics using assays described herein. Antagonistic antibodies specifically binding TIM-3T-cell immunoglobulin domain and mucin domain 3 (TIM-3, also known as Hepatitis A virus cellular receptor 2 (HAVCR2)) is a co-inhibitory immune checkpoint receptor that has been proposed to negatively regulate both adaptive and innate immune responses. TIM-3 is expressed on specific subsets of CD4+ and CD8+ T cells and functions to limit the duration and magnitude of T cell responses.Multiple lines of evidence support the inhibitory role of TIM-3 in regulating T cell responses. Tim-3-deficient mice exhibit defects in the induction of both antigen-specific and transplantation tolerance, consistent with TIM-3 inhibiting effector T cells during normal immune responses (Sabatos et al., (2003) Nat Immunol 4(11):1102-1110, Sanchez- Fueyo et al., (2003) Nat Immunol 4(11):1093-1101). Anti-TIM-3 antibodies exacerbate experimental autoimmune encephalomyelitis (EAE) in animal models (Monney et al., (2002) Nature 415(6871):536-541). TIM-3 has been shown to be a critical driver of the dysfunctional or exhausted T cell state that occurs in chronic infection and cancer (Sakuishi, K. and A. C. Anderson (2014). Tim-3 Regulation of Cancer Immunity. Tumor- Induced Immune Suppression. D. I. Gabrilovich and A. A. Hurwitz, Springer New York: 239-261).Blockade of TIM-3 has been shown to restore activity in effector cells, such as cytokine secretion and proliferation. In virally exhausted cell populations, e.g., cells infected with HCV, TIM-3-expressing cells (TIM-3+ cells) express less TNF- ^ and IFN- ^ cytokines than TIM-3 negative cells in both effector cell populations, CD4+ and CD8+ T cells (Golden-Mason et al., (2009) J Virol 83:9122). Blockade of TIM-3 restored proliferation in CD8+ T cells from an HIV patient, or in cells that recapitulated viral exhaustion (Jones et al., (2008) J Exp Med 205:2763), or proliferation and IFN-γ and / or TNF-α secretion in NY-ESO-1 specific T cells from PBMCs from metastatic patients (Fourcade et al., (2010) J Exp Med 207:2175). TIM-3+ T cells have been found to be concentrated in tumors, and contribute to the immunosuppressive tumor environment (Sakuishi et al., (2013) Oncoimmunology, 2:e23849).Blockade of TIM-3 (partially alone and additively or synergistically in combination with PD-1 pathway blockade) has shown anti-tumor efficacy in several preclinical cancer models, including CT26 colon carcinoma (Sakuishi et al., (2010) J Exp Med 207(10):2187-94), WT3 sarcoma and TRAMP-C1 prostate carcinoma (Ngiow et al., (2011) Cancer Res 71(10):3540-3551).The mechanisms through which TIM-3 inhibits T cell responses are not fully understood. The cytoplasmic tail of TIM-3 contains multiple tyrosine residues (Ferris et al., (2014) J Immunol 193(4): 1525-1530) but lacks inhibitory signaling motifs such as ITIMs or ITSMs that are found in the PD-1 intracellular tail. The Src family tyrosine kinases Fyn and Lck have been shown to bind to TIM-3, although the exact consequences of these interactions remain to be confirmed in vivo. Two opposing models have been proposed for how TIM-3 regulates T cell signaling. On one hand, TIM-3 has been postulated to negatively regulate TCR signaling by recruiting a phosphatase to the immunological synapse, and de-phosphorylating Lck (Clayton, et al., (2014) J Immunol 192(2):782-791). In contrast, TIM-3 has also been proposed to enhance TCR signaling and paradoxically drive T cells towards a more exhausted state, through increased activation of NFAT activity and NF ^B signaling.In addition to expression on effector T cells, TIM-3 is also expressed on regulatory T cells (T-regs) and has been shown to mark a suppressive T-reg subset in tumors. Analyses using both primary human cells and mouse preclinical models have shown that TIM-3+ T-regs are more effective at inhibiting T helper1 (Th1) and T helper 17 (Th17) T cell responses than TIM-3- T-regs (Gautron et al., (2014) Eur J Immunol 44(9): 2703-2711; Sakuishi et al., (2013) Oncoimmunology, 2:e23849). Since TIM-3 is expressed on highly suppressive Tregs, it can directly inhibit CD4+ and CD8+ T cell responses. In addition, TIM-3+ Tregs express high levels of IL-10, which has been proposed to drive exhaustion of effector T cells in the TME as an additional indirect mechanism of suppressing anti-tumor immune responses ( Sakuishi et al., (2013) Oncoimmunology, 2:e23849).TIM-3 is expressed on several innate immune cell types, includingmonocytes / macrophages, dendritic cells, and NK cells. Existing data are consistent with a suppressive role for TIM-3 in these different cell types.TIM-3 is constitutively expressed by circulating CD14+ monocytes in healthy donors, and its expression on peripheral monocytes is significantly increased in patients with chronic inflammation and cancer (Rong et al., (2014) Tissue Antigens 83(2):76-81). TIM-3 levels are also upregulated on macrophages that infiltrate hepatocellular carcinoma (HCC) tumors, compared to macrophages from adjacent tissues, and is proposed to play a role in driving the polarization of macrophages to an M2 tumor-promoting phenotype.Recently, TIM-3 was reported to be expressed on dendritic cells that infiltrate mouse tumors. In this setting, interaction of TIM-3 with HMBG1 was proposed to suppress innate immunity by interfering with the recognition of and response to immunostimulatory nucleic acid (Chiba et al., (2012) Immunol 13(9): 832-842). TIM-3 is also constitutively expressed on NK cells in peripheral blood. A recent study showed that NK cells from advanced melanoma patients express high levels of TIM-3 on peripheral NK cells. Importantly, TIM-3+ NK cells were functionally exhausted and anti-TIM-3 blockade was able to reverse the exhaustion and enhance NK cell functionality (da Silva et al., (2014) Cancer Immunol Res 2(5): 410-422). TIM-3 binds ligands galectin-9 (Gal-9), phosphatidylserine (PtdSer), HMGB1 and CEACAM-1. S-type lectin galectin-9 can inhibit TIM-3-associated Th1 effector function and induce apoptosis on TIM-3-expressing T cells in murine models. PtdSer usually resides on the intracellular side of the plasma membrane, but is flipped to the extracellular side during apoptosis. PtdSer binds a preserved cleft in all three human TIM family members (TIM-1, 3, 4). Inhibition of PtdSer binding to TIM-3 may activate T-cell response. Galectin-9 is secreted by tumor cells and can contribute to evasion from anti- tumor immunity. DNA alarmin HMGB1, for which TIM-3 may act as a“sink,” can prevent the HMGB1 / RAGE interactions that stimulate innate immunity. CEACAM-1 can interact with TIM-3 both in cis as a heterodimer on T cells and in trans as a ligand.Interaction between CEACAM-1 and TIM-3 may help mediate block immune response signaling. Co-blockade of TIM-3 and CEACAM-1 in CT26 colon carcinoma showed similar efficacy to that seen for co-blockade of PD-L1 and TIM-3.Thus, blockade of TIM-3 using the antibodies of the invention described herein that inhibit TIM-3 function may improve the immune response against infection and anti- tumor immunity.The invention also provides an isolated antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, wherein the antibody inhibits binding of TIM-3 to galectin-9.Inhibition of binding of TIM-3 to galectin-9 by the antibodies of the invention may be assessed using competition ELISA. In an exemplary assay, 1 µg / ml recombinant human Fc-TIM-3 is bound on wells of microtiter plates, the wells are washed and blocked, and 10 µg / ml of the test antibody is added. Without washing, 7.5 µg / ml galectin-9 is added into the wells and incubated for 30 min, after which 0.5 µg / ml anti-galectin-9-biotin antibody is added and incubated for 30 min. The plates are washed and 0.5 µg / mL neutravidin-HRP conjugate polyclonal antibody is added and incubated for 30 minutes. The plates are washed and POD Chemiluminescence substrate added immediately prior to reading the luminescence signal. Antibodies of the invention inhibit binding of TIM-3 to galectin-9 when the binding of galectin-9 is reduced by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% using an assay described herein and in Example 1. Exemplary antibodies that inhibit TIM-3 binding to galectin-9 are antibodies TM3B103, TM3B105, TM3B107, TM3B108, TM3B109, TM3B113, TM3B189, TM3B190 and TM3B196. In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof enhances activation of antigen specific CD4+ or CD8+ T cells.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof enhances an activation of antigen specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4+ or CD8+ T cells according to methods described in Example 14.Use of CD137 as a marker of antigen specific CD8+ and CD4+ T cells that expand in response to CMV antigen stimulation allowed the detection of the functional effects of the antagonistic TIM-3 antibodies of the invention.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 32-47(WGKGACPVFECGNVVL) (SEQ ID NO: 261).In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 32-47(WGKGACPVFECGNVVL) (SEQ ID NO: 261) and residues 50-56 (DERDVNY) (SEQ ID NO: 262).In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 90-102(RIQIPGIMNDEKF) (SEQ ID NO: 263).In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 90-102(RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262.“Within” means that 80% or more of the epitope residues the antibody binds to reside within the recited amino acid stretches, and that up to 20% of the epitope residues the antibody binds to reside outside of the recited amino acid stretches.The Tim-3 epitope the antibody binds to may be resolved for example using hydrogen / deuterium exchange (H / D exchange) or by analyzing a crystal structure of the antibody in complex with TIM-3. The epitope residues are those which are protected by the antibody by at least 5% difference in deuteration levels through H / D exchange or those surface exposed amino acid residues determined to bind the antibody in a crystal structure of a complex of the antibody and TIM-3. In the crystal structure of a complex of the antibody and TIM-3, the epitope residues are those TIM-3 residues that reside within 4 Å distance or less from any of the antibody CDR residues.In an H / D exchange assay, TIM-3 protein is incubated in the presence or absence of the antibody in deuterated water for predetermined times resulting in deuterium incorporation at exchangeable hydrogen atoms which are unprotected by the antibody, followed by protease digestion of the protein and analyses of the peptide fragments using LC-MS. In an exemplary assay, 5 µL of the test antibody ( 10 µg) or 5 µL of the complex of TIM-3 and the test antibody (10 and 7.35 µg, respectively) is incubated with 120 µL deuterium oxide labeling buffer (50mM phosphate, 100mM sodium chloride at pH 7.4) for 0 sec, 60 sec, 300 sec, 1800 sec, 7200 sec, and 14400 sec. Deuterium exchange is quenched by adding 63 µL of 5 M guanidine hydrochloride and final pH is 2.5. The quenched sample is subjected to on-column pepsin / protease type XIII digestion and LC- MS analysis. For pepsin / protease type XIII digestion, 5 µg of the samples in 125 µL control buffer (50mM phosphate, 100mM sodium chloride at pH 7.4) are denatured by adding 63 µL of 5 M guanidine hydrochloride (final pH is 2.5) and incubating the mixture for 3 min. Then, the mixture is subjected to on-column pepsin / protease type XIII digestion and the resultant peptides analyzed using an UPLC-MS system comprised of a Waters Acquity UPLC coupled to a Q ExactiveTM Hybrid Quadrupole-Orbitrap Mass Spectrometer (Thermo). Raw MS data is processed using HDX WorkBench, software for the analysis of H / D exchange MS data. The deuterium levels are calculated using the average mass difference between the deuteriated peptide and its native form (t0). Peptide identification is done through searching MS / MS data against the TIM-3 sequence with Mascot. The mass tolerance for the precursor and product ions is 20 ppm and 0.05 Da, respectively.For X-ray crystallography, TIM-3 and the test antibody are expressed and purified using standard protocols. The TIM-3 / test antibody complex is incubated overnight at 4 ^C, concentrated, and separated from the uncomplexed species using size-exclusion chromatography. The complex is crystallized by the vapor-diffusion method from various known test solutions for example solutions containing PEG3350, ammonium citrate and 2-Antibodies binding within Tim-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261), 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and / or 50-56 (DERDVNY) (SEQ ID NO: 262) may be generated by isolating antibodies binding TIM-3 using phage display libraries, selecting those antibodies that compete with the reference antibody TM3B105 (VH of SEQ ID NO: 146 and VL of SEQ ID NO: 156) or TM3B291 (VH of SEQ ID NO: 172 and VL of SEQ ID NO: 173) for binding to TIM-3 by 100%, and confirming the epitope of the generated antibodies by solving the crystal structure of the antibody / TIM-3 complex. Alternatively, mice, rats or rabbits may be immunized using peptides encompassing residues 32-47, 90-102 and / or 50-56 of TIM-3 and the generated antibodies may be evaluated for their binding within the recited region.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 164, 165 and 166, respectively.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 167, 168 and 169 respectively.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 164, 165 and 166, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 167, 168 and 169 respectively.SEQ ID NOs: 164, 165, 166, 167, 168 and 169 represent the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 genus sequences of TIM-3 antagonists derived from phage display libraries. The genus sequences were generated based on structural models that resulted in the sequence alignments given in Figure 13, Figure 14, Figure 15, Figure 16, Figure 17 and Figure 18 and summarized herein. SEQ ID NO: 164 wherein SEQ ID NO: 165X20IX21X22SGGSX23YYADSVKG,whereinX20 is A or V; X22 is G or Y; andX23 is T or K. SEQ ID NO: 166X24X25X26X27X28X29X30X31DY,whereinX24 is D, S, N, G or E;X25 is H, P, E, T or L;X26 is W, E, N or deleted;X27 is D, P or deleted;X28 is P, Y, D or deleted;X29 is N, A, D, G or deleted;X30 is F, P, R, W or V; andX31 is L or F. SEQ ID NO: 167X32X33SQSVX34X35X36X37X38X39X40X41X42LA, whereinX32 is R or K;X33 is A or S;X34 is S, N or L;X35 is S, A, N or deleted;X36 is S or deleted;X37 is S or deleted;X38 is N or deleted;X39 is N or deleted;X40 is K or deleted;X41 is S, D or N; andX42 is Y or T. SEQ ID NO: 168X43ASX44RX45X46,whereinX43 is G, D, W or T;X44 is S, N or T; X45 is A or E; andX46 is T or S. SEQ ID NO: 169QQX47X48X49X50PX51T (SEQ ID NO: 169),whereinX47 is Y, G or S;X48 is G or Y;X49 is S, H or T;X50 is S, A or T; andX51 is L, I or W. The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 contained within a heavy chain variable region (VH) of SEQ ID NOs: 145, 146, 147, 148 or 149, wherein the HCDR1, the HCDR2 and the HCDR3 are defined by Chothia, Kabat, or IMGT.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the LCDR1, the LCDR2 and the LCDR3 contained within a light chain variable region (VL) of SEQ ID NOs: 155, 156, 157 or 158, wherein the LCDR1, the LCDR2 and the LCDR3 are defined by Chothia, Kabat, or IMGT.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprisesthe HCDR1 of SEQ ID NOs: 90, 91, 92 or 93;the HCDR2 of SEQ ID NOs: 99, 100 or 101; andthe HCDR3 of SEQ ID NOs: 107, 108, 109, 110 or 111.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof of the invention comprisesthe LCDR1 of SEQ ID NOs: 117, 118, 119 or 120;the LCDR2 of SEQ ID NOs: 126, 127, 128 or 129; andthe LCDR3 of SEQ ID NOs: 135, 136, 137 or 139.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprisesthe HCDR1 of SEQ ID NOs: 90, 91, 92 or 93; the HCDR2 of SEQ ID NOs: 99, 100 or 101;the HCDR3 of SEQ ID NOs: 107, 108, 109, 110 or 111;the LCDR1 of SEQ ID NOs: 117, 118, 119 or 120;the LCDR2 of SEQ ID NOs: 126, 127, 128 or 129; orthe LCDR3 of SEQ ID NOs: 135, 136, 137 or 139.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 90, 99 and 107, respectively;SEQ ID NOs: 91, 99 and 108, respectively;SEQ ID NOs: 91, 99 and 109, respectively;SEQ ID NOs: 92, 100 and 110, respectively; orSEQ ID NOs: 93, 101 and 111, respectively;In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 117, 126 and 135, respectively;SEQ ID NOs: 118, 127 and 136, respectively;SEQ ID NOs: 119, 128 and 137, respectively; orSEQ ID NOs: 120, 129 and 139, respectively.In some embodiments, the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 ofSEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively;SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively;SEQ ID NOs: 91, 99, 109, 119, 128 and 137, respectively;SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively; orSEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively.The invention also provides an isolated antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2 and, the HCDR3 of SEQ ID NOs: 164, 165 and 108, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 118, 168 and 169 respectively.The invent ion also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively. In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 32-47(WGKGACPVFECGNVVL) (SEQ ID NO: 261).In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 32-47(WGKGACPVFECGNVVL) (SEQ ID NO: 261) and residues 50-56 (DERDVNY) SEQ ID NO: 262.In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof inhibits binding of TIM-3 to galectin-9.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-11 (SEQ ID NO: 171).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 204 and 205, respectively.In some embodiments, the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4+ or CD8+ T cells, wherein activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4+ or CD8+ T cells according to methods described in Example 14.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 / ^ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG4 ^ isotype comprising the S228P substitution when compared to the wild type IgG4. In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG2 / ^ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the HC of SEQ ID NO: 78 and the LC of SEQ ID NO: 79.In some embodiments, the antibody comprises the HC of SEQ ID NO: 240 and the LC of SEQ ID NO: 79. SEQ ID NO: 78EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPYAPLDYWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K SEQ ID NO: 79EIVLTQSPATLSLSPGERATLSCRASQSVNDYLAWYQQKPGQAPRLLIYDA SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQGGHAPITFGQGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 240EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPYAPLDYWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The antibody is suitable for use in therapy, for example in treating a melanoma. The antibody is suitable for use in therapy, for example in treating a lung cancer. The antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).The antibody is suitable for use in therapy, for example in treating a squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.The antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).The antibody is suitable for use in therapy, for example in treating amesothelioma.The antibody is suitable for use in therapy, for example in treating anasopharyngeal carcinoma (NPC).The antibody is suitable for use in therapy, for example in treating a colorectal cancer. The antibody is suitable for use in therapy, for example in treating a prostate cancer.The antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.The antibody is suitable for use in therapy, for example in treating a stomach cancer.The antibody is suitable for use in therapy, for example in treating an ovarian cancer.The antibody is suitable for use in therapy, for example in treating a gastric cancer.The antibody is suitable for use in therapy, for example in treating a liver cancer. The antibody is suitable for use in therapy, for example in treating a pancreatic cancer.The antibody is suitable for use in therapy, for example in treating a thyroid cancer.The antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.The antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.The antibody is suitable for use in therapy, for example in treating a breast cancer. The antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.The antibody is suitable for use in therapy, for example in treating a brain cancer. The antibody is suitable for use in therapy, for example in treating an urethral cancer.The antibody is suitable for use in therapy, for example in treating an endometriosis.The antibody is suitable for use in therapy, for example in treating a cervical cancer.The antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody that specifically binds PD-1. The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an antagonistic antibody specifically binding TIGIT (SEQ ID NO: 301).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA®(pembrolizumab)).The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)). The antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA® (pembrolizumab)).The antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g.KEYTRUDA® (pembrolizumab).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV5-51 (SEQ ID NO: 179) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).In some embodiments, the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 206 and 207, respectively.In some embodiments, the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4+ or CD8+ T cells according to methods described in Example 14.In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263).In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262. In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof inhibits binding of TIM-3 to galectin-9.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 / ^ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG4 ^ isotype comprising the S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG2 / ^ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG2 / ^ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody comprises the HC of SEQ ID NO: 80 and the LC of SEQ ID NO: 81. SEQ ID NO: 80EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWMQWVRQMPGKGLEWMGAIYP GDGDIRYTQNFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARWEKSTTVVQ RNYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKV DKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPMLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK SEQ IN NO: 81DIQMTQSPSSLSASVGDRVTITCKASENVGTFVSWYQQKPGKAPKLLIYGASNRY TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQSYSYPTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the antibody is a bispecific antibody, such as a bispecific PD-1 / TIM-3 antibody.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The antibody is suitable for use in therapy, for example in treating a melanoma. The antibody is suitable for use in therapy, for example in treating a lung cancer. The antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).The antibody is suitable for use in therapy, for example in treating a squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.The antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).The antibody is suitable for use in therapy, for example in treating amesothelioma.The antibody is suitable for use in therapy, for example in treating anasopharyngeal carcinoma (NPC).The antibody is suitable for use in therapy, for example in treating a colorectal cancer. The antibody is suitable for use in therapy, for example in treating a prostate cancer.The antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.The antibody is suitable for use in therapy, for example in treating a stomach cancer.The antibody is suitable for use in therapy, for example in treating an ovarian cancer.The antibody is suitable for use in therapy, for example in treating a gastric cancer.The antibody is suitable for use in therapy, for example in treating a liver cancer. The antibody is suitable for use in therapy, for example in treating a pancreatic cancer.The antibody is suitable for use in therapy, for example in treating a thyroid cancer.The antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.The antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.The antibody is suitable for use in therapy, for example in treating a breast cancer. The antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.The antibody is suitable for use in therapy, for example in treating a brain cancer. The antibody is suitable for use in therapy, for example in treating an urethral cancer.The antibody is suitable for use in therapy, for example in treating an endometriosis.The antibody is suitable for use in therapy, for example in treating a cervical cancer.The antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.The antibody is suitable for use in therapy, for example in treating ahematological malignancy.The antibody is suitable for use in therapy, for example in treating an acute lymphoblastic leukemia (ALL). The antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody that specifically binds PD-1.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.The antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 65 and the VL of SEQ ID NO: 65.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an antagonistic antibody specifically binding TIGIT (SEQ ID NO: 301).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).The antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g.KEYTRUDA® (pembrolizumab)). The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA® (pembrolizumab)).The antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g.KEYTRUDA® (pembrolizumab).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 208 and 209, respectively.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 109, 119, 128 and 137, In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157. The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.In some embodiments, the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 201 and 211, respectively.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 94, 102, 112, 121, 130 and 140, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-02 (SEQ ID NO: 175) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 95, 103, 113, 122, 131 and 141, respectively. In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV4-30-4 (SEQ ID NO: 176) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 96, 104, 114, 123, 132 and 142, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-03 (SEQ ID NO: 177) and a light chain framework derived from IGKV1-33 (SEQ ID NO: 183).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-03 (SEQ ID NO: 177) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 98, 106, 116, 125, 134 and 144, respectively.In some embodiments, the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV2-26 (SEQ ID NO: 178) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).In some embodiments, the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.In some embodiments, the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4+ or CD8+ T cells, wherein activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4+ or CD8+ T cells according to methods described in Example 14.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.The VH, the VL, the HCDR and the LCDR sequences of exemplary antagonistic antibodies specifically binding TIM-3 of the invention are shown in Table 3.Although the embodiments illustrated in the Examples comprise pairs of variable regions, one from a heavy chain and one from a light chain, a skilled artisan will recognize that alternative embodiments may comprise single heavy or light chain variable regions. The single variable region may be used to screen for variable domains capable of forming a two-domain specific antigen-binding fragment capable of, for example, binding to human TIM-3. The screening may be accomplished by phage display screening methods similarly as described herein.In some embodiments, the antagonistic antibody specifically binding TIM-3 is a multispecific antibody.In some embodiments, the antagonistic antibody specifically binding TIM-3 is a bispecific antibody.In some embodiments, the bispecific or the multispecific antibody binds PD-1 (SEQ ID NO: 1), PD-L1 (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), NKG2D (SEQ ID NO: 282), or TIGITI (SEQ ID NO: 301). Bispecific and multispecific antibodies may be generated using methods described herein. Table 3.Homologous antibodiesVariants of the antagonistic antibodies specifically binding TIM-3 of the invention comprising VH or VL amino acid sequences shown in Table 3, Table 36 and Table 37 are within the scope of the invention. For example, variants may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions in the VH and / or the VL as long as the homologous antibodies retain or have improved functional properties when compared to the parental antibodies. In some embodiments, the sequence identity may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% to a VH or the VL amino acid sequence of the invention.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof,, comprising the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ IS NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172 and the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs. The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs. The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173. Optionally, any variation from the sequences of the SEQ ID NOs is not within the CDRs.The homologous antibodies of the invention described herein have substantially similar functionality when compared to the parental TIM-3 antibodies. Antagonistic antibodies specifically binding TIM-3 of the invention with conservative modificationsThe invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH comprising the HCDR1, the HCDR2 and the HCDR3 sequences and the VL comprising the LCDR1, the LCDR2 and the LCDR3 sequences, wherein one or more of the CDR sequences comprise specified amino acid sequences based on the antibodies described herein (e.g., antibodies shown in Table 3, Table 36 or Table 37 or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the parental antagonistic antibodies specifically binding TIM-3 of the invention.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 109, 119, 128 and 137, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 94, 102, 112, 121, 130 and 140, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 95, 103, 113, 122, 131 and 141, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 96, 104, 114, 123, 132 and 142, respectively, and conservative modifications thereof.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively, and conservative modifications thereof. The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 98, 106, 116, 125, 134 and 144, respectively, and conservative modifications thereof.“Conservative modification” refers to modifications as described herein. Antagonistic antibodies specifically binding TIM-3 of the invention with specific framework sequencesThe invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL derived from particular human germline immunoglobulin sequences.The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174), IGHV1-02 (SEQ ID NO: 175), IGHV4-30-4 (SEQ ID NO: 176), IGHV1-03 (SEQ ID NO: 177), IGHV2-26 (SEQ ID NO: 178) or IGHV5-51 (SEQ ID NO: 179).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VL framework derived from IGKV3-20 (A27) (SEQ ID NO: 180), IGKV3-11 (L6) (SEQ ID NO: 171), IGKV4-1 (B3) (SEQ ID NO: 181), IGKV1-39) (O12) (SEQ ID NO: 182) or IGKV1-33 (O18) (SEQ ID NO: 183).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV3-20 (SEQ ID NO: 180).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV3-11 (SEQ ID NO: 171).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-02 (SEQ ID NO: 175) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV4-30-4 (SEQ ID NO: 176) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-03 (SEQ ID NO: 177) and the VL framework derived from IGKV1-33 (SEQ ID NO: 183).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-03 (SEQ ID NO: 177) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV2-26 (SEQ ID NO: 178) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).The invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV5-51 (SEQ ID NO: 179) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).The antibodies of the invention comprising heavy or light chain variable regions “derived from” a particular framework or germline sequence refer to antibodies obtained from a system that uses human germline immunoglobulin genes, such as from transgenic mice or from phage display libraries as discussed herein. An antibody that is“derived from” a particular framework or germline sequence may contain amino acid differences as compared to the sequence it was derived from, due to, for example, naturally-occurring somatic mutations or intentional substitutions.Exemplary antagonistic antibodies specifically binding TIM-3 having certain VH and VL framework sequences are shown in Table 38. Bispecific anti-PD-1 / TIM-3 antibodiesThe invention also provides antagonistic bispecific PD-1 / TIM-3 antibodies. The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances activation of antigen-specific CD4+ or CD8+ T cells.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances activation of antigen-specific CD4+ or CD8+ T cells, wherein enhanced activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4+ or CD8+ T cells.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention inhibits TIM-3 binding to galectin-9.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the inventionbinds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;binds human PD-1 with the KD of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;binds cynomolgus PD-1 with the KD of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC; orbinds cynomolgus PD-1 with the KD of less than about 1 nM;wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances an activation of antigen-specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4+ or CD8+ T cells and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances the activation of antigen-specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4+ or CD8+ T cells, and binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC. In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances the activation of antigen-specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4+ or CD8+ T cells and binds cynomolgus PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention enhances the activation of antigen-specific CD4+ or CD8+ T cells, wherein the activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4+ or CD8+ T cells, and binds cynomolgus PD-1 with an equilibrium dissociation constant (KD) of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.The antagonistic bispecific PD-1 / TIM-3 antibodies of the invention described herein may be evaluated for their ability to enhance antigen specific CD4+ or CD8+ T cell activation, to inhibit TIM-3 binding to galectin-9, and binding kinetics to human or cynomolgus PD-1 or TIM-3 may be assessed using methods described herein.For example, CD137 may be used as a marker for activation of antigen specific CD4+ or CD8+ T cells. CD137 surface expression may be measured on T cells cultured in the presence or in the absence of a test antibody, such as the bispecific PD-1 / TIM-3 antibody, using anti-CD137 antibody and a secondary antibody conjugated for example to a fluorescent dye. The statistically significant difference in the obtained signal on T cells cultured in the presence or in the absence of the test antibody is evaluated.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261).In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261) and residues 50-56 (DERDVNY) SEQ ID NO: 262.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263).In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262. In some embodiments, the first domain comprises a heavy chain complementarity determining region (HCDR) 1 a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively.In some embodiments, the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively.In some embodiments, the first domain comprises a light chain complementarity determining regions (LCDR) 1, a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.In some embodiments, the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.In some embodiments, the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.In some embodiments, the second domain comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 164, 165 and 166, respectively.In some embodiments, the second domain comprises the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 167, 168 and 169, respectively.In some embodiments, the second domain comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 164, 165 and 166, respectively, and the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 167, 168 and 169 respectively.In some embodiments, the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 ofSEQ ID NOs: 10, 13, 16, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 16, 21, 26 and 32, respectively;SEQ ID NOs: 10, 14, 16, 22, 27 and 33, respectively;SEQ ID NOs: 10, 14, 16, 22, 26 and 34, respectively;SEQ ID NOs: 10, 14, 16, 23, 28 and 35, respectively;SEQ ID NOs: 10, 13, 17, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 17, 20, 26 and 36, respectively;SEQ ID NOs: 10, 13, 17, 21, 26 and 32, respectively;SEQ ID NOs: 10, 13, 17, 21, 27 and 37, respectively;SEQ ID NOs: 10, 13, 17, 23, 26 and 32, respectively;SEQ ID NOs: 10, 13, 17, 22, 26 and 32, respectively; SEQ ID NOs: 10, 13, 18, 20, 26 and 31, respectively;SEQ ID NOs: 11, 15, 18, 20, 26 and 31, respectively;SEQ ID NOs: 10, 13, 19, 20, 26 and 31, respectively;SEQ ID NOs: 12, 13, 19, 20, 26 and 31, respectively;SEQ ID NOs: 10, 14, 17, 23, 28 and 35, respectively;SEQ ID NOs: 10, 14, 17, 22, 26 and 34, respectively;SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively;SEQ ID NOs: 12, 13, 19, 24, 26 and 38, respectively;SEQ ID NOs: 12, 13, 19, 20, 29 and 39, respectively;SEQ ID NOs: 11, 15, 18, 20, 30 and 32, respectively;SEQ ID NOs: 11, 15, 18, 25, 26 and 40, respectively;SEQ ID NOs: 11, 15, 18, 24, 26 and 32, respectively; orSEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively.In some embodiments, the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 ofSEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively;SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively;SEQ ID NOs: 91, 99, 109, 119, 128 and 137, respectively;SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively;SEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively;SEQ ID NOs: 94, 102, 112, 121, 130 and 140, respectively;SEQ ID NOs: 95, 103, 113, 122, 131 and 141, respectively;SEQ ID NOs: 96, 104, 114, 123, 132 and 142, respectively;SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively; orSEQ ID NOs: 98, 106, 116, 125, 134 and 144, respectively.In some embodiments, the first domain comprises the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs.In some embodiments, the first domain comprises the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs. In some embodiments, the first domain comprises the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 and 65, the VH, the VL, or the VH and the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs.In some embodiments, the second domain comprises the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs.In some embodiments, the second domain comprises the VL of SEQ IS NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs.In some embodiments, the second domain comprises the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172 and the VL of SEQ ID NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173, the VH and the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions. Optionally, any substitutions are not within the CDRs.In some embodiments, the first domain comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.In some embodiments, the first domain comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.In some embodiments, the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51.In some embodiments, the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52.In some embodiments, the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49. In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.In some embodiments, the first domain comprises the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.In some embodiments, the first domain comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49.In some embodiments, the first domain comprises the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49.In some embodiments, the first domain comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49.In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53.In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52.In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.In some embodiments, the first domain comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.In some embodiments, the first domain comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59.In some embodiments, the first domain comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.In some embodiments, the first domain comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61.In some embodiments, the first domain comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62. In some embodiments, the first domain comprises the VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65.In some embodiments, the first domain comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.In some embodiments, the second domain comprises the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.In some embodiments, the second domain comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.In some embodiments, the second domain comprises the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157.In some embodiments, the second domain comprises the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.In some embodiments, the second domain comprises the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.In some embodiments, the second domain comprises the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.In some embodiments, the second domain comprises the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.In some embodiments, the second domain comprises the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.In some embodiments, the second domain comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.In some embodiments, the second domain comprises the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.In some embodiments, the second domain comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3, wherein the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261). In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261) and residues 50-56 (DERDVNY) SEQ ID NO: 262.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody inhibits TIM-3 binding to galectin-9.In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and the second domain comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising a F405L and / or a K409R substitution.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 isotype comprising a F405L and a K409R substitution.In some embodiments, the antibody is an IgG4 isotype comprising a heavy chain substitution S228P when compared to the wild type IgG4.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises a first heavy chain (HC1) a first light chain (LC1), a second heavy chain (HC2) and a second light chain (LC2) of SEQ ID NOs: 241, 188, 245 or 194, respectively.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 186, 188, 191 or 194, respectively.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 186, 188, 248 or 194, respectively.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 243, 188, 246 or 194, respectively.The antibody is suitable for use in therapy, for example in treating a cancer. The antibody is suitable for use in therapy, for example in treating a solid tumor. The antibody is suitable for use in therapy, for example in treating a melanoma. The antibody is suitable for use in therapy, for example in treating a lung cancer. The antibody is suitable for use in therapy, for example in treating a non-small cell lung cancer (NSCLC)The antibody is suitable for use in therapy, for example in treating a squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.The antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.The antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).The antibody is suitable for use in therapy, for example in treating a mesothelioma.The antibody is suitable for use in therapy, for example in treating a nasopharyngeal carcinoma (NPC).The antibody is suitable for use in therapy, for example in treating a colorectal cancer.The antibody is suitable for use in therapy, for example in treating a prostate cancer.The antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.The antibody is suitable for use in therapy, for example in treating a stomach cancer.The antibody is suitable for use in therapy, for example in treating an ovarian cancer.The antibody is suitable for use in therapy, for example in treating a gastric cancer.The antibody is suitable for use in therapy, for example in treating a liver cancer. The antibody is suitable for use in therapy, for example in treating pancreatic cancer.The antibody is suitable for use in therapy, for example in treating a thyroid cancer. The antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.The antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.The antibody is suitable for use in therapy, for example in treating a breast cancer. The antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.The antibody is suitable for use in therapy, for example in treating a brain cancer. The antibody is suitable for use in therapy, for example in treating an urethral cancer.The antibody is suitable for use in therapy, for example in treating an endometriosis.The antibody is suitable for use in therapy, for example in treating a cervical cancer.The antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with anti-PD-1 antibody comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA® (pembrolizumab)).The antibody is suitable for use in therapy in a subject who is being treated or who has been treated with anti-PD-1 antibody comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The antibody is suitable for use in therapy in a subject who is refractory to treatment with the anti-PD-1 antibody comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA® (pembrolizumab)).The antibody is suitable for use in therapy in a subject who is refractory to treatment with the anti-PD-1 antibody comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the anti-PD-1 antibody comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g. KEYTRUDA® (pembrolizumab).The antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the anti-PD-1 antibody comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO® (nivolumab)). The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3, wherein the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs 97, 105, 115, 124, 133 and 143, respectively.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263).In some embodiments, the bispecific PD-1 / TIM-3 antibody binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262.In some embodiments, the bispecific PD-1 / TIM-3 antibody inhibits binding of TIM-3 to galectin-9.In some embodiments, the first domain comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and the second domain comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising a F405L and / or a K409R substitution.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 isotype comprising a F405L and a K409R substitution.In some embodiments, the antibody is an IgG4 isotype comprising a heavy chain substitution S228P when compared to the wild type IgG4.In some embodiments, the isolated bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 187, 189, 190 and 193, respectively.The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3, wherein the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively.In some embodiments, the first domain comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and the second domain comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising a F405L and / or a K409R substitution.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 isotype comprising a F405L and a K409R substitution.In some embodiments, the antibody is an IgG4 isotype comprising a heavy chain substitution S228P when compared to the wild type IgG4.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 187, 189, 191 and 194, respectively.In some embodiments, the isolated bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 242, 189, 246 and 194, respectively.The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3, wherein the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively. In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and the second domain comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising a F405L and / or a K409R substitution.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 isotype comprising a F405L and a K409R substitution.In some embodiments, the antibody is an IgG4 isotype comprising a heavy chain substitution S228P when compared to the wild type IgG4.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 186, 188, 192 and 195, respectively.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 241, 188, 244 and 195, respectively.In some embodiments, the isolated antagonistic bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 243, 188, 247 and 195, respectively.In some embodiments, the antibody enhances activation of antigen specific CD4+ or CD8+ T cells, wherein activation of antigen-specific CD4+ or CD8+ T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4+ or CD8+ T cells according to methods described in Example 14.The invention also provides an isolated antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3, wherein the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively.In some embodiments, the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and the second domain comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 156.In some embodiments, the antibody is an IgG1 isotype.In some embodiments, the antibody is an IgG2 isotype.In some embodiments, the antibody is an IgG2 isotype comprising a F405L and / or a K409R substitution.In some embodiments, the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.In some embodiments, the antibody is an IgG3 isotype.In some embodiments, the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.In some embodiments, the antibody is an IgG4 isotype comprising a F405L and a K409R substitution.In some embodiments, the antibody is an IgG4 isotype comprising a heavy chain substitution S228P when compared to the wild type IgG4.In some embodiments, the isolated bispecific PD-1 / TIM-3 antibody comprises the HC1, the LC1, the HC2 and the LC2 of SEQ ID NOs: 186, 188, 190 and 193, respectively.Exemplary antagonistic bispecific PD-1 / TIM-3 antibodies of the invention having certain VH, VL, HCDR and LCDR sequences as shown in Table 4 and Table 5. Table 4.PTBB24 48 56 10 14 17 23 26 32 PTBB30 48 56 10 14 17 23 26 32 PTBB27 48 56 10 14 17 23 26 32 PTBB28 48 56 10 14 17 23 26 32 PTBB18 64 65 66 67 68 69 70 71 PTBB20 48 56 10 14 17 23 26 32 PTBB21 48 56 10 14 17 23 26 32Table 5. TIM-3 binding arm SEQ ID NOs:mAb HCDRs LCDR2VH VL1 2 3 1 2 3 PTBB14 153 162 97 105 115 124 133 143 PTBB15 146 156 91 99 108 118 127 136 PTBB16 153 162 97 105 115 124 133 143 PTBB17 146 156 91 99 108 118 127 136 PTBB24 172 173 97 105 115 124 133 143 PTBB30 146 156 91 99 108 118 127 136 PTBB27 172 173 97 105 115 124 133 143 PTBB28 146 156 91 99 108 118 127 136 PTBB18 146 156 91 99 108 118 127 136 PTBB20 146 156 91 99 108 118 127 136 PTBB21 172 173 97 105 115 124 133 143Engineered and modified antibodiesThe antibodies of the invention may further be engineered to generate modified antibodies with similar or altered properties when compared to the parental antibodies. The VH, the VL, the VH and the VL, the constant regions, VH framework, VL framework, or any or all of the six CDRs may be engineered in the antibodies of the invention.“The antibodies of the invention” as used herein refers to the antagonistic antibodies specifically binding PD-1, the antagonistic antibodies specifically binding TIM- 3, and the antagonistic bispecific PD-1 / TIM-3 antibodies comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 (e.g. bispecific PD-1 / TIM-3 antibodies) as described herein.The antibodies of the invention may be engineered by CDR grafting. One or more CDR sequences of the antibodies of the invention described herein may be grafted to a different framework sequence. CDR grafting may be done using known methods and methods described herein.In some embodiments, the antagonistic antibodies specifically binding PD-1 or the bispecific PD-1 / TIM-3 antibodies of the invention comprise the VH that comprises the HDCR1 of SEQ ID NOs: 10, 11 or 12, the HCDR2 of SEQ ID NOs: 13, 14 or 15, the HCDR3 of SEQ ID NOs: 16, 17, 18 or 19, and the VL that comprises the LCDR1 of SEQ ID NOs: 20, 21, 22, 23, 24 or 25, the LCDR2 of SEQ ID NOs: 26, 27, 28, 29 or 30, and / or the LCDR3 of SEQ ID NOs: 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, wherein the VH framework is derived from the VH framework other than VH1-69 (SEQ ID NO: 170) and the VL framework is derived from the VL framework other than IGKV3-11 (SEQ ID NO: 171).In some embodiments, the antagonistic antibodies specifically binding TIM-3 or the bispecific PD-1 / TIM-3 antibodies of the invention comprise the HDCR1 of SEQ ID NOs: 90, 91, 92, 93, 94, 95, 96, 97 or 98, the HCDR2 of SEQ ID NOs: 99, 100, 101, 102, 10, 104, 105 or 106, the HCDR3 of SEQ ID NOs: 107, 108, 109, 110, 111, 112, 113, 114, 115 or 116, and the VL that comprises the LCDR1 of SEQ ID NOs: 117, 118, 119, 120, 121, 122, 123, 124 or 125, the LCDR2 of SEQ ID NOs: 126, 127, 128, 129, 130, 131, 132, 133 or 134, and / or the LCDR3 of SEQ ID NOs: 135, 136, 137, 139, 140, 141, 142, 143 or 144, wherein the VH framework is derived from the human VH germline gene sequences other than those of IGHV3-23 (SEQ ID NO: 174), IGHV1-02 (SEQ ID NO: 175), IGHV4- 30-4 (SEQ ID NO: 176), IGHV1-03 (SEQ ID NO: 177), IGHV2-26 (SEQ ID NO: 178) or IGHV5-51 (SEQ ID NO: 179), and the VL framework is derived from the human VL germline gene sequences other than those of IGKV3-20 (A27) (SEQ ID NO: 180 ), IGKV3-11 (L6) (SEQ ID NO: 171), IGKV4-1 (B3) (SEQ ID NO: 181), IGKV1-39 (O12) (SEQ ID NO: 182) or IGKV1-33 (O18) (SEQ ID NO: 183). The framework sequences to be used may be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA and the encoded protein sequences of human heavy and light chain variable region genes may be found at IMGT®, the international ImMunoGeneTics information system® (http: / / _www-imgt_org). Framework sequences that may be used to replace the existing framework sequences in the antibodies of the invention may be those that show the highest percent identity to the parental frameworks over the entire length of the VH or the VL, or over the length of the FR1, FR2, FR3 and FR4. In addition, suitable frameworks may further be selected based on the VH and the VL CDR1 and CDR2 lengths or identical LCDR1, LCDR2, LCDR3, HCDR1 and HCDR2 canonical structure. Suitable frameworks may be selected using known methods, such as human framework adaptation described in U.S. Patent No.8,748,356 or superhumanization described in U.S. Patent No.7,709, 226.The framework sequences of the parental and engineered antibodies may further be modified, for example by backmutations to restore and / or improve binding of the generated antibody to the antigen as described for example in U.S. Patent No.6,180,370. The framework sequences of the parental or engineered antibodies may further be modified by mutating one or more residues within the framework region, or within one or more CDR regions, to remove T-cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as“deimmunization” and described in further detail in U.S. Patent Publ. No. US20070014796.The CDR residues of the antibodies of the invention may be mutated to improve affinity of the antibodies to PD-1, TIM-3, or PD-1 and TIM-3.The CDR residues of the antibodies of the invention may be mutated for example to minimize risk of post-translational modifications. Amino acid residues of putative motifs for deamination (NS), acid-catalyzed hydrolysis (DP), isomerization (DS), or oxidation (W) may be substituted with any of the naturally occurring amino acids to mutagenize the motifs, and the resulting antibodies may be tested for their functionality and stability using methods described herein.Fc substitutions may be made to the antibodies of the invention to modulate antibody effector functions and pharmacokinetic properties. In traditional immune function, the interaction of antibody-antigen complexes with cells of the immune system results in a wide array of responses, ranging from effector functions such as antibody- dependent cytotoxicity, mast cell degranulation, and phagocytosis to immunomodulatory signals such as regulating lymphocyte proliferation and antibody secretion. All of these interactions are initiated through the binding of the Fc domain of antibodies or immune complexes to specialized cell surface receptors on hematopoietic cells. The diversity of cellular responses triggered by antibodies and immune complexes results from the structural heterogeneity of the three Fc receptors: FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). FcγRI (CD64), FcγRIIA (CD32A) and FcγRIII (CD16) are“activating Fcγ receptors” (i e, immune system enhancing); FcγRIIB (CD32B) is an inhibiting Fcγ receptor” (i.e., immune system dampening). Binding to the FcRn receptor modulates antibody half-life.In some embodiments, the antagonistic antibodies of the invention comprise at least one substitution in an Fc regionIn some embodiments, the antagonistic antibodies of the invention comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or Fc positions that may be substituted to modulate antibody half-life are those described for example in Dall’Acqua et al., (2006) J Biol Chem 281:23514–240, Zalevsky et al., (2010) Nat Biotechnol 28:157-159, Hinton et al., (2004) J Biol Chem 279(8):6213- 6216, Hinton et al., (2006) J Immunol 176:346-356, Shields et al.(2001) J Biol Chem 276:6591-6607, Petkova et al., (2006). Int Immunol 18:1759-1769, Datta-Mannan et al., (2007) Drug Metab Dispos, 35:86-94, 2007, Vaccaro et al., (2005) Nat Biotechnol 23:1283-1288, Yeung et al., (2010) Cancer Res, 70:3269-3277 and Kim et al., (1999) Eur J Immunol 29: 2819, and include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434 and 435. Exemplary substitutions that may be made singularly or in combination are substitutions T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R. Exemplary singular or combination substitutions that may be made to increase the half-life of the antibody are substitutions M428L / N434S, M252Y / S254T / T256E, T250Q / M428L, N434A and T307A / E380A / N434A. Exemplary singular or combination substitutions that may be made to reduce the half-life of the antibody are substitutions H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A and H435R.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc at amino acid position 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434 or 435.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc selected from the group consisting of T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R. In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc selected from the group consisting of M428L / N434S, M252Y / S254T / T256E, T250Q / M428L, N434A, T307A / E380A / N434A, H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A and H435R.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc that reduces binding of the antibody to an activating Fc ^ receptor (Fc ^R) and / or reduces Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).Fc positions that may be substituted to reduce binding of the antibody to the activating Fc ^R and subsequently to reduce effector function are those described for example in Shields et al., (2001) J Biol Chem 276:6591-6604, Intl. Patent Publ. No. WO2011 / 066501, U.S. Patent Nos. 6,737,056 and 5,624,821, Xu et al., (2000) Cell Immunol, 200:16-26, Alegre et al., (1994) Transplantation 57:1537-1543, Bolt et al., (1993) Eur J Immunol 23:403-411, Cole et al., (1999) Transplantation, 68:563-571, Rother et al., (2007) Nat Biotechnol 25:1256-1264, Ghevaert et al., (2008) J Clin Invest 118:2929-2938, An et al., (2009) mAbs, 1:572-579) and include positions 214, 233, 234, 235, 236, 237, 238, 265, 267, 268, 270, 295, 297, 309, 327, 328, 329, 330, 331 and 365. Exemplary substitutions that may be made singularly or in combination are substitutions K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A330S and P331S in IgG1, IgG2, IgG3 or IgG4. Exemplary combination substitutions that result in antibodies with reduced ADCC are substitutions L234A / L235A on IgG1, V234A, / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deleted / A327G / P331A / D365E / L358M on IgG1, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1,S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236- deleted / G237A / P238S on IgG4. Hybrid IgG2 / 4 Fc domains may also be used, such as Fc with residues 117-260 from IgG2 and residues 261-447 from IgG4. Well-known S228P substitution may be made in IgG4 antibodies to enhance IgG4 stability.In some embodiments, the antibodies of the invention comprise a substitution in at least one residue position 214, 233, 234, 235, 236, 237, 238, 265, 267, 268, 270, 295, 297, 309, 327, 328, 329, 330, 331 or 365, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise at least one substitution selected from the group consisting of K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A330S and P331S, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a substitution in at least one residue position 228, 234, 235, 237, 238, 268, 330 or 331, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a S228P substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a V234A substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a F234A substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a G237A substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a P238S substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a H268A substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a Q268A substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise an A330S substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise a P331S substitution, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise L234A, L235A, G237A, P238S, H268A, A330S and P331S substitutions, wherein residue numbering is according to the EU Index. In some embodiments, the antibodies of the invention comprise V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise F234A, L235A, G237A, P238S and Q268A substitutions, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise L234A, L235A or L234A and L235A substitutions, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise F234A, L235A or F234A and L235A substitutions, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise S228P, F234A and L235A substitutions, wherein residue numbering is according to the EU Index.In some embodiments, the antibodies of the invention comprise at least one substitution in an antibody Fc that enhances binding of the antibody to an Fc ^ receptor (Fc ^R) and / or enhances Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).In addition to their immunomodulatory activity, the PD-1 or the TIM-3 antibodies of the invention may kill tumor cells expressing PD-1 and / or TIM-3 directly via antibody- mediated effector functions, for example by ADCC, ADCP or CDC.Fc positions that may be substituted to increase binding of the antibody to the activating Fc ^ and / or enhance antibody effector functions are those described for example in U.S. Patent No.6,737,056, U.S. Patent Publ. No.2015 / 0259434, Shields et al., (2001) J Biol Chem 276:6591-6604, Lazar et al., (2006) Proc Natal Acad Sci, 103:4005-4010, Stavenhagen et al., (2007) Cancer Res 67:8882-8890, Richards et al., (2008) Mol Cancer Ther 7:2517-2527, Diebolder et al., Science; published online March 13, 2014;doi:10.1126 / science.1248943, and include positions 236, 239, 243, 256, 290, 292, 298, 300, 305, 312, 326, 330, 332, 333, 334, 345, 360, 339, 378, 396 or 430 (residue numbering according to the EU index). Exemplary substitutions that may be made singularly or in combination are G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T and P396L. Exemplary combination substitutions that result in antibodies with increased ADCC or ADCP are substitutions S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L andG236A / S239D / I332E on IgG1.Fc positions that may be substituted to enhance CDC of the antibody are those described for example in Int. Patent Appl. WO2014 / 108198, Idusogie et al., (2001) J Immunol 166:2571-2575 and Moore et al., (2010) Mabs, 2:181-189, and include positions 267, 268, 324, 326, 333, 345 and 430. Exemplary substitutions that may be made singularly or in combination are substitutions S267E, H268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F and E430T. Exemplary combination substitutions that result in antibodies with increased CDC are substitutions K326A / E333A, K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T and S267E / H268F / S324T on IgG1."Antibody-dependent cellular cytotoxicity", "antibody-dependent cell-mediated cytotoxicity" or“ADCC" is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells with effector cells possessing lytic activity, such as natural killer cells, monocytes, macrophages and neutrophils via Fc gamma receptors (Fc ^R) expressed on effector cells. For example, NK cells express Fc ^RIIIa, whereas monocytes express Fc ^RI, Fc ^RII and Fc ^RIIIa. Death of the antibody-coated target cell, such as PD-1 or TIM-3 expressing cells, occurs as a result of effector cell activity through the secretion of membrane pore-forming proteins and proteases. To assess ADCC activity of the antibody of the invention described herein, the antibody may be added to TIM-3 or PD-1 expressing cells in combination with immune effector cells, which may be activated by the antigen antibody complexes resulting in cytolysis of the target cell. Cytolysis may be detected by the release of label (e.g. radioactive substrates, fluorescent dyes or natural intracellular proteins) from the lysed cells. Exemplary effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells. Exemplary target cells include cells expressing TIM-3 or PD-1 either endogenously or recombinantly. In an exemplary assay, target cells are used with a ratio of 1 target cell to 50 effector cells. Target cells are pre-labeled with BATDA (PerkinElmer) for 20 minutes at 37°C, washed twice and resuspended in DMEM, 10% heat-inactivated FBS, 2mM L-glutamine (all from Invitrogen). Target (1x104 cells) and effector cells (0.5x106 cells) are combined and 100 μl of cells are added to the wells of 96-well U-bottom plates. An additional 100 μl is added with or without the test antibodies. The plates are centrifuged at 200g for 3 minutes, incubated at 37°C for 2 hours, and then centrifuged again at 200g for 3 minutes. A total of 20 μl of supernatant is removed per well and cell lysis is measured by the addition of 200 μl of the DELPHIA Europium-based reagent (PerkinElmer). Data is normalized to maximal cytotoxicity with 0.67% Triton X-100 (Sigma Aldrich) and minimal control determined by spontaneous release of BATDA from target cells in the absence of any antibody. The antibody of the invention may induce ADCC by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% ."Antibody-dependent cellular phagocytosis" ("ADCP") refers to a mechanism of elimination of antibody-coated target cells by internalization by phagocytic cells, such as macrophages or dendritic cells. ADCP may be evaluated by using monocyte-derived macrophages as effector cells and Daudi cells (ATCC® CCL-213™) or B cell leukemia or lymphoma or tumor cells expressing TIM-3 or PD-1 as target cells engineered to express GFP or other labeled molecule. Effector:target cell ratio may be for example 4:1. Effector cells may be incubated with target cells for 4 hours with or without the antibody of the invention. After incubation, cells may be detached using accutase. Macrophages may be identified with anti-CD11b and anti-CD14 antibodies coupled to a fluorescent label, and percent phagocytosis may be determined based on % GFP fluorescence in theCD11+CD14+ macrophages using standard methods. The antibody of the invention may induce ADCP by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% .“Complement-dependent cytotoxicity”, or”CDC”, refers to a mechanism for inducing cell death in which the Fc effector domain of a target-bound antibody binds and activates complement component C1q which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes. CDC of TIM-3 or PD-1 expressing cells may be measured for example by plating Daudi cells at 1×105 cells / well (50 μl / well) in RPMI-B (RPMI supplemented with 1% BSA), adding 50 μl of test antibodies to the wells at final concentration between 0-100 μg / ml, incubating the reaction for 15 min at room temperature, adding 11 μl of pooled human serum to the wells, and incubation the reaction for 45 min at 37° C. Percentage (%) lysed cells may be detected as % propidium iodide stained cells in FACS assay using standard methods. Antibodies of the invention may induce CDC by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% .The ability of antibodies of the invention described herein to induce ADCC may be enhanced by engineering their oligosaccharide component. Human IgG1 or IgG3 are N-glycosylated at Asn297 with the majority of the glycans in the well-known biantennary G0, G0F, G1, G1F, G2 or G2F forms. Antibodies produced by non-engineered CHO cells typically have a glycan fucose content of about at least 85%. The removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc regions enhances the ADCC of antibodies via improved FcγRIIIa binding without altering antigen binding or CDC activity. Such mAbs may be achieved using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., (2012) Cytotechnology 64:249-65), application of a variant CHO line Lec13 as the host cell line (Shields et al., (2002) J Biol Chem 277:26733-26740), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., (2003) J Biol Chem 278:3466-3473), introduction of small interfering RNA specifically against the ^ 1,6-fucosyltrasferase ( FUT8) gene (Mori et al., (2004) Biotechnol Bioeng 88:901-908), or coexpression of β-1,4-N- acetylglucosaminyltransferase III and Golgi α-mannosidase II or a potent alpha- mannosidase I inhibitor, kifunensine (Ferrara et al., (2006) J Biol Chem 281:5032-5036, Ferrara et al., (2006) Biotechnol Bioeng 93:851-861; Xhou et al., (2008) Biotechnol Bioeng 99:652-65).In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc that enhances effector function of the antibody.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc at amino acid position 236, 239, 243, 256, 267, 268, 290, 292, 298, 300, 305, 312, 324, 326, 330, 332, 333, 334, 345, 360, 339, 378, 396 or 430.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc selected from the group consisting of G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T, P396L, S267E, H268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F and E430T.In some embodiments, the antibodies of the invention comprise at least one substitution in the antibody Fc selected from the group consisting of S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L,F243L / R292P / Y300L / V305I / P396L, G236A / S239D / I332E, K326A / E333A,K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T and S267E / H268F / S324T. In some embodiments, the antibodies of the invention have a biantennary glycan structure with fucose content of about between 0% to about 15%, for example 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%.In some embodiments, the antibodies of the invention have a biantennary glycan structure with fucose content of about 50%, 40%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%.Substitutions in the Fc and reduced fucose content may enhance the ADCC activity of the antagonistic antibodies specifically binding TIM-3 or PD-1 of the invention. TIM-3 or PD-1 antibodies with enhanced ADCC, ADCP and / or CDC activity may be useful in the treatment of patients with TIM-3 and / or PD-1 expressing tumors, including heme malignancies.“Fucose content” means the amount of the fucose monosaccharide within the sugar chain at Asn297. The relative amount of fucose is the percentage of fucose- containing structures related to all glycostructures. These may be characterized and quantified by multiple methods, for example: 1) using MALDI-TOF of N-glycosidase F treated sample (e.g. complex, hybrid and oligo- and high-mannose structures) as described in Intl. Patent Publ. No. WO2008 / 077546; 2) by enzymatic release of the Asn297 glycans with subsequent derivatization and detection / quantitation by HPLC (UPLC) with fluorescence detection and / or HPLC-MS (UPLC-MS); 3) intact protein analysis of the native or reduced mAb, with or without treatment of the Asn297 glycans with Endo S or other enzyme that cleaves between the first and the second GlcNAc monosaccharides, leaving the fucose attached to the first GlcNAc; 4) digestion of the mAb to constituent peptides by enzymatic digestion (e.g., trypsin or endopeptidase Lys-C), and subsequent separation, detection and quantitation by HPLC-MS (UPLC-MS) or 5) separation of the mAb oligosaccharides from the mAb protein by specific enzymatic deglycosylation with PNGase F at Asn 297. The oligosaccharides released may be labeled with a fluorophore, separated and identified by various complementary techniques which allow fine characterization of the glycan structures by matrix-assisted laser desorption ionization (MALDI) mass spectrometry by comparison of the experimental masses with the theoretical masses, determination of the degree of sialylation by ion exchange HPLC (GlycoSep C), separation and quantification of the oligosaccharide forms according to hydrophilicity criteria by normal-phase HPLC (GlycoSep N), and separation and quantification of the oligosaccharides by high performance capillary electrophoresis-laser induced fluorescence (HPCE-LIF). “Low fucose” or“low fucose content” refers to antibodies with fucose content of about 0% - 15%.“Normal fucose” or‘normal fucose content” refers to antibodies with fucose content of about over 50%, typically about over 60%, 70%, 80% or over 85%.The antibodies of the invention may be post-translationally modified by processes such as glycosylation, isomerization, deglycosylation or non-naturally occurring covalent modification such as the addition of polyethylene glycol moieties (pegylation) and lipidation. Such modifications may occur in vivo or in vitro. For example, the antibodies of the invention described herein may be conjugated to polyethylene glycol (PEGylated) to improve their pharmacokinetic profiles. Conjugation may be carried out by techniques known to those skilled in the art. Conjugation of therapeutic antibodies with PEG has been shown to enhance pharmacodynamics while not interfering with function (Knigh et al., (2004) Platelets 15:409-18; Leong et al., (2001) Cytokine 16:106-19; Yang et al., (2003) Protein Eng 16:761-70).Antibodies of the invention may be modified to improve stability, selectivity, cross-reactivity, affinity, immunogenicity or other desirable biological or biophysical property are within the scope of the invention. Stability of an antibody is influenced by a number of factors, including (1) core packing of individual domains that affects their intrinsic stability, (2) protein / protein interface interactions that have impact upon the HC and LC pairing, (3) burial of polar and charged residues, (4) H-bonding network for polar and charged residues; and (5) surface charge and polar residue distribution among other intra- and inter-molecular forces (Worn et al., (2001) J Mol Biol 305:989-1010). Potential structure destabilizing residues may be identified based upon the crystal structure of the antibody or by molecular modeling in certain cases, and the effect of the residues on antibody stability may be tested by generating and evaluating variants harboring mutations in the identified residues. One of the ways to increase antibody stability is to raise the thermal transition midpoint (Tm) as measured by differential scanning calorimetry (DSC). In general, the protein Tm is correlated with its stability and inversely correlated with its susceptibility to unfolding and denaturation in solution and the degradation processes that depend on the tendency of the protein to unfold (Remmele et al., (2000) Biopharm 13:36- 46). A number of studies have found correlation between the ranking of the physical stability of formulations measured as thermal stability by DSC and physical stability measured by other methods (Gupta et al., (2003) AAPS PharmSci 5E8; Zhang et al., (2004) J Pharm Sci 93:3076-89; Maa et al., (1996) Int J Pharm 140:155-68; Bedu-Addo et al., (2004) Pharm Res 21:1353-61; Remmele et al., (1997) Pharm Res 15:200-8). Formulation studies suggest that a Fab Tm has implication for long-term physical stability of a corresponding mAb.C-terminal lysine (CTL) may be removed from injected antibodies by endogenous circulating carboxypeptidases in the blood stream (Cai et al., (2011) Biotechnol Bioeng 108:404-412). During manufacturing, CTL removal may be controlled to less than the maximum level by control of concentration of extracellular Zn2+, EDTA or EDTA– Fe3+ as described in U.S. Patent Publ. No. US20140273092. CTL content in antibodies can be measured using known methods.In some embodiments, the antibodies of the invention have a C-terminal lysine content of about 10% to about 90%, about 20% to about 80%, about 40% to about 70%, about 55% to about 70%, or about 60%.In some embodiments, the antibodies of the invention have a C-terminal lysine content of about 0%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. Methods of generating homologous antibodies, antibodies with conservative modifications, and engineered and modified antibodiesThe antibodies of the invention that have altered amino acid sequences when compared to the parental antibodies may be generated using standard cloning and expression technologies. For example, site-directed mutagenesis or PCR-mediated mutagenesis may be performed to introduce the mutation(s) and the effect on antibody binding or other property of interest, may be evaluated using well known methods and the methods described herein in the Examples. Antibody allotypesThe antibody of the invention may be an IgG1, IgG2, IgG3 or IgG4 isotype. In some embodiments, the antibody of the invention is an IgG1 isotype.In some embodiments, the antibody of the invention is an IgG2 isotype.In some embodiments, the antibody of the invention is an IgG3 isotype.In some embodiments, the antibody of the invention is an IgG4 isotype.Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host may be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 6 shows select IgG1, IgG2 and IgG4 allotypes.In some embodiments, the antagonistic antibodies specifically binding PD-1 of the invention are of G2m(n), G2m(n-), G2m(n) / (n-), nG4m(a), G1m(17) or G1m(17,1) allotype.In some embodiments, the antagonistic antibodies specifically binding TIM-3 of the invention are of G2m(n), G2m(n-), G2m(n) / (n-), nG4m(a), G1m(17) or G1m(17,1) allotype.In some embodiments, the bispecific PD-1 / TIM-3 antibodies of the invention are of G2m(n), G2m(n-), G2m(n) / (n-), nG4m(a), G1m(17) or G1m(17,1) allotype. Table 6.Anti-idiotypic antibodiesThe present invention provides an anti-idiotypic antibody binding to the antibody of the invention.The invention also provides an anti-idiotypic antibody specifically binding to the anti-PD-1 antibody of the invention.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51. The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59. The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.The invention also provides an anti-idiotypic antibody specifically binding the antagonistic antibody specifically binding TIM-3 of the invention.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.In some embodiments, the kit comprises the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56. In some embodiments, the kit comprises the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.The invention also provides an anti-idiotypic antibody specifically binding the antibody comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.In some embodiments, the anti-idiotypic antibody is used for detecting the level of the therapeutic antibodies (e.g. anti-PD-1, anti-TIM-3 or the bispecific PD-1 / TIM-3 antibodies of the invention described herein) in a sample.An anti-idiotypic (Id) antibody is an antibody which recognizes the antigenic determinants (e.g. the paratope or CDRs) of the antibody. The Id antibody may be antigen-blocking or non-blocking. The antigen-blocking Id may be used to detect the free antibody in a sample (e.g. anti-PD-1, anti-TIM-3 or the bispecific PD-1 / TIM-3 antibody of the invention described herein). The non-blocking Id may be used to detect the total antibody (free, partially bond to antigen, or fully bound to antigen) in a sample. An Id antibody may be prepared by immunizing an animal with the antibody to which an anti-Id is being prepared.An anti-Id antibody may also be used as an immunogen to induce an immune response in yet another animal, producing a so-called anti-anti-Id antibody. An anti-anti-Id may be epitopically identical to the original mAb, which induced the anti-Id. Thus, by using antibodies to the idiotypic determinants of a mAb, it is possible to identify other clones expressing antibodies of identical specificity. Anti-Id antibodies may be varied (thereby producing anti-Id antibody variants) and / or derivatized by any suitable technique, such as those described elsewhere herein with respect to the antibodies specifically binding PD-1 or TIM-3, or the bispecific PD-1 / TIM-3 antibodies. ImmunoconjugatesAn "immunoconjugate" refers to the antibody of the invention conjugated to one or more heterologous molecule(s).In some embodiments, the antibody of the invention is conjugated to one or more cytotoxic agents or an imaging agent.Exemplary cytotoxic agents include chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), and radionuclides.The cytotoxic agent may be one or more drugs, such as to a mayatansinoid (see, e.g., U.S. Patent No.5,208,020, 5,416,06), an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see, e.g., U.S. Patent Nos.5,635,483 and 5,780,588, and 7,498,298), a dolastatin, a calicheamicin or derivative thereof (see, e.g., U.S. Patent Nos.5,712,374, 5,714,586, 5,739, 116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., (1993) Cancer Res 53:3336-3342; and Lode et al.,(1998) Cancer Res 58:2925-2928); an anthracycline such as daunomycin or doxorubicin (see, e.g., Kratz et al., (2006) Current Med. Chem 13:477-523; Jeffrey et al., (2006) Bioorganic & Med Chem Letters 16:358-362; Torgov et al., (2005) Bioconj Chem 16:717-721; Nagy et al., (2000) Proc Natl Acad Sci USA 97:829-834; Dubowchik et al, Bioorg. & Med. Chem. Letters 12: 1529-1532 (2002); King et al., (2002) J Med Chem 45:4336-4343; and U.S. Patent No.6,630,579), methotrexate, vindesine, a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel.The cytotoxic agent may also be an enzymatically active toxin or fragment thereof, such as diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthins, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.The cytotoxic agent or an imaging agent may also be a radionuclide. Exemplary radionuclides include Ac-225, At-211, 1-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi- 212, P-32, Pb-212 and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example Tc- 99m or I-123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as I-123, I-131, In-111, F-19, C-13, N-15 or O- 17.Conjugates of the antibodies of the invention and the heterologous molecule may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-l- carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HQ), 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). For example, a ricin immunotoxin may be prepared as described in Vitetta et al., (1987) Science 238: 1098. Carbon- 14- labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX- DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See, e.g., W094 / 11026. The linker may be a "cleavable linker" facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., (1992) Cancer Res 52: 127-131; U.S. Patent No.5,208,020) may be used.Conjugates of the antibodies of the invention and the heterologous molecule may be prepared with cross-linker reagents such as BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo- SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).The invention also provides an immunoconjugate comprising the antagonistic antibody specifically binding PD-1 of the invention linked to a therapeutic agent or an imaging agent.The invention also provides an immunoconjugate comprising the antagonistic antibody specifically binding TIM-3 of the invention linked to a therapeutic agent or an imaging agent.The invention also provides an immunoconjugate comprising the bispecific PD- 1 / TIM-3 antibody of the invention linked to a therapeutic agent or an imaging agent. Generation of monospecific antibodies of the inventionIn some embodiments, the antibodies of the invention are human.In some embodiments, the antibodies of the invention are humanized.Monospecific antibodies of the invention described herein (e.g. antibodies specifically binding PD-1 or TIM-3) may be generated using various technologies. For example, the hybridoma method of Kohler and Milstein, Nature 256:495, 1975 may be used to generate monoclonal antibodies. In the hybridoma method, a mouse or other host animal, such as a hamster, rat or monkey, is immunized with human or cyno PD-1 or TIM- 3 or fragments of PD-1 or TIM-3, such as the extracellular domain of PD-1 or TIM-3, followed by fusion of spleen cells from immunized animals with myeloma cells using standard methods to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986)). Colonies arising from single immortalized hybridoma cells are screened for production of antibodies with desired properties, such as specificity of binding, cross-reactivity or lack thereof, and affinity for the antigen. Various host animals may be used to produce the antibodies of the invention. For example, Balb / c mice may be used to generate mouse anti-human PD-1 or TIM-3 antibodies. The antibodies made in Balb / c mice and other non-human animals may be humanized using various technologies to generate more human-like sequences.Exemplary humanization techniques including selection of human acceptor frameworks are known and include CDR grafting (U.S. Patent No.5,225,539), SDR grafting (U.S. Patent No. 6,818,749), Resurfacing (Padlan, (1991) Mol Immunol 28:489- 499), Specificity Determining Residues Resurfacing (U.S. Patent Publ. No.2010 / 0261620), human framework adaptation (U.S. Patent No.8,748,356) orsuperhumanization (U.S. Patent No.7,709, 226). In these methods, CDRs of parental antibodies are transferred onto human frameworks that may be selected based on their overall homology to the parental frameworks, based on similarity in CDR length, or canonical structure identity, or a combination thereof.Humanized antibodies may be further optimized to improve their selectivity or affinity to a desired antigen by incorporating altered framework support residues to preserve binding affinity (backmutations) by techniques such as those described in Int. Patent Publ. Nos. WO1090 / 007861 and WO1992 / 22653, or by introducing variation at any of the CDRs for example to improve affinity of the antibody.Transgenic animals, such as mice or rats carrying human immunoglobulin (Ig) loci in their genome may be used to generate human antibodies against a target protein, and are described in for example U.S. Patent No.6,150,584, Int. Patent Publ. No. WO99 / 45962, Int. Patent Publ. Nos. WO2002 / 066630, WO2002 / 43478, WO2002 / 043478 andWO1990 / 04036, Lonberg et al (1994) Nature 368:856-9; Green et al (1994) Nature Genet. 7:13-21; Green & Jakobovits (1998) Exp. Med.188:483-95; Lonberg and Huszar (1995) Int Rev Immunol 13:65-93; Bruggemann et al., (1991) Eur J Immunol 21:1323- 1326; Fishwild et al., (1996) Nat Biotechnol 14:845-851; Mendez et al., (1997) Nat Genet 15:146-156; Green (1999) J Immunol Methods 231:11-23; Yang et al., (1999) Cancer Res 59:1236-1243; Brüggemann and Taussig (1997) Curr Opin Biotechnol 8:455-458. The endogenous immunoglobulin loci in such animal may be disrupted or deleted, and at least one complete or partial human immunoglobulin locus may be inserted into the genome of the antimal using homologous or non-homologous recombination, usingtranschromosomes, or using minigenes. Companies such as Regeneron(http: / / _www_regeneron_com), Harbour Antibodies(http: / / _www_harbourantibodies_com), Open Monoclonal Technology, Inc. (OMT) (http: / / _www_omtinc_net), KyMab (http: / / _www_kymab_com), Trianni (http: / / _www.trianni_com) and Ablexis (http: / / _www_ablexis_com) may be engaged to provide human antibodies directed against a selected antigen using technologies as described above.Human antibodies may be selected from a phage display library, where the phage is engineered to express human immunoglobulins or portions thereof such as Fabs, single chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., (2000) J Mol Biol 296:57-86; Krebs et al., (2001) J Immunol Meth 254:67-84; Vaughan et al., (1996) Nature Biotechnology 14:309-314; Sheets et al., (1998) PITAS (USA) 95:6157- 6162; Hoogenboom and Winter (1991) J Mol Biol 227:381; Marks et al., (1991) J Mol Biol 222:581). The antibodies of the invention may be isolated for example from phage display library expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein as described in Shi et al., (2010) J Mol Biol 397:385-96, and Int. Patent Publ. No. WO09 / 085462). The libraries may be screened for phage binding to human and / or cyno PD-1 or TIM-3 and the obtained positive clones may be further characterized, the Fabs isolated from the clone lysates, and expressed as full length IgGs. Such phage display methods for isolating human antibodies are described in for example: U.S. Patent Nos.5,223,409, 5,403,484, 5,571,698, 5,427,908, 5, 580,717, 5,969,108, 6,172,197, 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081.Preparation of immunogenic antigens and monoclonal antibody production may be performed using any suitable technique, such as recombinant protein production. The immunogenic antigens may be administered to an animal in the form of purified protein, or protein mixtures including whole cells or cell or tissue extracts, or the antigen may be formed de novo in the animal’s body from nucleic acids encoding said antigen or a portion thereof. Generation of bispecific PD-1 / TIM-3 antibodies of the inventionThe bispecific PD-1 / TIM-3 antibodies of the invention (e.g. the bispecific antibodies comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3) may be generated by combining PD-1 binding VH / VL domains with TIM-3 binding VH / VL domains isolated and characterized herein.Alternatively, the bispecific PD-1 / TIM-3 antibodies may be engineered using VH / VL domains from publicly available monospecific anti-PD-1 and anti-TIM-3 antibodies, and / or by mix-matching the PD-1 or TIM-3 binding VH / VL domains identified herein with publicly available PD-1 or TIM-3 binding VH / VL domains. Exemplary anti-PD-1 antibodies that may be used to engineer bispecific PD- 1 / TIM-3 molecules are for example those described in U.S. Patent Nos.5,897,862 and 7,488,802, and in Int. Patent Publ. Nos. WO2004 / 004771, WO2004 / 056875,WO2006 / 121168, WO2008 / 156712, WO2010 / 029435, WO2010 / 036959,WO2011 / 110604, WO2012 / 145493, WO2014 / 194302, WO2014 / 206107,WO2015 / 036394, WO2015 / 035606, WO2015 / 085847, WO2015 / 112900 andWO2015 / 112805. For example, the VH / VL domains of KEYTRUDA® (pembrolizumab) and OPDIVO® (nivolumab) may be used. These PD-1 VH / VL domains may be incorporated into bispecific antibodies comprising TIM-3 binding VH / VL domains described herein and in Table 3. For example, the VH / VL domains of the TIM-3 antibodies TM3B103, TM3B105, TM3B107, TM3B108, TM3B109, TM3B113,TM3B189, TM3B190 and TM3B196 described herein may be used to generate bispecific PD-1 / TIM-3 antibodies.Similarly, exemplary anti-TIM-3 antibodies that may be used to engineer bispecific PD-1 / TIM-3 molecules are for example those described in Int. Patent Publ. Nos. WO2011 / 155607, WO2013 / 006490, and WO2015 / 117002. These TIM-3 VH / VL domains may be incorporated into bispecific antibodies comprising PD-1 binding VH / VL domains described herein and in Table 2. For example, the VH / VL domains of the PD-1 antibodies PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B192, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201, PD1B131 and PD1B132 described herein may be used to generate bispecific PD-1 / TIM-3 antibodies.The generated bispecific PD-1 / TIM-3 antibodies may be tested for their binding to PD-1 and TIM-3, and for their desired functional characteristics, such as enhancement of activation of antigen specific CD4+ and CD4+ T cells using methods described herein.Bispecific antibodies of the invention comprise antibodies having a full length antibody structure.Full length bispecific antibodies may be generated for example using Fab arm exchange (e.g., half molecule exchange, exchanging on heavy chain– light chain pair) between two monospecific bivalent antibodies by introducing mutations at the heavy chain CH3 interface in each half-molecule to favor heterodimer formation of two antibody half- molecules having distinct specificity either in vitro in cell-free environment or using co- expression. The Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parental monospecific antibodies are reduced. The resulting free cysteines of one of the parental monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parental monospecific antibody molecule and simultaneously CH3 domains of the parental antibodies release and reform by dissociation-association. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms r half molecules which each bind a distinct epitope. Mutations F405L in one heavy chain and K409R in the other heavy chain may be used in case of IgG1 antibodies. For IgG2 antibodies, a wild-type IgG2 and a IgG2 antibody with F405L and R409K substitutions may be used. To generate bispecific antibodies, first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have a F405L or a K409R mutation in the Fc region, the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange. The incubation conditions may optimally be restored to non- reducing. Exemplary reducing agents that may be used are 2- mercaptoethylamine (2- MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2carboxyethyl)phosphine (TCEP), L-cysteine and beta- mercaptoethanol. For example, incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol at a pH of from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.Bispecific antibodies may also be generated using designs such as the Knob-in- Hole (Genentech), CrossMAbs (Roche) and the electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody)(EMD Serono), and the Biclonic (Merus).The“knob-in-hole” strategy (see, e.g., Intl. Publ. No. WO 2006 / 028936) may be used to generate full length bispecific antibodies of the invention. Briefly, selected amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a“hole” with the heavy chain with a“knob”. Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.The CrossMAb technology may be used to generate full length bispecific antibodies of the invention. CrossMAbs, in addition to utilizing the“knob-in-hole” strategy to promoter Fab arm exchange, have in one of the half arms the CH1 and the CL domains exchanged to ensure correct light chain pairing of the resulting bispecific antibody (see e.g. U.S. Patent No.8,242,247).Other cross-over strategies may be used to generate full length bispecific antibodies of the invention by exchanging variable or constant, or both domains between the heavy chain and the light chain or within the heavy chain in the bispecific antibodies, either in one or both arms. These exchanges include for example VH-CH1 with VL-CL, VH with VL, CH3 with CL and CH3 with CH1 as described in Int. Patent Publ. Nos. WO2009 / 080254, WO2009 / 080251, WO2009 / 018386 and WO2009 / 080252.Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US Patent Publ. No. US2010 / 0015133; US Patent Publ. No. US2009 / 0182127; US Patent Publ. No. US2010 / 028637 or US Patent Publ. No. US2011 / 0123532. In other strategies, heterodimerization may be promoted by following substitutions (expressed as modified positions in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W,T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in U.S. Patent Publ. No. US2012 / 0149876 or U.S. Patent Publ. No. US2013 / 0195849.LUZ-Y technology may be utilized to generate bispecific antibodies of the invention. In this technology, a leucine zipper is added into the C terminus of the CH3 domains to drive the heterodimer assembly from parental mAbs that is removed post- purification as described in Wranik et al., (2012) J Biol Chem 287(52): 42221-9.SEEDbody technology may be utilized to generate bispecific antibodies of the invention. SEEDbodies have, in their constant domains, select IgG residues substituted with IgA residues to promote heterodimerization as described in U.S. Patent No.US20070287170. Mutations are typically made at the DNA level to a molecule such as the constant domain of the antibody using standard methods.The antibodies of the invention may be engineered into various well known antibody formats.In some embodiments, the bispecific antibodies include recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; IgG fusion molecules, wherein full length IgG antibodies are fused to an extra Fab fragment or parts of Fab fragment; Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; Fab fusion molecules, wherein different Fab-fragments are fused together; ScFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different single chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g. domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule. Polynucleotides, vectors and host cellsThe invention also provides an antagonistic antibody that specifically binds PD-1, TIM-3 or PD-1 and TIM-3 having certain VH and VL sequences, wherein the antibody VH is encoded by a first polynucleotide and the antibody VL is encoded by a second polynucleotide. The polynucleotide may be a complementary deoxynucleic acid (cDNA), and may be codon optimized for expression in suitable host. Codon optimization is a well- known technology.The invention also provides an isolated polynucleotide encoding the VH of the antibody of the invention, the VL of the antibody of the invention, the heavy chain of the antibody of the invention or the light chain of the antibody of the invention.The invention also provides an isolated polynucleotide encoding the VH, the VL, or the VH and the VL of the antagonistic antibody specifically binding PD-1 of the invention.The invention also provides an isolated polynucleotide encoding the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64.The invention also provides an isolated polynucleotide encoding the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.The invention also provides an isolated polynucleotide comprising the polynucleotide sequence of SEQ ID NOs: 196, 197, 198, 199, 200, 201, 202 or 203. The invention also provides an isolated polynucleotide encoding the VH, the VL, or the VH and the VL of the antagonistic antibody specifically binding TIM-3 of the invention.The invention also provides an isolated polynucleotide encoding the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172.The invention also provides an isolated polynucleotide encoding the VL of SEQ ID NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173.The invention also provides an isolated polynucleotide comprising the polynucleotide sequence of SEQ ID NOs: 204, 205, 206, 207, 208, 209, 210 or 211.The invention also provides an isolated polynucleotide encoding the HC1, the LC1, the HC2 or the LC2 of the antagonistic bispecific PD-1 / TIM-3 antibody of the invention.The invention also provides an isolated polynucleotide encoding the HC1 of SEQ ID NOs: 186, 187, 241, 242 or 243.The invention also provides an isolated polynucleotide encoding the LC1 of SEQ ID NOs: 188 or 189.The invention also provides an isolated polynucleotide encoding the HC2 of SEQ ID NOs: 190, 191, 192, 244, 245, 246, 247 or 248.The invention also provides an isolated polynucleotide encoding the LC2 of SEQ ID NOs: 193, 194 or 195.The invention also provides an isolated polynucleotide comprising the polynucleotide sequence of SEQ ID NOs: 253, 254, 255, 256, 257, 258, 259 and 260.The polynucleotide sequences encoding the VH or the VL or an antigen-binding fragment thereof of the antibodies of the invention, or the heavy chain and the light chain of the antibodies of the invention may be operably linked to one or more regulatory elements, such as a promoter or enhancer, that allow expression of the nucleotide sequence in the intended host cell. The polynucleotide may be a cDNA. The invention also provides a vector comprising the polynucleotide of the invention. Such vectors may be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon based vectors or any other vector suitable for introduction of the synthetic polynucleotide of the invention into a given organism or genetic background by any means. For example, polynucleotides encoding light and / or heavy chain variable regions of the antibodies of the invention, optionally linked to constant regions, are inserted into expression vectors. The light and / or heavy chains may be cloned in the same or different expression vectors. The DNA segments encoding immunoglobulin chains may be operably linked to control sequences in the expression vector(s) that ensure the expression of immunoglobulin polypeptides. Such control sequences include signal sequences, promoters (e.g. naturally associated or heterologous promoters), enhancer elements, and transcription termination sequences, and are chosen to be compatible with the host cell chosen to express the antibody. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the proteins encoded by the incorporated polynucleotides.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 196 and 197.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 198 and 199.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 200 and 201.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 202 and 203.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 204 and 205.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 206 and 207.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 208 and 209.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 210 and 211.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 253 and 254.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 255 and 256. In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 257 and 258.In some embodiments, the vector comprises the polynucleotide of SEQ ID NO: 259 and 260.Suitable expression vectors are typically replicable in the host organisms either as episomes or as an integral part of the host chromosomal DNA. Commonly, expression vectors contain selection markers such as ampicillin-resistance, hygromycin-resistance, tetracycline resistance, kanamycin resistance or neomycin resistance to permit detection of those cells transformed with the desired DNA sequences.Suitable promoter and enhancer elements are known in the art. For expression in a eukaryotic cell, exemplary promoters include light and / or heavy chain immunoglobulin gene promoter and enhancer elements; cytomegalovirus immediate early promoter; herpes simplex virus thymidine kinase promoter; early and late SV40 promoters; promoter present in long terminal repeats from a retrovirus; mouse metallothionein-I promoter; and various known tissue specific promoters. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art.Exemplary vectors that may be used are Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene, La Jolla, Calif., USA); pTrc99A, pKK223-3, pKK233-3, pDR540, and pRIT5 (Pharmacia, Uppsala, Sweden). Eukaryotic: pWLneo, pSV2cat, pOG44, PXR1, pSG (Stratagene) pSVK3, pBPV, pMSG and pSVL (Pharmacia), pEE6.4 (Lonza) and pEE12.4 (Lonza).The invention also provides a host cell comprising one or more vectors of the invention.“Host cell” refers to a cell into which a vector has been introduced. It is understood that the term host cell is intended to refer not only to the particular subject cell but to the progeny of such a cell, and also to a stable cell line generated from the particular subject cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein. Such host cells may be eukaryotic cells, prokaryotic cells, plant cells or archeal cells. Escherichia coli, bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species are examples of prokaryotic host cells. Other microbes, such as yeast, are also useful for expression. Saccharomyces (for example, S. cerevisiae) and Pichia are examples of suitable yeast host cells. Exemplary eukaryotic cells may be of mammalian, insect, avian or other animal origins. Mammalian eukaryotic cells include immortalized cell lines such as hybridomas or myeloma cell lines such as SP2 / 0 (American Type Culture Collection (ATCC), Manassas, VA, CRL-1581), NS0 (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No.85110503), FO (ATCC CRL-1646) and Ag653 (ATCC CRL-1580) murine cell lines. An exemplary human myeloma cell line is U266 (ATTC CRL-TIB-196). Other useful cell lines include those derived from Chinese Hamster Ovary (CHO) cells such as CHOK1SV (Lonza Biologics, Walkersville, MD), Potelligent® CHOK2SV (Lonza), CHO-K1 (ATCC CRL-61) or DG44.The invention also provides a method of producing an antibody of the invention comprising culturing the host cell of the invention in conditions that the antibody is expressed, and recovering the antibody produced by the host cell. Methods of making antibodies and purifying them are well known in the art. Once synthesized (either chemically or recombinantly), the whole antibodies, their dimers, individual light and / or heavy chains, or other antibody fragments such as VH and / or VL, may be purified according to standard procedures, including ammonium sulfate precipitation, affinity columns, column chromatography, high performance liquid chromatography (HPLC) purification, gel electrophoresis, and the like (see generally Scopes, Protein Purification (Springer- Verlag, N.Y., (1982)). A subject antibody may be substantially pure, for example, at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or at least about 98% to 99%, or more, pure, for example, free from contaminants such as cell debris, macromolecules, etc. other than the subject antibody.The polynucleotide sequences of the invention may be incorporated into vectors using standard molecular biology methods. Host cell transformation, culture, antibody expression and purification are done using well known methods. Another embodiment of the invention is a method of producing the antagonistic antibody specifically binding PD-1 of the invention, comprising:incorporating the first polynucleotide encoding the VH of the antibody and the second polynucleotide encoding the VL of the antibody into an expression vector; transforming a host cell with the expression vector;culturing the host cell in culture medium under conditions wherein the VL and the VH are expressed and form the antibody; andrecovering the antibody from the host cell or culture medium.Another embodiment of the invention described herein is a method of producing the antagonistic antibody specifically binding TIM-3 of the invention, comprising:incorporating the first polynucleotide encoding the VH of the antibody and the second polynucleotide encoding the VL of the antibody into an expression vector; transforming a host cell with the expression vector;culturing the host cell in culture medium under conditions wherein the VL and the VH are expressed and form the antibody; andrecovering the antibody from the host cell or culture medium.The polynucleotides encoding certain VH or VL sequences of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, may be incorporated into vectors using standard molecular biology methods. Host cell transformation, culture, antibody expression and purification are done using well known methods. Pharmaceutical compositions / AdministrationThe invention provides pharmaceutical compositions comprising the antibodies of the invention and a pharmaceutically acceptable carrier. For therapeutic use, the antibodies of the invention may be prepared as pharmaceutical compositions containing an effective amount of the antibody as an active ingredient in a pharmaceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered. Such vehicles may be 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. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc. The concentration of the antibodies of the invention in such pharmaceutical formulation may vary, from less than about 0.5%, usually to at least about 1% to as much as 15 or 20% by weight and may be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the particular mode of administration selected. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g. Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp.958-989.The mode of administration for therapeutic use of the antibodies of the invention may be any suitable route that delivers the antibody to the host, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using a formulation in a tablet, capsule, solution, powder, gel, particle; and contained in a syringe, an implanted device, osmotic pump, cartridge, micropump; or other means appreciated by the skilled artisan, as well known in the art. Site specific administration may be achieved by for example intratumoral, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intracardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery.The antibodies of the invention may be administered to a subject by any suitable route, for example parentally by intravenous (i.v.) infusion or bolus injection, intramuscularly or subcutaneously or intraperitoneally. i.v. infusion may be given over for example 15, 30, 60, 90, 120, 180, or 240 minutes, or from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours.The dose given to a subject is sufficient to alleviate or at least partially arrest the disease being treated (“therapeutically effective amount”) and may be sometimes 0.005 mg to about 100 mg / kg, e.g. about 0.05 mg to about 30 mg / kg or about 5 mg to about 25 mg / kg, or about 4 mg / kg, about 8 mg / kg, about 16 mg / kg or about 24 mg / kg , or for example about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / kg, but may even higher, for example about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg / kg.A fixed unit dose may also be given, for example, 50, 100, 200, 500 or 1000 mg, or the dose may be based on the patient's surface area, e.g., 500, 400, 300, 250, 200, or 100 mg / m2. Usually between 1 and 8 doses, (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) may be administered to treat the patient, but 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more doses may be given.The administration of the antibodies of the invention may be repeated after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or longer. Repeated courses of treatment are also possible, as is chronic administration. The repeated administration may be at the same dose or at a different dose. For example, the antibodies of the invention may be administered at 8 mg / kg or at 16 mg / kg at weekly interval for 8 weeks, followed by administration at 8 mg / kg or at 16 mg / kg every two weeks for an additional 16 weeks, followed by administration at 8 mg / kg or at 16 mg / kg every four weeks by intravenous infusion.For example, the antibodies of the invention may be provided as a daily dosage in an amount of about 0.1-100 mg / kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 after initiation of treatment, or any combination thereof, using single or divided doses of every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof.The antibodies of the invention, may also be administered prophylactically in order to reduce the risk of developing cancer, delay the onset of the occurrence of an event in cancer progression, and / or reduce the risk of recurrence when a cancer is in remission.The antibodies of the invention may be lyophilized for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective with conventional protein preparations and well known lyophilization and reconstitution techniques can be employed. Methods and UsesThe antibodies of the invention have in vitro and in vivo diagnostic, as well as therapeutic and prophylactic utilities. For example, the antibodies of the invention may be administered to cells in culture, in vitro or ex vivo, or to a subject to treat, prevent, and / or diagnose a variety of disorders, such as cancers and infectious disorders.The invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody of the invention for a time sufficient to modify the immune response.In some embodiments, the immune response is enhanced, stimulated or up- regulated.In some embodiments described herein, the subject is a human patient.In some embodiments described herein, the subject is a human patient in need of enhancement of the immune response.In some embodiments, the subject is immunocompromised. In some embodiments, the subject is at risk of being immunocompromised.Immunocompromised subject may be undergoing, or has undergone a chemotherapeutic or radiation therapy.In some embodiment, the subject is or is at risk of being immunocompromised as a result of an infection.The antibodies of the invention are suitable for treating a subject having a disorder that may be treated by augmenting T-cell mediated immune responses.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention described herein is PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201, PD1B243, PD1B244, PD1B131 or PD1B132. The VH and the VL amino acid sequences of these antibodies are shown in Table 2.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention described herein is TM3B103, TM3B105, TM3B109, TM3B108, TM3B113, TM3B189, TM3B190, TM3B193, TM3B195, TM3B196 or TM3B291. The VH and the VL amino acid sequences of these antibodies are shown in Table 3.In some embodiments, the bispecific PD-1 / TIM-3 antibody used in the methods of the invention is PTBB14, PTBB15, PTBB16, PTBB17, PTBB24, PTBB30, PTBB27, PTBB28, PTBB18, PTBB20 or PTBB21. The HC1, the LC1, the HC2 and the LC2 amino acid sequences of these antibodies are shown in Table 41 and Table 42.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52. In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49. In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61.In some embodiments, the antagonistic antibody specifically binding PD-1 used in the methods of the invention comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157. In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.In some embodiments, the antagonistic antibody specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 in the first domain, and the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162 in the second domain.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 in the first domain, and the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 in the second domain. In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 in the first domain, and the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162 in the second domain.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 used in the methods of the invention, comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 in the first domain, and the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 in the second domain.In some embodiments, the antagonistic bispecific PD-1 / TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3 used in the methods of the invention comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 in the first domain, and the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 in the second domain. CancerBlockade of PD-1 may enhance an immune response to cancerous cells in a subject. The ligand for PD-1, PD-L1, is abundantly expressed in a variety of human cancers (Dong et al., (2002) Nat Med 8:787-9). The interaction between PD-1 and PD-L1 can result in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and / or immune evasion by the cancerous cells (Dong et al., (2003) J Mol Med 81:281-7; Blank et al., (2005) Cancer Immunol Immunother 54:307-314; Konishi et al., (2004) Clin Cancer Res 10:5094-100). Immune suppression may be reversed by inhibiting the local interaction of PD-1 to PD-L1; the effect is additive when the interaction of PD-1 to the second PD-1 ligand, PD-L2, is blocked as well (Iwai et al., (2002) PorcNatl Acad Sci 99:12293-7; Brown et al., (2003) J Immunol 170:1257-66). Thus, inhibition of PD-1 may result in augmenting an immune response.TIM-3 is a coinhibitory protein expressed on activated T helper 1 (Thl) CD4+ and cytotoxic CD8+ T cells that secrete IFN-γ. TIM-3 is co-expressed on PD-1+ exhausted T cells as shown in preclinical models of cancer and viral exhaustion. Co-blockade of these pathways may restore effector T cell function (e.g., IFN-γ secretion, proliferation) in several models as well as human PBMCs derived from metastatic melanoma patients and patients with HIV or HCV. TIM-3 is also enriched on Foxp3+ regulatory T cells and Tregs co-expressing TIM-3, LAG3 and CTLA4 have been shown to be highly efficient suppressors of effector T cells (Teff) (Galuton et al., (2014) Eur J Immunol 44(9):2703- 11). TIM-3 expression has been correlated with poorer prognosis in NSCLC (Zhuang et al., (2012) Am J Clin Pathol 137(6):978-85). Lymphocytes from tumor tissues of ovarian, colorectal, cervical and hepatocellular carcinoma patients exhibit higher proportion of TIM-3+ CD4 T cells, which cells have impaired capacity to produce ILF- ^ (Yan et al., (2013) PLoS One 8(3):e58006).The invention also provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of the antagonistic antibody specifically binding PD-1 of the invention for a time sufficient to inhibit growth of tumor cells...The invention also provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of the antagonistic antibody specifically binding TIM-3 of the ...

Claims

WHAT IS CLAIMED 1) An isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.2) The antibody or the antigen-binding portion thereof of claim 1, wherein the antibody has one, two, three, four or five of the following properties:a) enhances an activation of antigen specific CD4+ or CD8+ T cells in a dosedependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1;b) binds human PD-1 with an equilibrium dissociation constant (KD) of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC;c) binds human PD-1 with the KD of less than about 1 nM, wherein the KD ismeasured using ProteOn XPR36 system at +25ºC;d) binds cynomolgus PD-1 of SEQ ID NO: 3 with the KD of less than about 100 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC; or e) binds cynomolgus PD-1 of SEQ ID NO: 3 with the KD of less than about 1 nM, wherein the KD is measured using ProteOn XPR36 system at +25ºC.3) The antibody or the antigen-binding portion thereof of claim 1 or 2, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs:l) 10, 14, 17, 22, 26 and 34, respectively; orm) 10, 14, 17, 23, 26 and 32, respectively.4) The antibody or the antigen-binding portion thereof of any of the claims 1-3,comprisinga) a heavy chain variable region (VH) of SEQ ID NOs: 41, 42, 43 or 48;b) a light chain variable region (VL) of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55 or 56; orc) the VH of SEQ ID NOs: 41, 42, 43 or 48 and the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55 or 56.5) The antibody or the antigen-binding portion thereof of any of the claims 1-4,comprisinga) the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49;b) the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50;c) the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51;d) the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52;e) the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53;f) the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49;g) the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54;h) the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50;i) the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55;j) the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56;k) the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53;l) the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52; orm) the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.6) The antibody or the antigen-binding portion thereof of any of the claims 1-5, wherein the antibody is human or humanized.7) The antibody or the antigen-binding portion thereof of any of the claims 1-6, wherein the antibody isa) an IgG1 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;b) an IgG2 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region;c) an IgG3 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region; d) an IgG4 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region;e) an IgG1 isotype comprising L234A, L235A, G237A, P238S, H268A, A330S and P331S substitutions;f) an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions;g) an IgG4 isotype comprising F234A, L235A, G237A, P238S and Q268Asubstitutions;h) an IgG1 isotype comprising L234A, L235A or L234A and L235A substitutions; i) an IgG4 isotype comprising F234A, L235A or F234A and L235A substitutions; j) an IgG2 isotype comprising a V234A substitution;k) an IgG4 isotype comprising a S228P substitution; orl) an IgG4 isotype comprising S228P, F234A and L235A substitutions, wherein residue numbering is according to the EU Index.8) The antibody or the antigen-binding portion thereof of any of the claims 1-7,comprisinga) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively;b) the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56; and / orc) a heavy chain (HC) of SEQ ID NO: 72 and a light chain (LC) of SEQ ID NO:

73. 9) The antibody or the antigen-binding portion thereof of any of the claims 1-8, wherein the antibody is a bispecific antibody, optionally binding PD-L1 (SEQ ID NO: 5), PD- L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), TIM-3 (SEQ ID NO: 138), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), OX-40 (SEQ ID NO: 279), GITR (SEQ ID NO: 271), CD27 (SEQ ID NO: 280), VISTA (SEQ ID NO: 286), CD137 (SEQ ID NO: 281), TIGIT (SEQ ID NO: 301) or CTLA-4 (SEQ ID NO: 292).10) A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof of any of the claims 1-9 and a pharmaceutically accepted carrier.11) A polynucleotidea) encoding the VH of SEQ ID NOs: 41, 42, 43 or 48;b) encoding the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55 or 56;c) encoding the VH of SEQ ID NOs: 41, 42, 43 or 48 and the VL of SEQ ID NOs:49, 50, 51, 52, 53, 54, 55 or 56; ord) comprising the polynucleotide sequence of SEQ ID NOs: 196 or 197. 12) A vector comprising the polynucleotide of claim 11.13) A host cell comprising the vector of claim 12.14) A method of producing an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising culturing the host cell of claim 13 in conditions that the antibody of the antigen-binding portion thereof is expressed, and recovering the antibody or the antigen-binding portion thereof produced by the host cell.15) An isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprisinga) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively;b) the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; and / orc) the HC of SEQ ID NO: 74 and the LC of SEQ ID NO: 75.16) A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof of claim 15 and a pharmaceutically accepted carrier.17) A polynucleotidea) encoding the VH of SEQ ID NO: 64;b) encoding the VL of SEQ ID NO: 65;c) encoding the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; or d) comprising the polynucleotide sequence of SEQ ID NOs: 198 or 199.18) A vector comprising the polynucleotide of claim 17.19) A host cell comprising the vector of claim 18.20) A method of producing an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising culturing the host cell of claim 19 in conditions that the antibody or the antigen-binding portion thereof is expressed, and recovering the antibody or the antigen-binding portion thereof produced by the host cell.21) A method of treating a cancer in a subject, comprising administering a therapeutically effective amount of the isolated antibody or the antigen-binding portion thereof of any of the claims 1-9 or the pharmaceutical composition of claim 10 to the subject in need thereof for a time sufficient to treat the cancer.22) A method of treating a cancer in a subject, comprising administering a therapeutically effective amount of the isolated antibody or the antigen-binding portion thereof of claim 15 or the pharmaceutical composition of claim 16 to the subject in need thereof for a time sufficient to treat the cancer. 23) The method of claim 21 or 22, wherein the cancer is a solid tumor or a hematological malignancy.24) The method of any of the claims 21-23, wherein the solid tumor is a melanoma, a lung cancer, a squamous non-small cell lung cancer (NSCLC), a non-squamous NSCLC, a colorectal cancer, a prostate cancer, a castration-resistant prostate cancer, a stomach cancer, an ovarian cancer, a gastric cancer, a liver cancer, a pancreatic cancer, a thyroid cancer, a squamous cell carcinoma of the head and neck, carcinomas of the esophagus or gastrointestinal tract, a breast cancer, a fallopian tube cancer, a brain cancer, an urethral cancer, a genitourinary cancer, an endometriosis, a cervical cancer or a metastatic lesion of the cancer.25) The method of any of the claims 21-23, wherein the hematological malignancy is a lymphoma, a myeloma or a leukemia.26) A method of enhancing an immune response in a subject, comprising administering a therapeutically effective amount of the antibody or the antigen-binding portion thereof of any of the claims 1-9 or 15 or a pharmaceutical composition of claim 10 or 16 to the subject in need thereof for a time sufficient to enhance the immune response. 27) The method of claim 26, wherein the subject has a cancer or a viral infection.28) The method of any of the claims 21-27, wherein the antibody or the antigen-binding portion thereof is administered in combination with a second therapeutic agent.29) The method of any of the claims 21-28, wherein the second therapeutic agent isa) a standard of care drug for treatment of the solid tumor or the hematological malignancy;b) an agonist of a T cell activating molecule;c) an agonist of CD86 (SEQ ID NO: 264), CD80 (SEQ ID NO: 265), CD28 (SEQ ID NO: 266), ICOS (SEQ ID NO: 267), ICOS ligand (SEQ ID NO: 268), TMIGD2 (SEQ ID NO: 269), CD40 (SEQ ID NO: 270), GITR (SEQ ID NO: 271), 4-1BB ligand (SEQ ID NO: 271), OX40 ligand (SEQ ID NO: 272), CD70 (SEQ ID NO: 274), CD40L (SEQ ID NO: 275), TNFRSF25 (SEQ ID NO: 264), LIGHT (SEQ ID NO: 277), GITR ligand (SEQ ID NO: 278), OX-40 (SEQ ID NO: 279), CD27 (SEQ ID NO: 280), CD137 (SEQ ID NO: 281), NKG2D (SEQ ID NO: 282), CD48 (SEQ ID NO: 283), CD226 (SEQ ID NO: 284), or MICA (SEQ ID NO: 285);d) an inhibitor of a T cell inhibitory molecule;e) an inhibitor of PD-1 (SEQ ID NO: 1), PD-L1 (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), VISTA (SEQ ID NO: 286), BTNL2 (SEQ ID NO: 287), B7-H3 (SEQ ID NO: 288), B7-H4 (SEQ ID NO: 289), HVEM (SEQ ID NO: 290), HHLA2 (SEQ ID NO: 291), CTLA-4 (SEQ ID NO: 292), LAG-3 (SEQ ID NO: 293), TIM-3 (SEQ ID NO: 138), BTLA (SEQ ID NO: 294), CD160 (SEQ ID NO: 295), CEACAM-1 (SEQ ID NO: 296), LAIR1 (SEQ ID NO: 297), TGF ^ (SEQ ID NO: 298), IL-10 (SEQ ID NO: 299), CD96 (SEQ ID NO: 300), TIGIT (SEQ ID NO: 301), NKG2A (SEQ ID NO: 302), CD112 (SEQ ID NO: 303), CD47 (SEQ ID NO: 304), SIRPA (SEQ ID NO: 305) or CD244 (SEQ ID NO: 306);f) an antagonistic antibody specifically binding TIM-3;g) an antagonistic antibody specifically binding TIM-3 comprising the VH and the VL ofi) SEQ ID NOs: 145 and 155, respectively;ii) SEQ ID NOs: 146 and 156, respectively;iii) SEQ ID NOs: 148 and 157, respectively;iv) SEQ ID NOs: 147 and 155, respectively;v) SEQ ID NOs: 149 and 158, respectively;vi) SEQ ID NOs: 150 and 159, respectively;vii) SEQ ID NOs:151 and 160, respectively;viii) SEQ ID NOs: 152 and 161, respectively;ix) SEQ ID NOs: 153 and 162, respectively;x) SEQ ID NOs: 154 and 163, respectively; orxi) SEQ ID NOs: 172 and 173, respectively;h) a fibroblast growth factor receptor (FGFR) inhibitor;i) a vaccine;j) an agonistic antibody specifically binding GITR;k) an agonistic antibody specifically binding OX40;l) an agonistic antibody specifically binding OX40, comprising the VH and the VL of SEQ ID NOs: 309 and 310, respectively;m) an agonistic antibody specifically binding OX40, comprising the VH and the VL of SEQ ID NOs: 311 and 312, respectively;n) an agonistic antibody specifically binding CD137;o) radiation therapy; orp) surgery.30) The method of any of the claims 21-29, wherein the antibody or the antigen-binding portion thereof and the second therapeutic agent are administered simultaneously, sequentially or separately. 31) An anti-idiotypic antibody binding to the antibody or the antigen-binding portion thereof of any of the claims 1-9 or 15.32) A kit comprising the antibody of any of the claims 1-9 or 15.