ANTI-GITR ANTIBODIES AND THEIR METHODS OF USE

Abstract

The present invention relates to antibodies that bind specifically to the glucocorticoid-induced TNFR family-related receptor (GITR), and to compositions comprising said antibodies. In one aspect of the invention, the antibodies bind specifically to GITR and modulate human GITR activity, for example, by enhancing, activating, or inducing GITR activity, by means of these antibodies. The present invention further relates to methods of treating disorders, such as cancer and infectious diseases, by administering an antibody that binds specifically to human GITR and modulates GITR activity, for example, by enhancing, activating, or inducing GITR activity.

Description

1. FIELD

[0001] The present disclosure provides antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity, e.g., enhances, activates or induces GITR activity.2. BACKGROUND

[0002] Glucocorticoid-induced TNFR-related protein (GITR), a member of the TNFR superfamily, is expressed in many components of the innate and adaptive immune system and stimulates both acquired and innate immunity (Nocentini G et al., (1994) PNAS 94: 6216-6221; Hanabuchi S et al., (2006) Blood 107:3617-3623; Nocentini G & Riccardi C (2005) Eur J Immunol 35: 1016-1022; Nocentini G et al., (2007) Eur J Immunol 37:1165-1169). It is expressed in several cells and tissues, including T, B, dendritic (DC) and Natural Killer (NK) cells and is activated by its ligand, GITRL, mainly expressed on Antigen Presenting Cells (APCs), on endothelial cells, and also in tumor cells. The GITR / GITRL system participates in the development of autoimmune / inflammatory responses and potentiates response to infection and tumors. For example, treating animals with GITR-Fc fusion protein ameliorates autoimmune / inflammatory diseases while GITR triggering is effective in treating viral, bacterial, and parasitic infections, as well in boosting immune response against tumors (Nocentini G et al., (2012) Br J Pharmacol 165: 2089-99). These effects are due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells, NK-cell co-activation, activation of macrophages, modulation of dendritic cell function and regulation of the extravasation process. The membrane expression of GITR is increased following T cell activation (Hanabuchi S et al., (2006) supra; Nocentini G & Riccardi C supra). Its triggering coactivates effector T lymphocytes (McHugh RS et al., (2002) Immunity 16: 311-323; Shimizu J et al., (2002) Nat Immunol 3: 135-142; Roncheti S et al., (2004) Eur J Immunol 34: 613-622; Tone M et al., (2003) PNAS 100: 15059-15064). GITR activation increases resistance to tumors and viral infections, is involved in autoimmune / inflammatory processes and regulates leukocyte extravasation (Nocentini G & Riccardi C (2005) supra; Cuzzocrea S et al., (2004) J Leukoc Biol 76: 933-940; Shevach EM & Stephens GL (2006) Nat Rev Immunol 6: 613-618; Cuzzocrea S et al., (2006) J Immunol 177: 631-641; Cuzzocrea S et al., (2007) FASEB J 21: 117-129).

[0003] Human GITR is expressed at very low levels in peripheral (non-activated) T cells. After T cell activation, GITR is strongly up-regulated for several days in both CD4 +< and CD8 +< cells (Kwon B et al., (1999) J Biol Chem 274: 6056-6061; Gurney AL et al., (1999) Curr Biol 9: 215-218; Ronchetti S et al., (2004) supra; Shimizu J et al., (2002) supra; Ji HB et al., (2004) supra; Ronchetti S et al., (2002) Blood 100: 350-352; Li Z et al., (2003) J Autoimmun 21: 83-92), with CD4 +< cells having a higher GITR expression than CD8 +< cells (Kober J et al., (2008) Eur J Immunol 38(10): 2678-88; Bianchini R et al., (2011) Eur J Immunol 41(8): 2269-78). WO 2013 / 039954 discloses anti-GITR antibodies. WO 2006 / 105021 discloses the antibody 6C8 which binds to GITR.

[0004] Given the role of human GITR in modulating immune responses, provided herein are antibodies that specifically bind to GITR and the use of those antibodies to modulate GITR activity.3. SUMMARY

[0005] In one aspect, provided herein are antibodies and fragments thereof that specifically bind to GITR (e.g., human GITR). In one aspect, an antibody or antigen-binding fragment thereof that specifically binds to GITR (e.g., human GITR) partially inhibits GITR ligand (e.g., human GITRL) from binding to GITR as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra). In a specific aspect, the antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In certain aspects, the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR). In another specific aspect, at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg / ml / bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads / µl with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) and 20 beads / µl of the GITR coupled beads; and (d) detecting the labeled GITRL (e.g., human GITRL) bound to the GITR (e.g., human GITR) coupled beads by, e.g., a suspension array assay. In some aspects, 20% to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof.

[0006] In certain aspects, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) complementarity determining region (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A; X 2 is A, V, L, I, P, F, M or Y; and X 3 is Y, G, N, Q, S, T, C, W, F or H; (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T; X 2 is R, K, H, Q or A; X 3 is T, G, N, Q, S, C, W, Y, V, I or P; X 4 is Y, G, N, Q, S, T, C, W, F, H, or A; X 5 is D, E, G or A; X 6 is V, A, L, I, P, F, M or T; X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A; X 8 is N, G, Q, S, T, C, W, Y or A; X 9 is K, R, H, Q or A; and X 10 is D, E, G or A; (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S; X 2 is A or D; and X 3 is Y, G, N, Q, S, T, C, W, F, H or V; (d) a light chain variable region (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, F or M; X 2 is L, A, V, I, P, F, M or S; X 3 is N, G, Q, S, T, C, W, Y or A; X 4 is S, G, N, Q, T, C, W, Y or A; X 5 is G, N, Q, S, T, C, W, Y or A; X 6 is N, G, Q, S, T, C, W, Y or A; X 7 is Q, G, N, S, T, C, W, Y or A; X 8 is N, G, Q, S, T, C, W, Y or A; and X 9 is T, G, N, Q, S, C, W, Y, V, I or A; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A; X 2 is E, D or A; and X 3 is S, G, N, Q, T, C, W, Y or A; and (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y; X 2 is D, E or Y; and X 3 is S, G, N, Q, T, C, W, Y or A, and X4 is Y, G, N, Q, S, T, C, W, F, H, L, or A. In other aspects, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (VH) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G; X 2 is A or V; and X 3 is Y or H; (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L; X 2 is R, K or Q; X 3 is Y or F; X 4 is D, E or G; X 5 is V or L; X 6 is T or S; X 7 is K, R or Q; and X 8 is D, E or G; (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 9); (d) a light chain variable region (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S; and X 2 is T or S; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of WASTRES (SEQ ID NO: 11); and (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E; and X 2 is Y, F or S.

[0007] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to GITR (e.g., human GITR), comprising: (a) a heavy chain variable region (VH) complementarity determining region (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A; X 2 is A, V, L, I, P, F, M or Y; and X 3 is Y, G, N, Q, S, T, C, W, F or H; (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T; X 2 is R, K, H, Q or A; X 3 is T, G, N, Q, S, C, W, Y, V, I or P; X 4 is Y, G, N, Q, S, T, C, W, F, H, or A; X 5 is D, E, G or A; X 6 is V, A, L, I, P, F, M or T; X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A; X 8 is N, G, Q, S, T, C, W, Y or A; X 9 is K, R, H, Q or A; and X 10 is D, E, G or A; (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S; X 2 is A, or D; and X 3 is Y, G, N, Q, S, T, C, W, F, H or V; (d) a light chain variable region (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, F or M; X 2 is L, A, V, I, P, F, M or S; X 3 is N, G, Q, S, T, C, W, Y or A; X 4 is S, G, N, Q, T, C, W, Y or A; X 5 is G, N, Q, S, T, C, W, Y or A; X 6 is N, G, Q, S, T, C, W, Y or A; X 7 is Q, G, N, S, T, C, W, Y or A; X 8 is N, G, Q, S, T, C, W, Y or A; and X 9 is T, G, N, Q, S, C, W, Y, V, I or A; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A; X 2 is E, D or A; and X 3 is S, G, N, Q, T, C, W, Y or A; and (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y; X 2 is D, E or Y; and X 3 is S, G, N, Q, T, C, W, Y or A, and X4 is Y, G, N, Q, S, T, C, W, F, H, L, or A. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 19-23, and 117-119. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 35 and SEQ ID NO:116. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 24-33, and 120-188. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 114, 115, and 194. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 34 and 189. In some aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 16 and 101-104. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 105. In some aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 18, 106-109, 192, and 193. In specific aspects, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in Table 2. In specific aspects, the antibody or antigen-binding fragment thereof comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in Table 6. In another specific aspect, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VL CDR1, VL CDR2, and VL CDR3 of an antibody in Table 1. In another specific aspect, the antibody or antigen-binding fragment thereof comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of an antibody in Table 5. In some aspects, the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra). In certain aspects, the antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In certain aspects, the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR). In specific aspects, at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg / ml / bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads / µl with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) 20 beads / µl of the GITR coupled beads; and (d) detecting the labeled GITRL (e.g., human GITRL) bound to the GITR (e.g., human GITR) coupled beads by, e.g., a suspension array assay. In some aspects, 20% to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof.

[0008] In another aspect, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to GITR (e.g., human GITR), comprising: (a) a heavy chain variable region (VH) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G; X 2 is A or V; and X 3 is Y or H; (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L; X 2 is R, K or Q; X 3 is Y or F; X 4 is D, E or G; X 5 is V or L; X 6 is T or S; X 7 is K, R or Q; and X 8 is D, E or G; (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 9); (d) a light chain variable region (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence of KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S; and X 2 is T or S; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of WASTRES (SEQ ID NO: 11); and (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E; and X 2 is Y, F or S. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 19-23, and 117-119. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of 35 and 116. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 24-33, and 120-188. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 114, 115, and 194. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VH CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 34 and 189. In some aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 16, and 101-104. In certain aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 105. In some aspects, the antibody or antigen-binding fragment thereof comprises a VL CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 18, 106-109, 192, and 193. In specific aspects, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in Table 2. In another specific aspect, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VL CDR1, VL CDR2, and VL CDR3 of an antibody in Table 1. In some aspects, the antibody or antigen-binding fragment thereof does not prevent GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra). In certain aspects, the antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In certain aspects, the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR). In specific aspects, at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg / ml / bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads / µl with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) and 20 beads / µl of the GITR coupled beads; and (d) detecting the labeled GITRL (e.g., human GITRL) bound to the GITR (e.g., human GITR) coupled beads by, e.g., a suspension array assay. In some aspects, 20% to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof.

[0009] In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to human GITR, comprising: (a) a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of DYAMY (SEQ ID NO: 13); (b) a VH CDR2 comprising the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO: 14); (c) a VH CDR3 comprising the amino acid sequence of SGTVRGFAY (SEQ ID NO: 15); (d) a light chain variable region (VL) CDR1 comprising the amino acid sequence of KSSQSLLNSGNQKNYLT (SEQ ID NO: 16); (e) a VL CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 17); and (f) a VL CDR3 comprising the amino acid sequence of QNDYSYPYT (SEQ ID NO: 18). In another aspect, provided herein is an antibody or fragment thereof that specifically binds to human GITR, comprising the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR 3 of an antibody 22 in Table 1 and Table 2. In some aspects, the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra). In certain aspects, the antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% of GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM GITRL (e.g., human GITRL) to the GITR coupled beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In some aspects, the antibody or antigen-binding fragment thereof inhibits 50% to 70% of human GITRL binding to human GITR. In specific aspects, at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg / ml / bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads / µl with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) and 20 beads / µl of the GITR coupled beads; and (d) detecting the labeled GITRL (e.g., human GITRL) bound to the GITR (e.g., human GITR) coupled beads by, e.g., a suspension array assay. In some aspects, 20% to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof. In some aspects, 30% to 50% of the amount of human GITRL that binds to human GITR in the absence of the antibody or antigen-binding fragment thereof binds to human GITR in the presence of the antibody or antigen-binding fragment thereof. The antibody of the invention or antigen-binding fragment thereof is agonistic.

[0010] In certain aspects, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region sequence comprising one, two, three or four of the framework regions of the heavy chain variable region sequence of SEQ ID NO: 203. In some aspects, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises one, two, three or four framework regions of a heavy chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95% or 100% identical to one, two, three or four of the framework regions of a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 201, SEQ ID NO: 206, and SEQ ID NOs: 215 to 389. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region having human derived framework regions. In another aspect, an antibody or antigen-binding fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGHV1-2*02 (SEQ ID NO: 601), IGHV1-3*01 (SEQ ID NO: 602), IGHV1-46*01 (SEQ ID NO: 603), IGHV1-18*01 (SEQ ID NO: 604), IGHV1-69*01 (SEQ ID NO: 605), and IGHV7-4-1*02 (SEQ ID NO: 606). In specific aspects, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region. In a specific aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable framework region that is derived from amino acid sequence SEQ ID NO: 601, wherein at least one, two, three, four, or five (in certain aspects up to 10) amino acids of amino acid sequence SEQ ID NO: 601 is substituted with an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region. In certain aspects, the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71, 73, and 94, wherein the amino acid position of each group member is indicated according to the Kabat numbering. In specific aspects, the amino acid substitution is selected from the group consisting of 24G, 481, 67A, 71V, 73K, and 94K, wherein the amino acid position of each group member is indicated according to the Kabat numbering

[0011] In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 201, 206, and SEQ ID NOS: 215 to 389. In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 203. In another specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 206. The present invention relates to an isolated agonistic antibody that specifically binds to human glucocorticoid-induced TNFR-related protein (GITR) comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 206 and comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 208, wherein the antibody further comprises a heavy chain constant region.

[0012] In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 553, 554 and 567 to 570. In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 581 and 582.

[0013] In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region sequence comprising one, two, three or four framework regions of the light chain variable region sequence of SEQ ID NO: 204 or SEQ ID NO: 205. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of a light chain variable region sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208, and SEQ ID NOs: 400-518. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 519. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable sequence having human derived framework regions. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGKV4-1*01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608). In specific aspects, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human light chain variable framework region. In another aspect, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable framework region that is or is derived from amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 wherein at least one, two, three, four, or five (in certain aspects up to 10) amino acids of amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 is substituted with an amino acid found in an analogous position in a corresponding non-human light chain variable framework region. In certain aspects, the amino acid substitution is at amino acid position 87, wherein the amino acid position is indicated according to the Kabat numbering. In specific aspects, the amino acid substitution is an amino acid substitution of 87H, wherein the amino acid position is indicated according to the Kabat numbering.

[0014] In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NOs: 400 to 518. In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 519. In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 204 or SEQ ID NO: 205. In another specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 207. In another specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 208. The present invention relates to an isolated agonistic antibody that specifically binds to human glucocorticoid-induced TNFR-related protein (GITR) comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 206 and comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 208, wherein the antibody further comprises a heavy chain constant region.

[0015] In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 555, 556 and 571 to 576.

[0016] In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences of an antibody in the table of Figure 23 or any one of Figures 24A-24C. In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences of an antibody in Table 17. In an specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 206; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 207. The antibody that specifically binds to GITR (e.g., human GITR) of the invention comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 206; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 208.

[0017] In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, a VH CDR3 and framework regions derived from a human immunoglobulin, wherein VH CDR1 comprises, consists of, or consists essentially of the amino acid sequence of DYAMY (SEQ ID NO: 13), VH CDR2 comprises, consists of, or consists essentially of the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO: 14) and VH CDR3 comprises, consists of, or consists essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 15). In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, a VL CDR3 and framework regions derived from a human immunoglobulin, wherein VL CDR1 comprises, consists of, or consists essentially of the amino acid sequence of KSSQSLLNSGNQKNYLT (SEQ ID NO: 16), VL CDR2 comprises, consists of, or consists essentially of the amino acid sequence of WASTRES (SEQ ID NO: 17) and VL CDR3 comprises, consists of, or consists essentially of the amino acid sequence of QNDYSYPYT (SEQ ID NO: 18). In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 201, 203, 206 and 215-389. In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 202, 204, 205, 207, 208 and 400-518. In another aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 519. In some aspects, the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra). In certain aspects, the antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In specific aspects, at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg / ml / bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads / µl with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) and 20 beads / µl of the GITR coupled beads; and (d) detecting the labeled GITRL (e.g., human GITRL) bound to the GITR (e.g., human GITR) coupled beads by, e.g., a suspension array assay. In some aspects, 20% to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof.

[0018] In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise the amino acid sequence of an antibody in Figure 23 or any one of Figures 24A-24C. In a specific aspect, provided herein is an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise the amino acid sequence of an antibody in Table 17.

[0019] In certain aspects, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises heavy and / or light chain constant regions. The antibody of the invention comprises a heavy chain constant region. In some embodiments, the heavy chain constant region is selected from the group of human immunoglobulins consisting of IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 . In certain embodiments, the light chain constant region is selected from the group of human immunoglobulins consisting of IgGκ and IgGλ. In a specific embodiment, the IgG 1 is non-fucosylated IgG 1 . In another specific embodiment, the antibody is an IgG 1 which comprises a N297A or N297Q mutation. In another specific embodiment, the antibody is an IgG 4 which comprises a S228P mutation. In another specific embodiment, the antibody is an IgG2 which comprises a C127S mutation. In certain aspects, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 557-562. In certain embodiments, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 583 and 584. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 557-560 with an amino acid substitution of N to A or Q at amino acid position 180. In certain aspects, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 588-591. In certain aspects, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 563-566.

[0020] In a specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 553, 554, and 567 to 570; and (b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 555, 556, and 571 to 576. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 581; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 582; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 567; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 573. In another specific embodiment, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 567; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576. In another specific embodiment, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 581; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 582; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576.

[0021] In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 555, 556, and 571 to 576. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556. In another specific aspect, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555.

[0022] In another aspect, provided herein is an antibody or fragment thereof that binds to the same epitope of GITR (e.g., human GITR) as the antibody described herein. In another aspect, provided herein is an isolated antibody that specifically binds to each of i) human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 and ii) a variant of cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 699, wherein the antibody does not specifically bind to cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 704. In another aspect, provided herein is an isolated antibody that specifically binds to each of i) human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 and ii) a variant of cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 699, wherein the antibody does not exhibit substantial binding to cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 704. In another aspect, provided herein is an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701, wherein the binding between the antibody and a variant GITR is substantially weakened relative to the binding between the antibody and the human GITR, and wherein the variant GITR comprises residues 26-241 of SEQ ID NO: 701 except for an amino acid substitution selected from the group consisting of D60A and G63A. In one aspect, the substitution is D60A. In another aspect, the substitution is G63A. In another aspect, provided herein is an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701, and wherein the antibody binds to an epitope comprising residues 60-63 of SEQ ID NO: 701. In another aspect, provided herein is an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701, and wherein the antibody binds to at least one residue within the amino acid sequence set forth by residues 60-63 of SEQ ID NO: 701. In one aspect, the antibody binds to at least one residue selected from the group consisting of residues 60, 62, and 63 of SEQ ID NO: 701. In one aspect, the antibody binds to at least one residue selected from the group consisting of residues 62 and 63 of SEQ ID NO: 701. In one aspect, the antibody activates or enhances an activity of the human GITR. In another aspect, provided herein is an isolated antibody that specifically binds human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO:701, and wherein the antibody binds an epitope of the human GITR comprising at least one of residues 60 or 63 of SEQ ID NO:701. In another aspect provided herein is an isolated antibody that specifically binds to human GITR, wherein the antibody exhibits, as compared to binding to human GITR, reduced or absent binding to a protein identical to human GITR except for the presence of a D60A or G63A amino acid substitution. In one aspect, the antibody induces, activates or enhances an activity of the human GITR. In another aspect, provided herein is an antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR). In a specific aspect, provided herein is an antibody or antigen-binding fragment thereof that competes with antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR) to the extent that the antibody or antigen-binding fragment thereof described herein self-competes for binding to GITR (e.g., human GITR). In another specific aspect, provided herein is a first antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR), wherein the first antibody or antigen-binding fragment thereof competes for binding in an assay comprising the following steps: (a) incubating GITR-transfected cells with the first antibody or antigen-binding fragment thereof in unlabeled form in a container; (b) adding the antibody or antigen-binding fragment thereof described herein in labeled form to the cells in the container and incubating the cells in the container; and (c) detecting the binding of the antibody or antigen-binding fragment thereof described herein in labeled form to the cells. In another specific aspect, provided herein is a first antibody or antigen-binding fragment thereof competes with an antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR), wherein the competition is exhibited as reduced binding of first antibody or antigen-binding fragment thereof to GITR (e.g., human GITR) by more than 80% (e.g., 85%, 90%, 95%, or 98%, or between 80% to 85%, 80% to 90%, 85% to 90%, or 85% to 95%).

[0023] In certain embodiments, an antibody or fragment thereof provided herein, which specifically binds to GITR (e.g., human GITR), activates, induces or enhances an activity of GITR (e.g., human GITR). In specific embodiments, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), is a humanized antibody, murine antibody or chimeric antibody. In certain embodiments, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), binds to GITR (e.g., human GITR) with a K D in the range of about 0.5 nM to 5 nM. In certain embodiments, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a detectable label. In specific embodiments, an antibody provided herein is isolated.

[0024] In certain embodiments, an antibody or fragment described herein, which immunospecifically binds to GITR (e.g., human GITR), induces, activates or enhances an activity of human GITR in a cell independent of TCR triggering. In specific embodiments, the cell is a T cell. In specific embodiments, the cell is not a T cell. In specific embodiments, the cell is selected from the group consisting of a B cell, a plasma cell, a memory cell, a natural killer cell, a granulocyte, a neutrophil, an eosinophil, a basophil, a mast cell, a monocyte, a dendritic cell, a plasmacytoid dendritic cell, an NKT cell, and a macrophage. In specific embodiments, an antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), induces, activates, or enhances an activity of NF-κB independent of TCR triggering. In certain embodiments, the activity of NF-κB can be assessed in, e.g., an assay comprising the following steps: (a) incubating T cells (e.g., Jurkat cells) expressing a NF-κB-luciferase reporter construct (e.g., GloResponse NF-κB-luc2P construct) and GITR (e.g., human GITR) with the antibody described herein or an isotype control antibody at an antibody concentration of, e.g., 12.5, 10, 5, 2.5, 1.25, or 0.625 µg / ml, in the absence of an anti-CD3 antibody; and (b) reading luciferase signal after, e.g., 2, 5, 6, 8 or 18 hours of incubation using, e.g., an EnVision multilabel reader 2100, wherein a positive luciferase signal relative to the isotype control antibody indicates activity of NF-κB. In a particular embodiment, the luciferase signal is read after 5 hours of incubation.

[0025] In certain embodiments, an antibody or fragment described herein, which immunospecifically binds to GITR (e.g., human GITR), increases the percentage of polyfunctional (IFNγ+ TNFα+) T cells. In specific embodiments, the increase in the percentage of polyfunctional (IFNγ+ TNFα+) T cells can be assessed in, e.g., an assay comprising the following steps: (a) incubating, e.g., human PBMCs with, e.g., an anti-CD3 antibody at various suboptimal concentrations (e.g., 0.3-5 µg / ml); and, e.g., an antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), at, e.g., 5 µg / ml or an isotype control antibody, for, e.g., 3-4 days at 37°C and 5% CO 2 ; (b) treating cells with, e.g., Brefeldin A for, e.g., 6 hours at 37°C and 5% CO 2 ; (c) staining the surface of the cells using, e.g., an anti-CD3 antibody, an anti-CD4 antibody, and an anti-CD8α antibody; (d) staining intracellularly using, e.g., an anti-IFNy antibody and an anti-TNFa antibody; and (e) determining the percentage of polyfunctional (IFNγ+ TNFα+) T cells relative to the isotype control antibody. In specific embodiments, the polyfunctional (IFNγ+ TNFα+) T cells are selected from the group consisting of polyfunctional (IFNγ+ TNFα+) CD4+ T cells and polyfunctional (IFNγ+ TNFα+) CD8+ T cells.

[0026] In specific embodiments, an antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), when bound to activated regulatory T cells, binds to activating Fc gamma receptors selected from the group consisting of CD16, CD32A and CD64 to a greater extent (e.g., 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold) than the antibody, when bound to activated effector T cells, binds to the activating Fc gamma receptors selected from the group consisting of CD16, CD32A and CD64, as assessed by methods described herein or known to one of skill in the art (e.g., an Fc gamma receptor IIIA (CD16) reporter assay or as described in the Examples, infra). In specific embodiments, the activating Fc gamma receptors are expressed on a cell selected from the group consisting of myeloid-derived effector cells and lymphocyte-derived effector cells. In a particular embodiment, the activating Fc gamma receptor is CD16.

[0027] In specific embodiments, an antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), when bound to activated regulatory T cells, causes stronger activation of activating Fc gamma receptors selected from the group consisting of CD16, CD32A and CD64 than the antibody, when bound to activated effector T cells, causes activation of activating Fc gamma receptors selected from the group consisting of CD16, CD32A and CD64. In particular embodiments, the activation of the activating Fc gamma receptors, when the antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), is bound to activated regulatory T cells, is at least about 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold stronger than the activation of the activating Fc gamma receptors, when the antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), is bound to activated effector T cells, as assessed by methods described herein or known to one of skill in the art (e.g., an Fc gamma receptor IIIA (CD16) reporter assay or as described in the Examples, infra). In specific embodiments, the activating Fc gamma receptors are expressed on a cell selected from the group consisting of myeloid-derived effector cells and lymphocyte-derived effector cells. In a particular embodiment, the activating Fc gamma receptor is CD16.

[0028] In certain aspects, an antibody or fragment described herein, which immunospecifically binds to GITR (e.g., human GITR), increases surface expression of OX40 and / or PD-1 in activated T cells by at least about 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, or 1000 fold as assessed by methods described herein and / or known to one of skill in the art, relative to surface expression of OX40 and / or PD-1 in activated T cells without the antibody described herein.

[0029] In another embodiment, provided herein are nucleic acid molecules encoding a heavy chain variable region and / or a light chain variable region, or a light chain and / or a heavy chain of an antibody of the invention. In a specific embodiment, the nucleic acid molecule encodes a heavy chain variable region comprising the nucleic acid sequence of SEQ ID NO: 209. In another specific aspect, the nucleic acid molecule encodes a light chain variable region comprising the nucleic acid sequence of SEQ ID NO: 210 or SEQ ID NO: 211. In specific embodiments, the nucleic acid molecule is isolated. In certain embodiments, a vector (e.g., an isolated vector) comprises a nucleic acid molecule encoding a heavy chain variable region and / or a light chain variable region, or a light chain and / or a heavy chain of an antibody of the invention. In certain embodiments, a host cell comprises the nucleic acid molecule or vector. Examples of host cells include E. coli, Pseudomonas, Bacillus, Streptomyces, yeast, CHO, YB / 20, NS0, PER-C6, HEK-293T, NIH-3T3, HeLa, BHK, Hep G2, SP2 / 0, R1.1, B-W, L-M, COS 1, COS 7, BSC1, BSC40, BMT10 cells, plant cells, insect cells, and human cells in tissue culture. In a specific embodiment, provided herein is a method of producing an antibody or antigen-binding fragment thereof that specifically binds to GITR (e.g., human GITR) comprising culturing a host cell so that the nucleic acid molecule is expressed and the antibody is produced.

[0030] In another aspect, provided herein is a method for enhancing the co-stimulation of T cells comprising incubating ex vivo T cells, which have been stimulated with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody), with an antibody or antigen-binding fragment thereof described herein. In another aspect, provided herein is a method for activating T cells comprising incubating ex vivo T cells with an antibody or antigen-binding fragment thereof described herein. In some aspects, the method further comprises, prior to, simultaneously with, or subsequent to the incubation with the anti-GITR antibody or antigen-binding fragment thereof, incubating ex vivo the T cells with a TCR complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In some aspects, the T cells were isolated from a subject. In certain disclosure, the stimulated and / or activated T cells are infused into a subject. In some disclosure, the T cells being infused into the subject are autologous or allogenic. In a specific embodiment, the subject is a human. In another disclosure, provided herein is a method for preferential expansion of effector T-cells over that of T-regulatory cells in a subject, comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof described herein. In a specific disclosure, the subject is human.

[0031] In another aspect, provided herein is a method for enhancing the expansion of T cells (e.g., CD4 +< and / or CD8 +< T cells) and / or T cell effector function, comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein. In some aspects, the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In certain aspects, the T cells were isolated from a subject. In some disclosure, the method further comprises infusing the T cells after their expansion and / or after their effector function is enhanced into a subject. In certain disclosure, the T cells being infused into the subject are autologous or allogenic. In a specific disclosure, the subject is a human.

[0032] In another aspect, provided herein is a method for enhancing the expansion of CD8 +< T cells, comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein. In some aspects, the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In certain aspects, the T cells were isolated from a subject. In some disclosure, the method further comprises infusing the T cells after their expansion and / or after their effector function is enhanced into a subject. In certain disclosure, the T cells being infused into the subject are autologous or allogenic. In a specific disclosure, the subject is a human.

[0033] In another aspect, provided herein is a method for enhancing the expansion of CD4 +< T cells, comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein. In some aspects, the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In certain aspects, the T cells were isolated from a subject. In some disclosure, the method further comprises infusing the T cells after their expansion and / or after their effector function is enhanced into a subject. In certain disclosure, the T cells being infused into the subject are autologous or allogenic. In a specific disclosure, the subject is a human.

[0034] In another aspect, provided herein is a method of activating GITR or activating NF-κB comprising incubating ex vivo T cells, which have not been stimulated with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody), with an antibody or antigen-binding fragment thereof described herein. In some aspects, the T cells were isolated from a subject. In certain disclosure, the activated T cells are infused into a subject. In some disclosure, the T cells being infused into the subject are autologous or allogenic. In a specific disclosure, the subject is a human.

[0035] In another aspect, provided herein is a method of activating T cells independent of TCR triggering comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.

[0036] In another aspect, provided herein is a method of inducing, activating or enhancing an activity of NF-κB independent of TCR triggering comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.

[0037] In another aspect, provided herein is a method of increasing the percentage of polyfunctional (IFNγ+ TNFα+) T cells comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.

[0038] In another aspect, provided herein is a method of increasing surface expression of OX40 and / or PD-1 in activated T cells comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.

[0039] In another embodiment, provided herein are pharmaceutical compositions comprising an antibody, or a nucleic acid molecule of the invention, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be used to modulate immune response and / or to treat and / or prevent a disorder, such as cancer or an infectious disease. In a specific disclosure, provided herein is a method of modulating an immune response in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein. In a particular aspect, the immune response is enhanced or induced. In another specific disclosure, provided herein is a method for enhancing the expansion of T cells and / or T cell effector function in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition described herein. In another specific disclosure, provided herein is a method for enhancing the expansion of CD8+ T cells in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition described herein. In some aspects, the disclosure provides use of an antibody as described herein in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the disclosure provides an antibody as described herein for use in the treatment of cancer. In certain aspects, the disclosure provides use of a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the disclosure provides a pharmaceutical composition as described herein for use in the treatment of cancer. In another specific disclosure, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein. In certain disclosure, the method of treating cancer further comprises administering an anti-cancer agent to the subject. Examples of anti-cancer agents that can be administered to a subject in combination with a pharmaceutical composition described herein are described in Section 5.4, infra (e.g., Sections 5.4.1 and 5.4.1.1). In a specific aspect, the anti-cancer agent is a vaccine. In a particular aspect, the vaccine comprises a heat shock protein peptide complex (HSPPC), in which the HSPPC comprises a heat shock protein (e.g., a gp96 protein) complexed with one or more antigenic peptides (e.g., tumor-associated antigenic peptides). In certain embodiments, the cancer treated is squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's or non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma, salivary gland carcinoma, kidney cancer, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a type of head or neck cancer. In certain embodiments, the cancer treated is desmoplastic melanoma, inflammatory breast cancer, thymoma, rectal cancer, anal cancer, or surgically treatable or non-surgically treatable brain stem glioma. In a specific embodiment, the subject treated is a human.

[0040] In another disclosure, provided herein is a method for activating T cells independent of TCR triggering in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein.

[0041] In another disclosure, provided herein is a method for inducing, activating or enhancing an activity of NF-κB independent of TCR triggering in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein.

[0042] In another disclosure, provided herein is a method for increasing the percentage of polyfunctional (IFNγ+ TNFα+) T cells in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein.

[0043] In another disclosure, provided herein is a method for increasing surface expression of OX40 and / or PD-1 in activated T cells in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein.

[0044] The antibody as described herein can be used in combination with an IDO inhibitor for treating cancer. In one disclosure, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein, wherein the method further comprises administering to the subject an inhibitor of indoleamine-2,3-dioxygenase (IDO). The IDO inhibitor as described herein for use in treating cancer is present in a solid dosage form of a pharmaceutical composition such as a tablet, a pill or a capsule, wherein the pharmaceutical composition includes an IDO inhibitor and a pharmaceutically acceptable excipient. As such, the antibody as described herein and the IDO inhibitor as described herein can be administered separately, sequentially or concurrently as separate dosage forms. In one aspect, the antibody is administered parenterally and the IDO inhibitor is administered orally. In particular aspects, the inhibitor is selected from the group consisting of epacadostat (Incyte Corporation), F001287 (Flexus Biosciences), indoximod (NewLink Genetics), and NLG919 (NewLink Genetics). Epacadostat has been described in PCT Publication No. WO 2010 / 005958. In one aspect, the inhibitor is epacadostat. In another aspect, the inhibitor is F001287. In another aspect, the inhibitor is indoximod. In another aspect, the inhibitor is NLG919.

[0045] The antibody as described herein can be used in combination with a checkpoint targeting agent for treating cancer. In one disclosure, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein, wherein the method further comprises administering to the subject a checkpoint targeting agent. In some aspects, the checkpoint targeting agent is selected from the group consisting of an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody), an antagonist of PD-L1 (e.g., an antagonist anti-PD-L1 antibody), an antagonist of PD-L2 (e.g., an antagonist anti-PD-L2 antibody), an antagonist of CTLA-4 (e.g., an antagonist anti-CTLA-4 antibody), an antagonist of TIM-3 (e.g., an antagonist anti-TIM-3 antibody), an antagonist of LAG-3 (e.g., an antagonist anti-LAG-3 antibody), and an agonist of OX40 (e.g., an agonist anti-OX40 antibody). In some aspects, a checkpoint targeting agent, e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered simultaneously with the anti-GITR antibody. In some aspects, a checkpoint targeting agent, e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered prior to the administration of the anti-GITR antibody. In some aspects, a checkpoint targeting agent, e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered subsequent to the administration of the anti-GITR antibody.

[0046] The antibody as described herein can be used in combination with an anti-CD25 antibody. In some aspects, an anti-CD25 antibody is administered simultaneously with the anti-GITR antibody. In some aspects, an anti-CD25 antibody is administered prior to the administration of the anti-GITR antibody. In some aspects, an anti-CD25 antibody is administered subsequent to the administration of the anti-GITR antibody.

[0047] In another specific disclosureaspect, provided herein is a method of treating cancer in a subject comprising administering an antagonist anti-PD-1 antibody to a subject in need thereof who has received an anti-GITR antibody, wherein the PD-1 antibody is administered at a time at which the anti-GITR antibody has increased expression of PD-1 in the subject relative to expression of PD-1 in the subject at the time of the administering. In another specific disclosure, provided herein is a method of treating cancer in a subject comprising administering an agonist anti-OX40 antibody to a subject in need thereof who has received an anti-GITR antibody, wherein the OX40 antibody is administered at a time at which the anti-GITR antibody has increased expression of OX40 in the subject relative to expression of OX40 in the subject at the time of the administering. In certain aspects, the anti-GITR antibody induces, activates, or enhances an activity of GITR.

[0048] In another specific disclosure, provided herein is a method of treating cancer in a subject comprising administering an anti-GITR antibody to a subject in need thereof, wherein the anti-GITR antibody increases expression of PD-1 in the subject relative to expression of PD-1 in the subject at the time of the administering, and administering an antagonist anti-PD-1 antibody to the subject when expression of PD-1 is increased. In another specific disclosure, provided herein is a method of treating cancer in a subject comprising administering an anti-GITR antibody to a subject in need thereof, wherein the anti-GITR antibody increases expression of OX40 in the subject relative to expression of OX40 in the subject at the time of the administering, and administering an agonist OX40 antibody to the subject when expression of OX40 is increased. In certain aspects, the anti-GITR antibody induces, activates, or enhances an activity of GITR.

[0049] In another specific disclosure, provided herein is a method of treating cancer or a viral infection in a subject, the method comprising the steps of: (a) incubating T cells ex vivo with an antibody or antigen-binding fragment thereof described herein; and (b) infusing the T cells into the subject. In a specific disclosure, the T cells infused into the subject are autologous or allogenic. In certain disclosure, the T cells were isolated from a subject. In some disclosure, the T cells are not incubated with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In certain disclosure, the method further comprises, prior to step (a): (1) assaying the T cells for cell surface expression of GITR; and (2) if step (1) does not result in detection of GITR above a threshold value, inducing expression of GITR on the surface of the T cells by incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In some disclosure, the method further comprises, prior to, simultaneously with or subsequent to step (a), incubating the T cells with a T cell receptor (TCR) complex stimulating agent phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody). In a specific aspect, the subject treated is a human.

[0050] In another disclosure, provided herein is a method of treating and / or preventing an infectious disease in a subject comprising administering to the subject an effective amount of a pharmaceutical composition described herein. See Section 5.4.1.2 below for examples of infectious diseases. In another specific disclosure, provided herein is a method of treating a viral infection in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein. In one embodiment, the invention relates to an antibody of the invention, or the pharmaceutical composition of the invention, for use in the treatment of a viral infection. In certain embodiments, the viral infection treated is caused by a human papilloma virus (HPV), a Herpes simplex or other herpes virus, hepatitis B virus (HBV), hepatitis C virus (HCV) or other hepatitis virus, measles virus, HIV or Epstein Barr virus (EBV). In certain embodiments, the antibody or pharmaceutical composition for use in treating a viral infection further comprises administering an anti-viral agent to the subject. In a specific embodiment, the subject treated is a human.

[0051] In another specific aspect, provided herein is a method of identifying an anti-GITR antibody that is capable of inducing, activating, or enhancing an activity of GITR in the absence of a TCR agonist comprising contacting a cell expressing GITR with an anti-GITR antibody in the absence of a TCR agonist and measuring GITR activity, wherein increased GITR activity compared to GITR activity in the absence of the anti-GITR antibody indicates the anti-GITR antibody is capable of inducing, activating, or enhancing an activity of GITR in the absence of a TCR agonist. In certain aspects, the GITR activity is assessed by measuring NF-κB activity. In certain aspects, the GITR activity is assessed by measuring activation of TRAF adaptor mediated signaling pathways, wherein the TRAF adaptor is selected from the group consisting of TRAF1, TRAF2, TRAF3, TRAF4, and TRAF5. In certain aspects, the GITR activity is assessed by measuring activation of the MAPK / ERK pathway. In certain aspects, the anti-GITR antibody increases the GITR activity at least two-fold compared to GITR activity in the absence of the anti-GITR antibody. In certain aspects, the anti-GITR antibody increases the GITR activity two-fold to twenty-fold compared to GITR activity in the absence of the anti-GITR antibody. In certain aspects, the anti-GITR antibody increases the GITR activity two-fold to ten-fold compared to GITR activity in the absence of the anti-GITR antibody. In certain aspects, the cell is a T cell. In certain aspects, the cell is not a T cell.

[0052] In another specific embodiment, provided herein is an anti-GITR antibody of the invention that specifically binds to human GITR, wherein said antibody is capable of inducing, activating, or enhancing an activity of GITR in a cell in the absence of TCR triggering. In another specific embodiment, provided herein is an anti-GITR antibody that specifically binds to human GITR, wherein said antibody induces, activates, or enhances an activity of NF-κB in a cell in the absence of TCR triggering. In another specific disclosure, provided herein is a method of treating cancer comprising administering to a subject in need thereof an anti-GITR antibody that specifically binds to human GITR, wherein said antibody is capable of inducing, activating, or enhancing an activity of GITR and / or NF-κB in the absence of TCR triggering.3.1 Terminology

[0053] As used herein, the terms "about" and "approximately," when used to modify a numeric value or numeric range, indicate that deviations of 5% to 10% above and 5% to 10% below the value or range remain within the intended meaning of the recited value or range.

[0054] As used herein, the binding between a test antibody and a first antigen is "substantially weakened" relative to the binding between the test antibody and a second antigen if the binding between the test antibody and the first antigen is reduced by at least 30%, 40%, 50%, 60%, 70%, or 80% relative to the binding between the test antibody and the second antigen, e.g., in a given experiment, or using mean values from multiple experiments, as assessed by, e.g., an assay comprising the following steps: (a) expressing on the surface of cells (e.g., 1624-5 cells) the first antigen or the second antigen; (b) staining the cells expressing the first antigen or the second antigen using, e.g., 2 µg / ml of the test antibody or a polyclonal antibody in a flow cytometry analysis and recording mean fluorescence intensity (MFI) values, e.g., as the mean from more than one measurement, wherein the polyclonal antibody recognizes both the first antigen and the second antigen; (c) dividing the MFI value of the test antibody for the cells expressing the second antigen by the MFI value of the polyclonal antibody for the cells expressing the second antigen (MFI ratio 2 ); (d) dividing the MFI value of the test antibody for the cells expressing the first antigen by the MFI value of the polyclonal antibody for the cells expressing the first antigen (MFI ratio 1 ); and (e) determining the percentage of reduction in binding by calculating 100% ∗< (1-(MFI ratio 1 / MFI ratio 2 )).

[0055] As used herein, an antibody does not exhibit "substantial binding" to an antigen if when measured in a flow cytometry analysis, the mean fluorescence intensity (MFI) value of the antibody to the antigen is not significantly higher than the MFI value of an isotype control antibody to the antigen or the MFI value in the absence of any antibody.

[0056] As used herein, the terms "antibody" and "antibodies" are terms of art and can be used interchangeably herein and refer to a molecule with an antigen binding site that specifically binds an antigen.

[0057] Antibodies can include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain- antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, F(ab') 2 fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), and antigen-binding fragments of any of the above. In certain aspects, antibodies described herein refer to polyclonal antibody populations. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 or IgA 2 ), or any subclass (e.g., IgG 2a or IgG 2b ) of immunoglobulin molecule. In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgG 1 or IgG 4 ) or subclass thereof. In a specific embodiment, the antibody is a humanized monoclonal antibody. In another specific embodiment, the antibody is a human monoclonal antibody, preferably that is an immunoglobulin. In certain embodiments, an antibody described herein is an IgG 1 , or IgG 4 antibody.

[0058] As used herein, the terms "antigen-binding domain," "antigen-binding region," "antigen-binding fragment," and similar terms refer to a portion of an antibody molecule which comprises the amino acid residues that confer on the antibody molecule its specificity for the antigen (e.g., the complementarity determining regions (CDR)). The antigen-binding region can be derived from any animal species, such as rodents (e.g., mouse, rat or hamster) and humans.

[0059] As used herein, the terms "variable region" or "variable domain" are used interchangeably and are common in the art. The variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In particular embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0060] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

[0061] The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

[0062] The term "Kabat numbering" and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen-binding portion thereof. In certain aspects, the CDRs of an antibody can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3). In a specific embodiment, the CDRs of the antibodies described herein have been determined according to the Kabat numbering scheme.

[0063] As used herein, the term "constant region" or "constant domain" are interchangeable and have its meaning common in the art. The constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0064] As used herein, the term "heavy chain" when used in reference to an antibody can refer to any distinct type, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG 1 , IgG 2 , IgG 3 and IgG 4 .

[0065] As used herein, the term "light chain" when used in reference to an antibody can refer to any distinct type, e.g., kappa (κ) or lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.

[0066] "Binding affinity" generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured and / or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (K D ), and equilibrium association constant (K A ). The K D is calculated from the quotient of k off / k on , whereas K A is calculated from the quotient of k on / k off . k on refers to the association rate constant of, e.g., an antibody to an antigen, and k off refers to the dissociation of, e.g., an antibody to an antigen. The k on and k off can be determined by techniques known to one of ordinary skill in the art, such as BIAcore® or KinExA.

[0067] As used herein, a "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In certain aspects, one or more amino acid residues within a CDR(s) or within a framework region(s) of an antibody or antigen-binding fragment thereof can be replaced with an amino acid residue with a similar side chain.

[0068] As used herein, an "epitope" is a term in the art and refers to a localized region of an antigen to which an antibody can specifically bind. An epitope can be, for example, contiguous amino acids of a polypeptide (linear or contiguous epitope) or an epitope can, for example, come together from two or more non-contiguous regions of a polypeptide or polypeptides (conformational, non-linear, discontinuous, or non-contiguous epitope). In certain aspects, the epitope to which an antibody binds can be determined by, e.g., NMR spectroscopy, X-ray diffraction crystallography studies, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligo-peptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization may be accomplished using any of the known methods in the art (e.g., Giegé R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; Chayen NE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251: 6300-6303). Antibody:antigen crystals may be studied using well known X-ray diffraction techniques and may be refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see e.g. Meth Enzymol (1985) volumes 114 & 115, eds Wyckoff HW et al.,; U.S. 2004 / 0014194), and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1): 37-60; Bricogne G (1997) Meth Enzymol 276A: 361-423, ed Carter CW; Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies may be accomplished using any method known to one of skill in the art. See, e.g., Champe M et al., (1995) J Biol Chem 270: 1388-1394 and Cunningham BC & Wells JA (1989) Science 244: 1081-1085 for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques. In a specific aspect, the epitope of an antibody or antigen-binding fragment thereof is determined using alanine scanning mutagenesis studies, such as described in Section 6, infra.

[0069] As used herein, the terms "immunospecifically binds," "immunospecifically recognizes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIAcore®, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, molecules that immunospecifically bind to an antigen bind to the antigen with a K A that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the K A when the molecules bind to another antigen.

[0070] In another specific embodiment, molecules that immunospecifically bind to an antigen do not cross react with other proteins under similar binding conditions. In another specific embodiment, molecules that immunospecifically bind to an antigen do not cross react with other non-GITR proteins. In a specific embodiment, provided herein is an antibody or fragment thereof that binds to GITR with higher affinity than to another unrelated antigen. In certain embodiments, provided herein is an antibody or fragment thereof that binds to GITR (e.g., human GITR) with a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or higher affinity than to another, unrelated antigen as measured by, e.g., a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay. In a specific embodiment, the extent of binding of an anti-GITR antibody or antigen-binding fragment thereof described herein to an unrelated, non-GITR protein is less than 10%, 15%, or 20% of the binding of the antibody to GITR protein as measured by, e.g., a radioimmunoassay.

[0071] In a specific embodiment, provided herein is an antibody or fragment thereof that binds to human GITR with higher affinity than to another species of GITR. In certain embodiments, provided herein is an antibody or fragment thereof that binds to human GITR with a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or higher affinity than to another species of GITR as measured by, e.g., a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay. In a specific embodiment, an antibody or fragment thereof described herein, which binds to human GITR, will bind to another species of GITR protein with less than 10%, 15%, or 20% of the binding of the antibody or fragment thereof to the human GITR protein as measured by, e.g., a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay.

[0072] As used herein, the terms "glucocorticoid-induced TNFR family related receptor" or "GITR" or "GITR polypeptide" refer to GITR including, but not limited to, native GITR, an isoform of GITR, or an interspecies GITR homolog of GITR. GITR is a 26 kDa type I transmembrane protein. GenBank™ accession numbers BC152381 and BC152386 provide exemplary human GITR nucleic acid sequences. Swiss-Prot accession number Q9Y5U5-1 (TNR18 HUMAN; SEQ ID NO: 701) and GenBank™ accession number NP_004186 provide exemplary human GITR amino acid sequences for isoform 1. This amino acid sequence is 241 amino acids in length with the first 25 amino acid residues encoding the signal sequence. Isoform 1 is a type I membrane protein. An exemplary mature amino acid sequence of human GITR is provided as SEQ ID NO: 700. In contrast, isoform 2 is a secreted form of human GITR and is approximately 255 amino acids in length. Swiss-Prot accession number Q9Y5U5-2 and GenBank™ accession number NP_683699 provide exemplary human GITR amino acid sequences for isoform 2. Isoform 3 of human GITR is approximately 234 amino acids in length. Swiss-Prot accession number Q9Y5U5-3 and GenBank™ accession number NP_683700 (isoform 3 precursor) provide exemplary human GITR amino acid sequences for isoform 3. In a specific embodiment, the GITR is human GITR. In another specific embodiment, the GITR is human GITR isoform 1 (SEQ ID NO: 701). In certain embodiments, the GITR is human isoform 2 (SEQ ID NO: 702) or isoform 3 (SEQ ID NO: 703). GITR is also known as tumor necrosis factor receptor superfamily member 18 (TNFRSF18), activation-inducible TNFR family receptor (AITR), GITR-D, and CD357. Human GITR is designated GeneID: 8784 by Entrez Gene.

[0073] The amino acid sequence of an immature form of an exemplary GITR protein from cynomolgus monkey is provided in SEQ ID NO: 704. The mature form of this exemplary protein is amino acids 26-234 of SEQ ID NO: 704.

[0074] As used herein, the terms "GITR ligand" and "GITRL" refer to glucocorticoid-induced TNFR-related protein ligand. GITRL is otherwise known as activation-induced TNF-related ligand (AITRL) and tumor necrosis factor ligand superfamily member 18 (TNFSF18). GenBank™ accession number AF125303 provides an exemplary human GITRL nucleic acid sequence. GenBank™ accession number NP_005083 and Swiss-Prot accession number Q9UNG2 provide exemplary human GITRL amino acid sequences. In a particular embodiment, the GITRL is a human GITRL of SEQ ID NO: 716.

[0075] As used herein, the term "host cell" can be any type of cell, e.g., a primary cell, a cell in culture, or a cell from a cell line. In specific embodiments, the term "host cell" refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule, e.g., due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.

[0076] As used herein, the term "effective amount" in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect. Examples of effective amounts are provided in Section 5.4.1.3, infra.

[0077] As used herein, the terms "subject" and "patient" are used interchangeably. The subject can be an animal. In some embodiments, the subject is a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat etc.) or a primate (e.g., monkey or human), most preferably a human. In certain embodiments, such terms refer to a non-human animal (e.g., a non-human animal such as a pig, horse, cow, cat or dog). In some embodiments, such terms refer to a pet or farm animal. In specific embodiments, such terms refer to a human.4. BRIEF DESCRIPTION OF THE FIGURES

[0078] Figure 1 is a Western Blot under non-reducing conditions showing specificity of anti-GITR antibody 231-32-15 versus an isotype control. Antibody is blotted against human GITR recombinant protein (Hu GITR recomb protein), mouse GITR recombinant protein (Mu GITR recomb protein), CMS5A cells expressing recombinant human GITR (CMS5A-huGITR), wild-type CMS5A cells (CMS5A-wt), protein from CD4 +< Activated cells (CD4 +< Activated) and protein from CD4 +< Untreated cells (CD4 +< Untreated). 231-32-15 reactivity is seen against human GITR, recombinant human GITR in CMS5A cells, and natural human GITR in activated CD4 +< cells. Figures 2A and 2B show FACS analysis of competitive binding of the anti-GITR antibodies versus commercial (R&D Systems) anti-GITR mAb. In Figure 2A blocking of the R&D Systems mAb is tested using the R&D mAb and the test antibodies (antibody 1042-7, antibody 1039-45, antibody 1333-21 and antibody 32-15) as indicated in the figure. The condition 'no antibody' shows binding of the R&D Systems mAb alone, in the absence of test antibodies. Figure 2B shows blocking of the anti-GITR antibody 231-1039-45 using no mAb, the R&D Systems mAb and the test antibodies (antibody 1042-7, antibody 1039-45, antibody 1333-21 and antibody 32-14) as indicated in the figure. The condition 'no antibody' shows binding of antibody 231-1039-45 alone, in the absence of test antibodies. Figures 3A, 3B and 3C: Figure 3A depicts staining of CMS5A-GITR by antibodies 1333-21 batch 1, 1333-21 batch 2 and R&D antibody at varying concentrations of antibody. Figure 3B graphs the fluorescence intensity of ex-vivo PBMC CD3-CD19-GITR+ and CD4+CD25+GITR+ cells on staining with antibodies 1042-7, 32-15, 1039-45, 1333-21 and R&D antibody. Figure 3C provides FACS analysis of CD3-CD19-GITR+ and CD4+CD25+GITR+ cells by antibody 1333-21 and the R&D Systems antibody. Figure 4 depicts an assessment of the costimulatory effect of anti-GITR antibody on CD4+ T cells in combination with varying concentrations of anti-CD3 (OKT3) antibody. In the top panel the % CFSE-low cells is plotted for each antibody tested (PBS control, R&D, 1042-7, 32-15, 1039-45 and 1333-21) in combination with decreasing concentrations of OKT3 antibody (5µg / ml, 1µg / ml, 0.2µg / ml, 0.04µg / ml and 0µg / ml). In the bottom panel the concentration of IFNγ (pg / ml) is plotted for each antibody tested (PBS control, R&D, 1042-7, 32-15, 1039-45 and 1333-21) in combination with decreasing concentrations of the OKT3 antibody (5µg / ml, 1µg / ml, 0.2µg / ml, 0.04µg / ml and 0µg / ml). Figure 5 shows GITRL-PE binding to GITR in the presence of anti-GITR antibodies chimeric parental 231-32-15 and m6C8. A further antibody SK48E26, which recognizes IL-1β, was used as a negative control. The percentage of GITRL-PE binding was measured by suspension array technology (Luminex® 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng / ml). Figure 5 shows the results from four independent repeats of this assay performed in duplicate and standard deviation was determined from n=8. Figure 6 is a similar graph to that shown in Figure 5 where the percentage of GITRL-PE binding was measured by suspension array technology (Luminex® 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng / ml). The anti-GITR antibodies tested were the chimeric parental 231-32-15 antibody and the two humanized variants Hum231#1 and Hum231#2. This figure shows the results from one experiment performed in duplicate. Figure 7 shows GITR ligand binding to GITR in the presence of mAbs as measured by surface plasmon resonance (BIAcore® T100 / 200). The anti-GITR antibodies tested were chimeric parental 231-32-15, humanized variants Hum231#1 and Hum231#2 and m6C8. The negative control was the anti-IL-1β antibody SK48E26. Figures 8A and 8B show FACS plots of the results of a suboptimal CD3 stimulation assay to assess the effects of stimulation of anti-GITR antibodies on enriched CD4 +< T cells from two different buffy coats. Figure 8A shows the FACS analysis of cell number and proliferation of CD4 T cells from a high responder to stimulation (buffy coat 6), whereas Figure 8B shows the FACS analysis for a low responder (buffy coat 8). Cell proliferation (CFSE; x-axis) is shown for 10µg / ml of anti-GITR antibody (chimeric parental 231-32-15 antibody and humanized variants Hum231#1 and Hum231#2). The controls used were either anti-CD3 / anti-CD28 antibody alone or no stimulation. The assay was performed in triplicate. Figures 9A and 9B are histograms showing the effect of anti-GITR humanized variant antibodies Hum231#1 and Hum231#2 on enriched CD4 T cell proliferation (Figure 9A) and cell number (Figure 9B), compared to the antibody m6C8, in a suboptimal CD3 stimulation assay. The antibodies were used at a concentration of 10µg / ml. The end column (solid black fill; Figures 9A and 9B) indicates anti-CD3 / anti-CD28 simulation without the addition of any anti-GITR antibodies. Figures 10A, 10B, 10C and 10D show the analysis of cytokine production for IFNγ, IL-6, IL-10 and TNFα, respectively induced by the administration of anti-GITR antibodies in a suboptimal CD3 stimulation assay. The anti-GITR antibodies tested were chimeric parental 231-32-15 and humanized variants Hum231#1 and Hum231#2 at concentrations of 10µg / ml and 5µg / ml. Figure 11 is a histogram showing the further titration of anti-GITR antibodies and their effect on cell proliferation in a suboptimal CD3 stimulation assay. The chimeric parental 231-32-15 antibody and humanized variants Hum231#1 and Hum231#2 were used at concentrations of 10µg / ml, 5µg / ml and 2.5µg / ml. Figures 12A and 12B show the further titration of anti-GITR antibodies and their effect on IFNγ production in a suboptimal CD3 stimulation assay. The chimeric parental 231-32-15 antibody and humanized variants Hum231#1 and Hum231#2 were used at concentrations of 10µg / ml, 5µg / ml and 2.5µg / ml as plate bound (Figure 12A) or 20µg / ml, 10µg / ml and 5µg / ml as soluble antibodies (Figure 12B). Figure 13 is a set of bar graphs showing the results of co-stimulation with 5 µg / ml, plate-bound Hum231#2 on cytokine secretion by PBMCs in a suboptimal CD3 stimulation assay. The data shown in Figure 13 are from two donors tested on day 2 and day 4 post-stimulation. The max fold induction over isotype control was plotted for six different cytokines (IFNγ, IL-2, TNFα, IL-10, IL-13 and IL-4). The error bars represent standard deviation for a replicate of two for each cytokine. Each donor has been tested in at least three individual experiments. Figures 14A, 14B and 14C are results of intracellular cytokine staining assays measuring the production of IFNy and TNFα, induced by plate-bound Hum231#2, Hum23 1#2w or pab1989 (the IgG4 counterpart of Hum231#2w) under suboptimal CD3 stimulation. Figure 14A is a set of flow cytometry plots showing the co-staining of IFNy and TNFα for CD4+ and CD8+ T cells. The percentage of IFNγ+ monofunctional T cells, TNFα+ monofunctional T cells or IFNγ+ TNFα+ polyfunctional T cells was plotted for Hum231#2, Hum231#2w, pab1989 or isotype control over a range of suboptimal anti-CD3 antibody concentrations (Figures 14B and 14C). Each dot in Figures 14B and 14C represents a replicate of two for the condition tested. The error bars represent standard deviation. The anti-GITR antibodies were used at a concentration of 5 µg / ml. The graphs are representative of experiments using PBMCs from six (Figures 14A and 14B) and four (Figure 14C) different donors, respectively. Figures 15A, 15B and 15C are a set of bar graphs showing results of experiments comparing the anti-GITR antibody Hum231#2 under different cross-linking conditions. Figure 15A is a bar graph showing the maximum fold induction from isotype control for the percentage of IFNγ+ TNFα+ polyfunctional CD8+ T cells using PBMCs co-stimulated by 5 µg / ml plate-bound (PB) or soluble Hum231#2 or isotype control. The error bars represent standard deviation. * represents p < 0.05 and ** represents p < 0.005 (unpaired T-test). In Figures 15B and 15C, the maximum fold induction over isotype control for six different cytokines was plotted for either plate-bound Hum231#2 (Figure 15B) or anti-Fc cross-linked Hum231#2 (Figure 15C). The error bars represent standard deviation from a replicate of two for each cytokine. Figures 16A and 16B show the results of anti-CD3 / anti-CD28 and anti-GITR antibody stimulation on T effector (T-eff) and T regulatory cells (Tregs). Figure 16A shows that activated T-effector and T-regulatory cells express GITR on their cell surface following stimulation with anti-CD3 / anti-CD28 alone or in conjunction with anti-GITR antibodies. However, as is shown in Figure 16B, costimulation with anti-GITR antibodies preferentially expands effector T-cells over T-regulatory cells. Cell expansion / proliferation (CFSE; y-axis) is shown for 10µg / ml of anti-GITR antibodies (chimeric parental 231-32-15 antibody and humanized variants Hum231#1 and Hum231#2) on buffy coat 8. The controls used were either anti-CD3 / anti-CD28 antibody at 125ng / ml alone or no stimulation. Figures 17A and 17B show the results on T cell proliferation by the anti-GITR antibodies tested. Figure 17A shows the proliferation of CD4 cells and Figure 17B shows the proliferation of CD8 cells in total PBMCs stimulated with 31.25ng / ml anti-CD3 antibody. Chimeric parental 231-32-15 antibody and humanized variants Hum231#1 and Hum231#2 were tested at a concentration of 10µg / ml. Figures 18A, 18B and 18C are graphs showing the results of a GITR NF-κB-luciferase reporter assay in the absence or presence of 0.3 µg / ml of a plate-bound anti-CD3 antibody (Clone SP34). Figure 18A is a graph showing the luciferase relative light units (RLU) at a range of anti-GITR antibody concentrations at 18-hour post-stimulation in the presence of the anti-CD3 antibody. Figure 18B is a graph showing luciferase RLU at different anti-GITR antibody concentrations at 5-hour post-stimulation in the absence of the anti-CD3 antibody. Figure 18C is a graph showing the highest ratios of luciferase expression (GITR Ab / isotype control) at 0, 2, 5, 6, 8 and 18 hrs post-stimulation. The error bars represent standard deviation from duplicates. The anti-GITR antibodies tested were Hum231#2w and m6C8. The data shown are representative of four experiments with anti-CD3 antibody or two experiments without anti-CD3 antibody. Figure 19A is a bar graph showing the normalized receptor density of human GITR on activated nTregs, CD4+ T cells or CD8+ T cells as measured by flow cytometry. The anti-GITR antibody used was a PE-conjugated mouse anti-human GITR antibody (Biolegend: 621; 311604 / B171072). The error bars represent standard deviation. Figure 19B is a graph examining the anti-GITR antibody Hum231#2w using an Fc gamma receptor IIIA (CD16) reporter cell line. Jurkat NFAT-luciferase reporter cells overexpressing CD16A with the high affinity 158 V / V polymorphism were co-cultured with activated primary nTregs and T effector cells for 20 hours at 37°C in the presence of Hum231#2w or an isotype control. The relative light units (RLU) were recorded after 20 hours, representing CD16A binding. Δ RLU represents the RLU of the anti-GITR antibody minus that of the isotype control. The error bars represent standard deviation (n=2). The data shown are representative of experiments using cells from three donors. Figure 19C is a set of histograms showing the surface expression of GITR measured by flow cytometry. Samples were collected from the blood of healthy human donors (a-c, n=3) or from tumor tissues of non-small cell lung cancer patients (NSCLC) (d-f, n=3). The cell populations were defined as: Tconv (CD3+, CD4+, CD8a-, CD25low, FOXP3-) or Treg (CD3+, CD4+, CD8a-, CD25high, FOXP3+). Figures 20A, 20B and 20C are results from experiments using PBMCs from African green monkey (AGM). Figure 20A is a set of flow cytometry plots of the staining of activated CD4+ and CD8+ T cells from African green monkey (AGM) using the anti-GITR antibody Hum231#2 and an anti-PD-1 antibody. Healthy AGM PBMCs were activated with anti-CD3 antibody (clone SP34.2) or ConA plus IL-2 (20 U / ml) for 3 days. The flow cytometry plots are representative of experiments using PBMCs from three different AGMs. Figures 20B and 20C are results of a CD3 substimulation assay using AGM PBMCs. Figure 20B is a pair of flow cytometry plots showing the co-staining of CD8 and IFNγ for cells co-stimulated by Hum231#2w or isotype control. In Figure 20C, the percentage of IFNγ+ AGM CD8+ T cells was plotted for different anti-GITR antibody concentrations. Each dot represents a replicate of two wells and the error bars represent standard deviation. The data shown in Figures 20B and 20C are representative of experiments using PBMCs from two AGMs. Figures 21A and 21B are results from the staining of surface OX40 and PD-1 on CD4+ and CD8+ T cells stimulated with plate-bound 0.8 µg / ml of an anti-CD3 antibody and 5 µg / ml of the anti-GITR antibody Hum231#2. Figure 21A is a set of flow cytometry plots and histograms showing co-staining of OX40 and PD-1. In Figure 21B, each bar represents the MFI value for PD-1 and OX40 on CD4+ and CD8+ T cells stimulated with Hum231#2 (black bars), isotype control (gray bars) or media only (white bars). The error bars represent standard deviation. The flow cytometry plots and graphs are representative of experiments using PBMCs from one donor. Figures 22A and 22B show the design of the mutated libraries for the generation of germlined antibody variants. The different framework and CDR positions included in the library based on the IGHV1-2 ∗< 02 VH human germline are shown in Figure 22A (SEQ ID NOS 37-53, respectively, in order of appearance) and for the library based on the IGKV4-1 ∗< 01 VL human germline in Figure 22B (SEQ ID NOS 54-71, respectively, in order of appearance). Figure 23 is a table listing 17 germlined antibody variants and detailing their heavy and light chain variable regions with corresponding SEQ ID numbers. The table shows the number of extra germline amino acids and the mean relative affinity of the variant antibodies compared to the chimeric parental 231-32-15 antibody. Figures 24A-C are a table listing 107 germlined antibody variants and detailing their heavy and light chain variable regions with corresponding SEQ ID numbers. Figures 25A and 25B show GITRL-PE binding to GITR in the presence of a selection of anti-GITR germlined antibody variants. The percentage of GITRL-PE binding was measured by suspension array technology (Luminex® 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng / ml). Figures 26A and 26B show the effect on cell proliferation (% CFSE Low) of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#1 and Hum231#2 on enriched CD4 T cells from two buffy coats, BC4 (Figure 26A) and BC9 (Figure 26B). A suboptimal CD3 stimulation assay was performed using plate bound anti-CD3 antibody at 125ng / ml with either plate bound or soluble isotype control. Anti-GITR antibodies were used at a concentration of 10µg / ml. Figures 27A and 27B show the effect on cytokine release of IFNγ and IL-10, respectively of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#1 and Hum231#2 on enriched CD4 T cells from buffy coat BC4. A suboptimal CD3 stimulation assay was performed using plate bound anti-CD3 antibody at 125ng / ml with either plate bound or soluble isotype control. Anti-GITR antibodies were used at a concentration of 10µg / ml and the cytokine levels were measured in the culture supernatant. Figures 28A and 28B show the effect on cytokine release of IFNy and IL-10, respectively of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#1 and Hum231#2 on enriched CD4 T cells from buffy coat BC9. A suboptimal CD3 stimulation assay was performed using plate bound anti-CD3 antibody at 125ng / ml with either plate bound or soluble isotype control. Anti-GITR antibodies were used at a concentration of 10µg / ml and the cytokine levels were measured in the culture supernatant. Figures 29A and 29B show the percentage of IFNy positive CD4 +< T-cells (as measured by intracellular staining) of germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#1 and Hum231#2 on enriched CD4 T cells from two buffy coats. Figure 29A shows the results from buffy coat 13 (BC13) and Figure 29B shows the results from buffy coat 18 (BC18). Figures 30A-C are a set of graphs showing the results of a GITR NF-κB-luciferase reporter assay in the presence of 0.3 µg / ml anti-CD3 antibody. The anti-GITR antibodies tested in this assay were Hum231#2w and 20 germline variants: pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, pab2159, pab2160 and pab2161. In Figures 30A-C, the luciferase RLU at 18-hour post-stimulation was plotted for different anti-GITR antibody concentrations tested. The error bars represent standard deviation. Figures 30D-F are a set of graphs showing the results of a GITR NF-κB-luciferase reporter assay in the absence of an anti-CD3 antibody. The anti-GITR antibodies tested in this assay were m6C8, Hum231#2w and 20 germline variants: pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, pab2159, pab2160 and pab2161. In Figures 30D-F, the luciferase RLU at 6-hour post-stimulation was plotted for different anti-GITR antibody concentrations tested. The error bars represent standard deviation. The graphs and plots are representative of data from two experiments (Figures 30A-C) or one experiment (Figures 30D-F). Figure 31 shows the loss of binding of 1624-5 pre-B cells expressing the chimeric parental 231-32-15 antibody to biotinylated GITR (GITR-bio) when GITR-bio was pre-incubated with chimeric parental 231-32-15, Hum231#1 or Hum231#2 antibodies. Figure 31 right-hand profile depicts the binding of 1624-5 pre-B cells expressing the chimeric parental 231-32-15 antibody to GITR-bio. In the left-hand profile however, there is loss of binding of 1624-5 cells expressing the chimeric parental 231-32-15 antibody to GITR-bio following pre-incubation of GITR-bio with either the chimeric parental 231-32-15, Hum231#1 or Hum231#2 antibodies. Figure 32 shows the results of an epitope competition assay measured by surface plasmon resonance (BIAcore® T100 / 200). GITR antigen was immobilized on a CM5 sensor chip and the anti-GITR antibodies applied at a concentration of 300nM. Chimeric parental 231-32-15 antibody was applied first followed by the application of the murine antibody 6C8. Figures 33A and 33B are the results of an epitope mapping experiment using a cellular library expressing GITR variants generated by error prone PCR. Shown in Figures 33A and 33B is an alignment of sequences from the GITR variants that bind to a polyclonal anti-GITR antibody but do not bind to the anti-GITR chimeric parental 231-32-15 antibody. Figures 34A and B are the result of an epitope mapping experiment using alanine scanning. The following positions in human GITR (numbered according to SEQ ID NO: 701) were separately mutated to an Alanine: P28A, T29A, G30A, G31A, P32A, T54A, T55A, R56A, C57A, C58A, R59A, D60A, Y61A, P62A, G63A, E64A, E65A, C66A, C67A, S68A, E69A, W70A, D71A, C72A, M73A, C74A, V75A and Q76A. The antibodies tested in the experiment shown in Figure 34A included: the monoclonal anti-GITR antibodies Hum231#2, three germline variants (pab1967, pab1975 and pab1979) and the m6C8 antibody; and a polyclonal anti-GITR antibody (AF689, R&D systems). Figure 34A is a table summarizing the binding of Hum231#2, three germline variants (pab1967, pab1975 and pab1979) and the reference antibody m6C8 to1624-5 cells expressing human GITR alanine mutants. Figure 34B is a set of flow cytometry plots showing the staining of 1624-5 cells expressing wild type human GITR, D60A mutant, or G63A mutant using the monoclonal antibodies 231-32-15, Hum231#2, or m6C8, or a polyclonal antibody. The percentage of GITR positive cells is indicated in each plot. Figure 35A is a sequence alignment of human GITR, V1M cynomolgus GITR, and V1M / Q62P / S63G cynomolgus GITR, highlighting the positions 62 and 63 where two amino acids from cynomolgus GITR (GlnSer) were replaced by corresponding residues in human GITR (ProGly). Figure 35B is a set of flow cytometry plots showing the staining of 1624-5 cells expressing human GITR, V1M cynomolgus GITR, or V1M / Q62P / S63G cynomolgus GITR using the monoclonal antibodies 231-32-15, Hum231#2, or m6C8, or a polyclonal anti-GITR antibody. 5. DETAILED DESCRIPTION

[0079] Provided herein are antibodies (e.g., monoclonal antibodies), and antigen-binding fragments thereof, that specifically bind to GITR (e.g., human GITR) and modulate GITR activity. For example, in one aspect, provided herein is an antibody(ies) or fragment(s) thereof that specifically binds to GITR and enhances, induces, or increases one or more GITR activities. In a specific embodiment, the antibody(ies) or antigen-binding fragment(s) is isolated.

[0080] Also provided are isolated nucleic acids (polynucleotides), such as complementary DNA (cDNA), encoding such antibodies, and antigen-binding fragments thereof. Further provided are vectors (e.g., expression vectors) and cells (e.g., host cells) comprising nucleic acids (polynucleotides) encoding such antibodies or antigen-binding fragments thereof. Also provided are methods of making such antibodies. In other aspects, provided herein are methods and uses for inducing, increasing or enhancing a GITR activity, and treating certain conditions, such as cancer and infectious diseases. Related compositions (e.g., pharmaceutical compositions), kits, and detection methods are also provided.5.1 Antibodies

[0081] In a specific aspect, provided herein are antibodies (e.g., monoclonal antibodies, such as chimeric or humanized antibodies) and fragments thereof which specifically bind to GITR (e.g., human GITR) as defined in the claims. In some aspects, an antibody or antigen-binding fragment thereof described herein partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR). In certain embodiments, an antibody or antigen-binding fragment thereof described herein inhibits binding of GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% as assessed by an assay known to one of skill in the art or described herein. In a specific embodiment, an antibody or antigen-binding fragment thereof described herein inhibits binding of GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% as assessed by the assay described in Example 2, infra (e.g., Sections 6.2.5.2 or 6.2.5.4, infra). In another specific embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 1000 ng / ml, 950 ng / ml, 900 ng / ml, 850 ng / ml, 800 ng / ml, 750 ng / ml, 700 ng / ml, 650 ng / ml, 600 ng / ml, 550 ng / ml, 500 ng / ml, 450 ng / ml, 400 ng / ml, 350 ng / ml, 333 ng / ml, 300 ng / ml, 250 ng / ml, 200 ng / ml, 100ng / ml, 50ng / ml or 10ng / ml inhibits binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., GITRL-PE) to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, an antibody or antigen-binding fragment thereof described herein at concentration of 1000 ng / ml to 750 ng / ml, 1000 ng / ml to 500 ng / ml, 850 ng / ml to 500 ng / ml, 750 ng / ml to 500 ng / ml, 600 ng / ml to 500 ng / ml, 500 ng / ml to 400 ng / ml, 400 ng / ml to 300 ng / ml, or 300 ng / ml to 200 ng / ml inhibits binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, 0.1nM of labeled GITRL (e.g., GITRL-PE) to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, an antibody or antigen-binding fragment thereof at a concentration of 1000ng / ml inhibits less than 80% (in some embodiments, 40% to 70%, 50%, to 80%, or 40% to 80%) of 0.5nM labeled GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.

[0082] In another specific embodiment, an antibody or antigen-binding fragment thereof described herein at concentration of 3500 ng / ml, 3400 ng / ml, 3300 ng / ml, 3200 ng / ml, 3100 ng / ml, 3000 ng / ml, 2900 ng / ml, 2800 ng / ml, 2700 ng / ml, 2600 ng / ml, 2500 ng / ml, 2400 ng / ml, 2300 ng / ml, 2200 ng / ml, 2100 ng / ml, 2000 ng / ml, 1900 ng / ml, 1800 ng / ml, 1700 ng / ml, 1600 ng / ml, 1500 ng / ml, 1400 ng / ml, 1300 ng / ml, 1200 ng / ml, or 1100 ng / ml inhibits binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., GITRL-PE) to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, an antibody or antigen-binding fragment thereof described herein at concentration of 3500 ng / ml to 3200 ng / ml, 3500 ng / ml to 3000ng / ml, 3200 ng / ml to 2500 ng / ml, 3000 to 2200 ng / ml, 2500 ng / ml to 1800 ng / ml, 2000 ng / ml to 1500 ng / ml, 1700 ng / ml to 1200 ng / ml, or 1500 ng / ml to 1000 ng / ml inhibits binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., GITRL-PE) to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system).

[0083] In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 3000ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85% or less than 80% (in some embodiments, 60% to 85%, 60% to 80%, 70% to 85% or 70% to 80%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 1000ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, less than 80% or less than 75% (in some embodiments, 60% to 85%, 60% to 80%, 70% to 85% or 70% to 80%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 333ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 70% or less than 65% (in some embodiments, 50% to 70%, 55% to 70%, 50% to 65% or 50% to 60%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 111ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 65%, less than 60% or less than 55% (in some embodiments, 40% to 65%, 40% to 60%, 40% to 55% or 30% to 60%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 37ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 40% (in some embodiments, 20% to 40%, 20% to 30%, or 15% to 35%)when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 12ng / ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 20% (in some embodiments, 10% to 20%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).

[0084] In certain embodiments, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of GITRL (e.g., human GITRL) binds to GITR (e.g., human GITR) in the presence of an antibody or antigen-binding fragment thereof described herein assessed by an assay known to one of skill in the art or described herein. In a specific embodiment, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of GITRL (e.g., human GITRL) binds to GITR (e.g., human GITR) in the presence of an antibody or antigen-binding fragment thereof described herein as assessed by the assay described in Example 2, infra (e.g., Section 6.2.5.2 or 6.2.5.4, infra). In another specific embodiment, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the presence of 1000 ng / ml, 950 ng / ml, 900 ng / ml, 850 ng / ml, 800 ng / ml, 750 ng / ml, 700 ng / ml, 650 ng / ml, 600 ng / ml, 550 ng / ml, 500 ng / ml, 450 ng / ml, 400 ng / ml, 350 ng / ml, 333 ng / ml, 300 ng / ml, 250 ng / ml or 200 ng / ml of an antibody or antigen-binding fragment thereof described herein relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the presence of 1000 ng / ml to 900 ng / ml, 1000 ng / ml to 850 ng / ml, 900 ng / ml to 800 ng / ml, or 850 ng / ml to 750 ng / ml, or 800 to 750 ng / ml relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, at least 20%, at least 25% or at least 30% of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 1000ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.

[0085] In another specific embodiment, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, 0.1nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the presence of 3500 ng / ml, 3400 ng / ml, 3300 ng / ml, 3200 ng / ml, 3100 ng / ml, 3000 ng / ml, 2900 ng / ml, 2800 ng / ml, 2700 ng / ml, 2600 ng / ml, 2500 ng / ml, 2400 ng / ml, 2300 ng / ml, 2200 ng / ml, 2100 ng / ml, 2000 ng / ml, 1900 ng / ml, 1800 ng / ml, 1700 ng / ml, 1600 ng / ml, 1500 ng / ml, 1400 ng / ml, 1300 ng / ml, 1200 ng / ml, 1100 ng / ml or 1000 ng / ml of an antibody or antigen-binding fragment thereof described herein relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system). In another specific embodiment, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the presence of 3500 ng / ml to 3200 ng / ml, 3500 ng / ml to 3000ng / ml, 3200 ng / ml to 2500 ng / ml, 3000 to 2200 ng / ml, 2500 ng / ml to 1800 ng / ml, 2000 ng / ml to 1500 ng / ml, 1700 ng / ml to 1200 ng / ml, or 1500 ng / ml to 1000 ng / ml of an antibody or antigen-binding fragment thereof described herein relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of labeled GITRL to the GITR coupled beads at a concentration of 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system).

[0086] In another specific embodiment, at least 20%, at least 25% or at least 30% of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 3000ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In another specific embodiment, at least 25%, at least 30%, at least 40%, or at least 50% (in some embodiments, 25% to 60%, 40% to 60%, 40% to 70%, or 25% to 50%) of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 1000ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In another specific embodiment, at least 30%, at least 40%, at least 50% or at least 60% (in some embodiments, 30% to 60%, 40% to 60%, 40% to 70%, or 30% to 50%) of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 333ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In another specific embodiment, at least 40%, at least 50%, at least 60% or at least 65% (in some embodiments, 40% to 70%, 40% to 60%, 40% to 65%, or 40% to 50%) of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 111ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In another specific embodiment, at least 60%, at least 70% or at least 80% (in some embodiments 60% to 80%, 70% to 80% or 75% to 85%) of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 37ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay. In another specific embodiment, at least 80%, at least 85% or at least 90% (in some embodiments 80% to 90% or 85% to 95%) of 0.5nM of labeled GITRL (e.g., labeled human GITRL, such as hGITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg / ml / bead in the presence of 12ng / ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay

[0087] In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 3000ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 15% or more than 20% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 1000ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 15%, more than 20% or more than 25% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 333ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 30% or more than 35% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 111ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 35%, more than 40% or more than 45% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 37ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 60% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system). In a certain embodiment, an antibody or antigen-binding fragment thereof described herein at a concentration of 12ng / ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 80% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg / ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg / ml / bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).

[0088] In another embodiment, a certain amount of labeled GITRL (e.g., human GITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) in the presence of an antibody or antigen-binding fragment thereof described herein in a method comprising: (a) coupling GITR (e.g., human GITR) to beads at a concentration of approximately 9pg / ml, 8pg / ml, 7pg / ml, 6pg / ml, 5pg / ml, 4pg / ml or 3pg / ml per bead; (b) incubating the GITR coupled beads at a concentration of approximately 30 beads / µl, 40 beads / µl, or 50 beads / µl with 3000ng / ml, 2500ng / ml, 2000ng / ml, 1500ng / ml, 1000ng / ml, 750ng / ml, 500ng / ml, 250ng / ml, 100ng / ml, 50ng / ml, 25ng / ml or 10ng / ml of an antibody or an antigen-binding fragment thereof described herein in a well for a first period of time (e.g., 30 minutes, 60 minutes, 1.5 hours, 2 hours, 2.5 hours or 3 hours); (c) adding labeled GITRL (e.g., human GITRL-PE) to the well to obtain a final concentration of approximately 1.5nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or 0.1nM of the labeled GITRL and approximately 15 beads / µl, 20 beads / µl, or 25 beads / µl, and incubating for a second period of time (e.g., 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours); and (d) detecting the labeled GITRL bound to the GITR coupled beads in, e.g., a suspension array assay such as the Luminex® 200 system. In specific embodiments, the amount of the labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined relative to the amount of labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof. In certain embodiments, the absence of the anti-GITR antibody or antigen-binding fragment thereof means that no antibody or antigen-binding fragment thereof is present in the well. In other embodiments, the absence of the anti-GITR antibody or antigen-binding fragment thereof means that an isotype control antibody that does not bind to GITR is present in the well. In accordance with these embodiments, the amount of labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined to be, in some embodiments, at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% or 15% to 60%, 20% to 60%, 30% to 70%, or 20% to 50% of the amount of the labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof.

[0089] In another embodiment, a certain amount of labeled GITRL (e.g., human GITRL-PE) binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) in the presence of an antibody or antigen-binding fragment thereof described herein in a method comprising: (a) coupling GITR (e.g., human GITR) to beads at a concentration of approximately 5pg / ml per bead; (b) incubating the GITR coupled beads at a concentration of approximately 40 beads / µl with 3000ng / ml, 2500ng / ml, 2000ng / ml, 1500ng / ml, 1000ng / ml, 750ng / ml, 500ng / ml, 250ng / ml, 100ng / ml, 50ng / ml or 10ng / ml of an antibody or an antigen-binding fragment thereof described herein in a well for a first period of time (e.g., 30 minutes, 60 minutes, 1.5 hours, 2 hours, 2.5 hours or 3 hours); (c) adding labeled GITRL (e.g., human GITRL-PE) to the well to obtain a final concentration of 0.5nM of the labeled GITRL and approximately 20 beads / µl, and incubating for a second period of time (e.g., 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours); and (d) detecting the labeled GITRL bound to the GITR coupled beads in, e.g., a suspension array assay such as the Luminex® 200 system. In specific embodiments, the amount of the labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined relative to the amount of labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof. In certain embodiments, the absence of the anti-GITR antibody or antigen-binding fragment thereof means that no antibody or antigen-binding fragment thereof is present in the well. In other embodiments, the absence of the anti-GITR antibody or antigen-binding fragment thereof means that an isotype control antibody that does not bind to GITR is present in the well. In accordance with these embodiments, the amount of labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined to be, in some embodiments, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% or 20 to 70%, 20% to 60%, 30% to 70%, or 20% to 50% of the amount of the labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof.

[0090] In certain embodiments, an antibody or antigen-binding fragment thereof described herein at a concentration of 150nM, 145nM, 140nM, 135nM, 130nM, 125nM, 120nM, 115nM, 110nM, 105nM or 100nM bound to GITR (e.g., human GITR) immobilized on a chip (e.g., CM5 sensor chip) inhibits binding of 150nM, 145nM, 140nM, 135nM, 130nM, 125nM, 120nM, 115nM, 110nM, 105nM or 100nM of GITRL (e.g., non-covalently linked trimer of human GITRL) to the GITR immobilized on the chip by less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20% or less than 15%. In certain embodiments, an antibody or antigen-binding fragment thereof described herein at a concentration of 125nM bound to GITR (e.g., human GITR) immobilized on a chip (e.g., CM5 sensor chip) inhibits binding of 125nM of GITRL (e.g., non-covalently linked trimer of human GITRL) to the GITR immobilized on the chip by less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20% or less than 15%.

[0091] In certain embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a dissociation rate constant (k off ) of 8.5 x 10 -3< s -1< or less, 3.5 x 10 -3< s -1< or less, 5 x 10 -3< s -1< or less, 2.5 x 10 -3< s -1< or less, 1 x 10 -3< s -1< or less, 8.5 x 10 -4< s -1< or less, 5 x10 -4< s -1< or less, 3.5 x 10 -4< s -1< or less, 2.5 x 10 -4< s -1< or less, 1 x 10 -4< s -1< or less, 8.5 x 10 -5-< s -1< or less, 3.5 x 10 -5-< s -1< or less, 5 x 10 -5-< s -1< or less, 2.5 x 10 -5-< s -1< or less, 1 x 10 -5-< s -1< or less, 8.5 x 10 -6-< s -1< or less, 5 x10 -6-< s -1< or less, 3.5 x 10 -6-< s -1< or less, 2.5 x 10 -6-< s -1< or less, 1 x 10 -6-< s -1< or less, 8.5 x 10 -7-< s -1< or less, 5 x 10 -7-< s -1< or less, 2.5 x 10 -7-< s -1< or less, 1 x 10 -7-< s -1< or less, 8.5 x 10 -8-< s -1< or less, 5 x 10 -8-< s -1< or less, 2.5 x 10 -8-< s -1< or less, 1 x 10 -8-< s -1< or less, 8.5 x 10 -9-< s -1< or less, 5 x 10 -9< s -1< or less, 2.5 x 10 -9-< s -1< or less, or 1 x 10 -9-< s -1< or less. In some embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a k off of between 9.5 x 10 -5-< s -1< to 1 x 10 -9-< s -1< , 8.5 x 10 -5-< s -1< to 1 x 10 -9-< s -1< , 5 x 10 -5-< s -1< to 1 x 10 -9-< s -1< , 9.5 x 10 -5-< s -1< to 1 x 10 -8-< s -1< , 5 x 10 -5< s -1< to 1 x 10 -8-< s -1< , 9.5 x 10 -5-< s -1< to 1 x 10 -7-< s -1< , 5 x 10 -5-< s -1< to 1 x 10 -7-< s -1< , 9.5 x 10 -5-< s -1< to 5 x 10 -6-< s -1< , 9.5 x 10 -5-< s -1< to 1 x 10 -5-< s -1< , 8.5 x 10 -3< s -1< to 1 x 10 -4< s -1< , 5 x 10 -3< s -1< to 2.5 x 10 -4< s -1< , 8.5 x 10 -3< s -1< , to 1 x 10 -5< s -1< , 8.5 x 10 -5-< s -1< to 5 x 10 -5-< s -1< . In certain embodiments, the k off is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon resonance technology. In other embodiments, the k off is determined using a bivalent antibody as measured by, e.g., BIAcore® surface plasmon resonance technology. In a particular embodiment, the k off is determined using an assay described in Section 6, infra.

[0092] In certain embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with an association rate constant (k on ) of at least 10 5< M -1< s -1< , at least 2.5 x 10 5< M -1< S -1< , at least 3.5 x 10 5< M -1< s -1< , at least 5 x 10 5< M -1< S -1< , at least 10 6< M -1< s -1< , at least 2.5 x 10 6< M -1< s -1< , at least 3.5 x 10 6< M -1< s -1< , at least 5 x 10 6< M -1< s -1< , at least 10 7< M -1< s -1< , at least 5 x 10 7< M -1< s -1< , at least 10 8< M -1< s -1< , at least 5 10 8< M -1< s -1< or at least 10 9< M -1< s -1< . In some embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a k on of between 1 x 10 5< m -1< s -1< to 5 x 10 5< M -1< s -1< , 1 x 10 5< m -1< s -1< to 1 x 10 6< M -1< s -1< , 3.5 x 10 5< m -1< s -1< to 2.5 x 10 6< M -1< s -1< , 3.5 x 10 5< m -1< s -1< to 3.5 x 10 6< M -1< s -1< , 1 x 10 5< m -1< s -1< to 5 x 10 6< M -1< s -1< , 1 x 10 5< M -1< s -< to 1 x 10 7< M -1< s -1< , 1 x 10 5< M -1< s -1< to 5 x 10 7< M -1< S -1< , 1 x 10 5< M -1< s -1< to 10 8< M -1< s -1< , 1 x 10 5< M -1< s -1< to 1 x 10 9< m -1< s -1< , 1 x 10 6< M -1< s -< to 1 x 10 7< M -1< s -1< , 1 x 10 6< m -1< s -1< to 1 x 10 8< M -1< s -1< , 1 x 10 6< m -1< s -1< to 1 x 10 9< M -1< s -1< , 1 x 10 7< m -1< s -1< to 1 x 10 8< M -1< s -1< , 1 x 10 7< m -1< s -1< to 1 x 10 9< M -1< s -1< , 1 x 10 8< m -1< s -1< to 1 x 10 9< M -1< s -1< , In certain embodiments, the k on is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore ®< surface plasmon resonance technology. In other embodiments, the k on is determined using a bivalent antibody as measured by, e.g., BIAcore ®< surface plasmon resonance technology. In a particular embodiment, the k on is determined using an assay described in Section 6, infra.

[0093] In certain embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of less than 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.1 nM. In some embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of about 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.1 nM. In certain embodiments, an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of 7 nM to 2 nM, 5 nM to 3 nM, 5 nM to 1 nM, 4 nM to 3 nM, 4 nM to 2 nM, 3 nM to 2 nM, 3 nM to 1 nM, 2 nM to 1 nM, 3 nM to 0.1 nM, 2 nM to 0.1 nM, 1 nM to 0.1 nM, or 0.5 nM to 0.1 nM. In certain embodiments, the K D is calculated as the quotient of k off / k on , and the k on and k off are determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore ®< surface plasmon resonance technology. In other embodiments, the K D is calculated as the quotient of k off / k on , and the k on and k off are determined using a bivalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon resonance technology. In a specific embodiment, the K D is determined as set forth in the Examples in Section 6, infra (e.g., Example 2).

[0094] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) comprising: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, F or M X 2 is L, A, V, I, P, F, M or S X 3 is N, G, Q, S, T, C, W, Y or A X 4 is S, G, N, Q, T, C, W, Y or A X 5 is G, N, Q, S, T, C, W, Y or A X 6 is N, G, Q, S, T, C, W, Y or A X 7 is Q, G, N, S, T, C, W, Y or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is T, G, N, Q, S, C, W, Y, V, I or A; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A X 2 is E, D or A X 3 is S, G, N, Q, T, C, W, Y or A; and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y X 2 is D, E or Y X 3 is S, G, N, Q, T, C, W, Y or A X 4 is Y, G, N, Q, S, T, C, W, F, H, L, or A. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, or all three of the VL CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row of Table 1, for example, all of the VL CDRs are from antibody 231-32-15). In some aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions (FRs) of an antibody set forth in Table 3 (e.g., one, two, three, or four of the framework regions in one row of Table 3).

[0095] In another aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region (VH) comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A X 2 is A, V, L, I, P, F, M or Y X 3 is Y, G, N, Q, S, T, C, W, F or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T X 2 is R, K, H, Q or A X 3 is T, G, N, Q, S, C, W, Y, V, I or P X 4 is Y, G, N, Q, S, T, C, W, F, H, or A X 5 is D, E, G or A X 6 is V, A, L, I, P, F, M or T X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is K, R, H, Q or A X 10 is D, E, G or A; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S X 2 is A, or D X 3 is Y, G, N, Q, S, T, C, W, F, H or V. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row of Table 2, for example, all of the VH CDRs are from the antibody 231-32-15). In some aspects, the antibody or antigen-binding fragment thereof comprises the VH frameworks described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VH framework regions of an antibody set forth in Table 4 (e.g., one, two, three or four of the framework regions in one row of Table 4). Table 1. VL CDR Amino Acid Sequences Antibody VL CDR1 (SEQ ID NO:) VL CDR2 (SEQ ID NO:) VL CDR3 (SEQ ID NO:) 231-32-15KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)Hum231#1KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)Hum231#2KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)pab1964KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)pab1965KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1966KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1967KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)pab1968KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1969KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)pab1970KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)pab1971KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1972KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)pab1973KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1975KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1976KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1977KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1979KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1980KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1981KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1983KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab2159KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)pab2160KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab2161KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)1KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)2KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)3KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)4KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)5KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)6KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)7KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNEYSFPYT (108)8KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSYPYT (106)9KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)10KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)11KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSFPYT (109)12KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)13KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)14KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)15KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)16KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)17KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)18KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)19KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSFPYT (109)20KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)21KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)22KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDHSFPYT (191)23KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSSPYT (192)24KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)25KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)26KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)27KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSFPYT (109)28KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)29KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)30KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)31KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)32KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)33KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)34KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)35KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)36KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)37KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSYPYT (106)38KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)39KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)40KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)41KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)42KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)43KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)44KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)45KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)46KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)47KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)48KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)49KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)50KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)51KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSSPYT (192)52KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)53KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)54KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)55KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)56KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)57KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)58KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)59KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)60KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSYPYT (106)61KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)62KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)63KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)64KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNEYSYPYT (106)65KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNEYSFPYT (108)66KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSFPYT (109)67KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)68KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)69KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)70KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)71KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)72KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)73KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)74KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)75KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)76KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)77KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)78KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)79KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)80KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)81KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)82KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)83KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)84KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)85KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)86KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)87KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)88KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)89KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)90KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSSPYT (193)91KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)92KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)93KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)94KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)95KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)96KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)97KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)98KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)99KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)100KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSSPYT (192)101KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)102KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)103KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSSPYT (192)104KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)105KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)106KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)107KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107) The VL CDRs in Table 1 are determined according to Kabat. Table 2. VH CDR Amino Acid Sequences 2< Antibody VH CDR1 (SEQ ID NO:) VH CDR2 (SEQ ID NO:) VH CDR3 (SEQ ID NO:) 231-32-15DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)Hum231#1DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)Hum231#2DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)pab1964GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab1965GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)pab1966GYAMY (19)VIKTYSGGVTYNQKFRG (26)SGTVRGFAY (34)pab1967GYAMH (20)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)pab1968DYAMY (21)VIRTFSGDLTYNQKFQD (28)SGTVRGFAY (34)pab1969EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1970DYAMY (21)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab1971DYAMY (21)VIRTYSGDVSYNQKFRG (177)SGTVRGFAY (34)pab1972EYAMY (23)LIRTYSGGVSYNQKFRD (31)SGTVRGFAY (34)pab1973GYAMY (19)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)pab1975EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1976EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1977EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1979EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1980EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1981EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1983GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab2159GYAMY (19)LIRTYSGEVSYNQKFRG (144)SGTVRGFAY (34)pab2160GYVMH (119)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)pab2161EYAMH (22)LIQTYSGDVSYNQKFRG (121)SGTVRGFAY (34)1EYAMY (23)VIRTYSGGVTYNQKFQG (187)SGTVRGFAY (34)2EYAMH (22)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)3GYVMH (119)VIRTYSGEVSYNQKFQE (181)SGTVRGFAY (34)4EYAMY (23)LIRTFSGDVSYNQKFQD (124)SGTVRGFAY (34)5EYAMH (22)LIRTYSGGVTYNQKFRG (151)SGTVRGFAY (34)6EYAMY (23)LIRTFSGGVSYNQKFKG (135)SGTVRGFAY (34)7GYAMH (20)LIRTFSGGLSYNQKFRE (132)SGTVRGFAY (34)8GYVMY (116)VIKTFSGGVSYNQKFQE (152)SGTVRGFAY (34)9GYAMY (19)LIRTYSGEVSYNQKFRG (144)SGTVRGFAY (34)10EYAMY (23)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)11DYAMH (117)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)12GYAMY (19)VIRTFSGEVSYNQKFKG (164)SGTVRGFAY (34)13GYAMY (19)LIRTFSGDVTYNQKFRG (127)SGTVRGFAY (34)14GYVMH (119)LIRTYSGDVSYNQKFRD (146)SGTVRGFAY (34)15DYAMY (21)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)16GYAMY (19)LIRTFSGGVTYNQKFRE (140)SGTVRGFAY (34)17EYAMY (23)VIQTFSGGVTYNQKFRG (157)SGTVRGFAY (34)18GYAMY (19)LIRTFSGEVTYNQKFRG (130)SGTVRGFAY (34)19GYAMY (19)LIRTYSGGLSYNQKFQD (145)SGTVRGFAY (34)20DYAMY (21)VIRTFSGDLSYNQKFRG (114)SGTVRGFAY (34)21GYVMH (119)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)22GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)23GYAMY (19)LIRTFSGDVTYNQKFRG (127)SGTVRGFAY (34)24DYAMH (117)LIRTYSGGVTYNQKFRG (151)SGTVRGFAY (34)25EYAMY (23)LIRTFSGGVSYNQKFRG (138)SGTVRGFAY (34)26EYAMH (22)LIRTFSGDVSYNQKFKG (123)SGTVRGFAY (34)27DYAMY (21)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)28DYAMY (21)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)29DYAMY (21)VIRTFSGGVTYNQKFKG (172)SGTVRGFAY (34)30DYVMY (35)VIRTFSGGLSYNQKFRG (165)SGTVRGFAY (34)31EYAMY (23)LIRTFSGGLTYNQKFKD (133)SGTVRGFAY (34)32DYAMY (21)VIRTFSGGVTYNQKFKD (171)SGTVRGFAY (34)33GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)34DYAMY (21)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)35GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)36DYAMY (21)VIRTFSGGVSYNQKFRD (168)SGTVRGFAY (34)37EYAMY (23)LIRTFSGEVTYNQKFKD (129)SGTVRGFAY (34)38GYAMY (19)VIKTYSGGVTYNQKFRG (26)SGTVRGFAY (34)39GYAMH (20)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)40EYAMY (23)VIRTYSGDLSYNQKFRG (174)SGTVRGFAY (34)41DYVMY (35)VIRTFSGGVSYNQKFRG (170)SGTVRGFAY (34)42DYAMY (21)VIRTFSGDLTYNQKFQD (28)SGTVRGFAY (34)43EYAMY (23)LIRTFSGDVSYNQKFKG (123)SGTVRGFAY (34)44EYAMH (22)LIRTYSGDVSYNQKFQG (142)SGTVRGFAY (34)45EYAMY (23)LIRTYSGGVSYNQKFQG (147)SGTVRGFAY (34)46EYAMY (23)LIRTFSGDLSYNQKFRG (122)SGTVRGFAY (34)47DYAMY (21)VIRTYSGGVTYNQKFRD (188)SGTVRGFAD (189)48DYAMY (21)LIRTYSGGVTYNQKFKE (149)SGTVRGFAY (34)49GYAMY (19)VIRTYSGDVTYNQKFRE (179)SGTVRGFAY (34)50DYAMY (21)LIRTFSGGVSYNQKFKE (134)SGTVRGFAY (34)51EYAMY (23)VIRTFSGGVTYNQKFKG (172)SGTVRGFAY (34)52DYAMY (21)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)53EYAMH (22)VIRTYSGGLSYNQKFRG (182)SGTVRGFAY (34)54EYAMH (22)LIRTYSGGVSYNQKFQG (147)SGTVRGFAY (34)55DYAMY (21)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)56DYAMY (21)VIRTYSGDVSYNQKFRG (177)SGTVRGFAY (34)57GYAMY (19)LIRTYSGDVTYNQKFKD (143)SGTVRGFAY (34)58DYAMY (21)VIRTYSGGVTYNQKFKG (186)SGTVRGFAY (34)59EYAMY (23)LIRTYSGGVSYNQKFRD (31)SGTVRGFAY (34)60DYAMY (21)VIKTYSGGVSYNQKFRG (153)SGTVRGFAY (34)61EYAMH (22)LIRTYSGGVSYNQKFQE (115)SGTVRGFAY (34)62GYVMY (116)VIRTFSGGVSYNQKFQG (167)SGTVRGFAY (34)63EYAMY (23)VIRTFSGDVTYNQKFKG (163)SGTVRGFAY (34)64DYAMY (21)VIRTYSGDVTYNQKFRG (180)SGTVRGFAY (34)65EYAMY (23)VIKTYSGGVTYNQKFRG (26)SGTVRGFAY (34)66DYVMY (35)VIRTYSGEVSYNQKFRG (183)SGTVRGFAY (34)67EYAMY (23)VIQTFSGDVSYNQKFKG (156)SGTVRGFAY (34)68GYAMY (19)LIRTYSGGVTYNQKFRG (151)SGTVRGFAY (34)69EYVMH (118)VIRTFSGGVSYNQKFRE (169)SGTVRGFAY (34)70GYAMY (19)VIRTYSGDVTYNQKFKD (178)SGTVRGFAY (34)71GYAMY (19)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)72GYAMY (19)VIRTYSGDVSYNQKFQE (175)SGTVRGFAY (34)73GYVMH (119)IIKTYSGGVSYNQKFQG (120)SGTVRGFAY (34)74DYAMY (21)VIKTYSGGVTYNQKFKD (154)SGTVRGFAY (34)75GYAMY (19)VIRTYSGGVTYNQKFQG (187)SGTVRGFAY (34)76DYAMH (117)LIRTFSGDVSYNQKFRE (125)SGTVRGFAY (34)77EYAMH (22)LIQTYSGDVSYNQKFRG (121)SGTVRGFAY (34)78DYAMY (21)VIKTYSGGVTYNQKFRD (155)SGTVRGFAY (34)79EYAMH (22)LIRTYSGGVTYNQKFRE (150)SGTVRGFAY (34)80EYAMH (22)LIRTFSGDVSYNQKFRG (126)SGTVRGFAY (34)81DYAMY (21)LIRTFSGEVSYNQKFQD (128)SGTVRGFAY (34)82GYVMH (119)VIRTFSGGVSYNQKFRG (170)SGTVRGFAY (34)83GYAMY (19)VIRTFSGDVSYNQKFRD (161)SGTVRGFAY (34)84GYAMY (19)LIRTFSGDVTYNQKFRG (127)SGTVRGFAY (34)85EYAMY (23)VIRTYSGGVTYNQKFKD (185)SGTVRGFAY (34)86EYAMY (23)VIRTYSGGVTYNQKFRD (188)SGTVRGFAY (34)87GYAMY (19)VIRTFSGDLSYNQKFKG (159)SGTVRGFAY (34)88EYAMH (22)VIRTYSGDVSYNQKFRG (177)SGTVRGFAY (34)89GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)90EYAMY (23)LIRTYSGDLSYNQKFKE (141)SGTVRGFAY (34)91EYAMH (22)LIRTYSGGVSYNQKFQE (115)SGTVRGFAY (34)92EYAMY (23)LIRTFSGGVTYNQKFQG (139)SGTVRGFAY (34)93DYAMH (117)VIQTYSGDVSYNQKFQG (158)SGTVRGFAY (34)94GYAMY (19)VIRTFSGGVTYNQKFRD (173)SGTVRGFAY (34)95DYAMY (21)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)96EYAMY (23)VIRTYSGGLTYNQKFRD (184)SGTVRGFAY (34)97EYAMH (22)LIRTFSGGLSYNQKFRD (131)SGTVRGFAY (34)98GYAMH (20)VIRTFSGGVSYNQKFQE (166)SGTVRGFAY (34)99DYAMH (117)LIRTFSGDLSYNQKFRG (122)SGTVRGFAY (34)100EYAMH (22)VIRTFSGGVSYNQKFQG (167)SGTVRGFAY (34)101DYAMH (117)LIRTFSGGVSYNQKFQD (136)SGTVRGFAY (34)102GYAMY (19)VIRTYSGGVSYNQKFRD (194)SGTVRGFAY (34)103GYAMY (19)VIRTYSGDVSYNQKFRG (177)SGTVRGFAY (34)104DYAMY (21)LIRTFSGGVSYNQKFRD (137)SGTVRGFAY (34)105EYAMY (23)LIRTFSGGVSYNQKFKG (135)SGTVRGFAY (34)106DYAMY (21)VIRTFSGDVSYNQKFQE (160)SGTVRGFAY (34)107GYAMY (19)VIRTYSGDVSYNQKFRD (176)SGTVRGFAY (34) The VH CDRs in Table 2 are determined according to Kabat. Table 3. VL FR Amino Acid Sequences 3< Antibody VL FR1 (SEQ ID NO:) VL FR2 (SEQ ID NO:) VL FR3 (SEQ ID NO:) VL FR4 (SEQ ID NO:) 231-32-15FGGGTKLEIK (641)Hum231 #1FGQGTKLEIK (643)Hum231 #2FGQGTKLEIK (643)pab1964FGQGTKLEIK (643)pab1965FGQGTKLEIK (643)pab1966FGQGTKLEIK (643)pab1967FGQGTKLEIK (643)pab1968FGQGTKLEIK (643)pab1969FGQGTKLEIK (643)pab1970FGQGTKLEIK (643)pab1971FGQGTKLEIK (643)pab1972FGQGTKLEIK (643)pab1973FGQGTKLEIK (643)pab1975FGQGTKLEIK (643)pab1976FGQGTKLEIK (643)pab1977FGQGTKLEIK (643)pab1979FGQGTKLEIK (643)pab1980FGQGTKLEIK (643)pab1981FGQGTKLEIK (643)pab1983FGQGTKLEIK (643)pab2159FGQGTKLEIK (643)pab2160FGQGTKLEIK (643)pab2161FGQGTKLEIK (643)1FGQGTKLEIK (643)2FGQGTKLEIK (643)3FGQGTKLEIK (643)4FGQGTKLEIK (643)5FGQGTKLEIK (643)6FGQGTKLEIK (643)7FGQGTKLEIK (643)8FGQGTKLEIK (643)9FGQGTKLEIK (643)10FGQGTKLEIK (643)11FGQGTKLEIK (643)12FGQGTKLEIK (643)13FGQGTKLEIK (643)14FGQGTKLEIK (643)15FGQGTKLEIK (643)16FGQGTKLEIK (643)17FGQGTKLEIK (643)18FGQGTKLEIK (643)19FGQGTKLEIK (643)20FGQGTKLEIK (643)21FGQGTKLEIK (643)22FGQGTKLEIK (643)23FGQGTKLEIK (643)24FGQGTKLEIK (643)25FGQGTKLEIK (643)26FGQGTKLEIK (643)27FGQGTKLEIK (643)28FGQGTKLEIK (643)29FGQGTKLEIK (643)30FGQGTKLEIK (643)31FGQGTKLEIK (643)32FGQGTKLEIK (643)33FGQGTKLEIK (643)34FGQGTKLEIK (643)35FGQGTKLEIK (643)36FGQGTKLEIK (643)37FGQGTKLEIK (643)38FGQGTKLEIK (643)39FGQGTKLEIK (643)40FGQGTKLEIK (643)41FGQGTKLEIK (643)42FGQGTKLEIK (643)43FGQGTKLEIK (643)44FGQGTKLEIK (643)45FGQGTKLEIK (643)46FGQGTKLEIK (643)47FGQGTKLEIK (643)48FGQGTKLEIK (643)49FGQGTKLEIK (643)50FGQGTKLEIK (643)51FGQGTKLEIK (643)52FGQGTKLEIK (643)53FGQGTKLEIK (643)54FGQGTKLEIK (643)55FGQGTKLEIK (643)56FGQGTKLEIK (643)57FGQGTKLEIK (643)58FGQGTKLEIK (643)59FGQGTKLEIK (643)60FGQGTKLEIK (643)61FGQGTKLEIK (643)62FGQGTKLEIK (643)63FGQGTKLEIK (643)64FGQGTKLEIK (643)65FGQGTKLEIK (643)66FGQGTKLEIK (643)67FGQGTKLEIK (643)68FGQGTKLEIK (643)69FGQGTKLEIK (643)70FGQGTKLEIK (643)71FGQGTKLEIK (643)72FGQGTKLEIK (643)73FGQGTKLEIK (643)74FGQGTKLEIK (643)75FGQGTKLEIK (643)76FGQGTKLEIK (643)77FGQGTKLEIK (643)78FGQGTKLEIK (643)79FGQGTKLEIK (643)80FGQGTKLEIK (643)81FGQGTKLEIK (643)82FGQGTKLEIK (643)83FGQGTKLEIK (643)84FGQGTKLEIK (643)85FGQGTKLEIK (643)86FGQGTKLEIK (643)87FGQGTKLEIK (643)88FGQGTKLEIK (643)89FGQGTKLEIK (643)90FGQGTKLEIK (643)91FGQGTKLEIK (643)92FGQGTKLEIK (643)93FGQGTKLEIK (643)94FGQGTKLEIK (643)95FGQGTKLEIK (643)96FGQGTKLEIK (643)97FGQGTKLEIK (643)98FGQGTKLEIK (643)99FGQGTKLEIK (643)100FGQGTKLEIK (643)101FGQGTKLEIK (643)102FGQGTKLEIK (643)103FGQGTKLEIK (643)104FGQGTKLEIK (643)105FGQGTKLEIK (643)106FGQGTKLEIK (643)107FGQGTKLEIK (643) The VL framework regions described in Table 3 are determined based upon the boundaries of the Kabat numbering system for CDRs. In other words, the VL CDRs are determined by Kabat and the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Table 4. VH FR Amino Acid Sequences 4< Antibody VHFR1 (SEQ ID NO:) VH FR2 (SEQ ID NO:) VH FR3 (SEQ ID NO:) VH FR4 (SEQ ID NO:) 231-32-15WGQGTL VTVSS (668)Hum231#1WGQGTL VTVSS (668)Hum231#2WGQGTL VTVSS (668)pab1964WGQGTL VTVSS (668)pab1965WGQGTL VTVSS (668)pab1966WGQGTL VTVSS (668)pab1967WGQGTLITVSS (667)pab1968WGQGTL VTVSS (668)pab1969WGQGTL VTVSS (668)pab1970WGQGTL VTVSS (668)pab1971WGQGTL VTVSS (668)pab1972WGQGTL VTVSS (668)pab1973WGQGTL VTVSS (668)pab1975WGQGTL VTVSS (668)pab1976WGQGTL VTVSS (668)pab1977WGQGTL VTVSS (668)pab1979WGQGTL VTVSS (668)pab1980WGQGTL VTVSS (668)pab1981WGQGTL VTVSS (668)pab1983WGQGTL VTVSS (668)pab2159WGQGTL VTVSS (668)pab2160WGQGTL VTVSS (668)pab2161WGQGTL VTVSS (668)1WGQGTL VTVSS (668)2WGQGTL VTVSS (668)3WGQGTL VTVSS (668)4WGQGTL VTVSS (668)5WGQGTL VTVSS(668)6WGQGTL VTVSS (668)7WGQGTL VTVSS (668)8WGQGTL VTVSS (668)9WGQGTL VTVSS (668)10WGQGTL VTVSS (668)11WGQGTL VTVSS (668)12WGQGTL VTVSS (668)13WGQGTL VTVSS (668)14WGQGTL VTVSS (668)15WGQGTL VTVSS (668)16WGQGTL VTVSS (668)17WGQGTL VTVSS (668)18WGQGTL VTVSS (668)19WGQGTL VTVSS (668)20WGQGTL VTVSS (668)21WGQGTL VTVSS (668)22WGQGTL VTVSS (668)23WGQGTL VTVSS (668)24WGQGTL VTVSS (668)25WGQGTL VTVSS (668)26WGQGTL VTVSS (668)27WGQGTL VTVSS (668)28WGQGTL VTVSS (668)29WGQGTL VTVSS (668)30WGQGTL VTVSS (668)31WGQGIPVTVSS (664)32WGQGTL VTVSS (668)33WGQGTL VTVSS (668)34WGQGTL VTVSS (668)35WGQGTL VTVSS (668)36WGQGTL VTVSS (668)37WGQGTL VTVSS (668)38WGQGTL VTVSS (668)39WGQGTLITVSS (667)40WGQGTL VTVSS (668)41WGQGTL VTVSS (668)42WGQGTL VTVSS (668)43WGQGTL VTVSS (668)44WGQGTL VTVSS (668)45WGQGTFVTVSS (665)46WGQGTL VTVSS(668)47WGQGTL VTVSS (668)48WGQGTL VTVSS (668)49WGQGTL VTVSS (668)50WGQGTL VTVSS (668)51WGQGTL VTVSS (668)52WGQGTL VTVSS (668)53WGQGTL VTVSS (668)54WGQGTL VTVSS (668)55WGQGTL VTVSS (668)56WGQGTL VTVSS (668)57WGQGTL VTVSS (668)58WGQGTL VTVSS (668)59WGQGTL VTVSS (668)60WGQGTL VTVSS (668)61WGQGTL VTVSS (668)62WGQGTL VTVSS (668)63WGQGTL VTVSS (668)64WGQGTL VTVSS (668)65WGQGTL VTVSS (668)66WGQGTL VTVSS (668)67WGQGTL VTVSS (668)68WGQGTL VTVSS (668)69WGQGTL VTVSS (668)70WGQGTL VTVSS (668)71WGQGTL VTVSS (668)72WGQGTL VTVSS (668)73WGQGTL VTVSS (668)74WGQGTL VTVSS (668)75WGQGTL VTVSS (668)76WGQGTL VTVSS (668)77WGQGTL VTVSS (668)78WGRGTLVTVSS (669)79WGQGTL VTVSS (668)80WGQGTL VTVSS (668)81WGQGTL VTVSS (668)82WGQGTL VTVSS (668)83WGQGTL VTVSS (668)84WGQGTL VTVSS (668)85WGQGTL VTVSS (668)86WGQGTL VTVSS (668)87WGQGTL VTVSS(668)88WGQGTL VTVSS (668)89WGQGTL VTVSS (668)90WGQGTL VTVSS (668)91WGQGTL VTVSS (668)92WGQGTL VTVSS (668)93WGQGTL VTVSS (668)94WGQGTFVTVSS (666)95WGQGTFVTVSS (666)96WGQGTL VTVSS (668)97WGQGTL VTVSS (668)98WGQGTL VTVSS (668)99WGQGTL VTVSS (668)100WGQGTL VTVSS (668)101WGQGTL VTVSS (668)102WGQGTL VTVSS (668)103WGQGTL VTVSS (668)104WGQGTL VTVSS (668)105WGQGTL VTVSS (668)106WGQGTL VTVSS (668)107WGQGTL VTVSS (668) 4< The VH framework regions described in Table 4 are determined based upon the boundaries of the Kabat numbering system for CDRs. In other words, the VH CDRs are determined by Kabat and the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0096] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) comprising: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, F or M X 2 is L, A, V, I, P, F, M or S X 3 is N, G, Q, S, T, C, W, Y or A X 4 is S, G, N, Q, T, C, W, Y or A X 5 is G, N, Q, S, T, C, W, Y or A X 6 is N, G, Q, S, T, C, W, Y or A X 7 is Q, G, N, S, T, C, W, Y or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is T, G, N, Q, S, C, W, Y, V, I or A; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A X 2 is E, D or A X 3 is S, G, N, Q, T, C, W, Y or A; and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y X 2 is D, E or Y X 3 is S, G, N, Q, T, C, W, Y or A X 4 is Y, G, N, Q, S, T, C, W, F, H, L, or A. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, or all three of the VL CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 5. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 5. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 5. In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 5 (e.g., the VL CDRs in one row of Table 5, for example, all of the VL CDRs are from antibody 231-32-15). In some aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions (FRs) of an antibody set forth in Table 7 (e.g., one, two, three, or four of the framework regions in one row of Table 7).

[0097] In another aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region (VH) comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A X 2 is A, V, L, I, P, F, M or Y X 3 is Y, G, N, Q, S, T, C, W, F or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T X 2 is R, K, H, Q or A X 3 is T, G, N, Q, S, C, W, Y, V, I or P X 4 is Y, G, N, Q, S, T, C, W, F, H, or A X 5 is D, E, G or A X 6 is V, A, L, I, P, F, M or T X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is K, R, H, Q or A X 10 is D, E, G or A; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S X 2 is A, or D X 3 is Y, G, N, Q, S, T, C, W, F, H or V. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 6. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 6. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 6. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of VH CDRs of one of the antibodies in Table 6 (e.g., the VH CDRs in one row of Table 6, for example, all of the VH CDRs are from the antibody 231-32-15). In some aspects, the antibody or antigen-binding fragment thereof comprises the VH frameworks described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VH framework regions of an antibody set forth in Table 8 (e.g., one, two, three or four of the framework regions in one row of Table 8). Table 5. VL CDR Amino Acid Sequences Antibody VL CDR1 (SEQ ID NO:) VL CDR2 (SEQ ID NO:) VL CDR3 (SEQ ID NO:) 231-32-15KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)Hum231#1KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)Hum231#2KSSQSLLNSGNQKNYLT (16)WASTRES (17)QNDYSYPYT (18)pab1964KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)pab1965KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1966KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1967KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)pab1968KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1969KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)pab1970KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)pab1971KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1972KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)pab1973KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1975KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1976KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1977KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1979KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab1980KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)pab1981KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)pab1983KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab2159KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)pab2160KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)pab2161KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)1KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)2KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)4KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)5KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)6KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)9KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)10KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)11KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSFPYT (109)15KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)16KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)18KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)20KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)21KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)25KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)29KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)31KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)33KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSYPYT (106)34KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)35KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)36KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)37KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSYPYT (106)38KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)39KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNEYSFPYT (108)42KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)43KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)45KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)46KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)47KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)49KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)50KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)52KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)54KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)55KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)58KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)59KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)61KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)68KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)70KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)71KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSYPYT (107)75KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)76KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSFPYT (109)78KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)79KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)80KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)85KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)86KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)91KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNEYSFPYT (108)92KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)94KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSYPYT (107)95KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNDYSFPYT (109)96KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)97KSSQSLLNSGNQKNYLT (102)WASTRES (105)QNEYSFPYT (108)101KSSQSLLNSSNQKNYLT (103)WASTRES (105)QNDYSFPYT (109)102KSSQSLLNSSNQKNYLS (104)WASTRES (105)QNDYSYPYT (107)105KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107)107KSSQSLLNSGNQKNYLS (101)WASTRES (105)QNDYSYPYT (107) 1< The VL CDRs in Table 5 are determined according to Kabat. Table 6. VH CDR Amino Acid Sequences 2< Antibody VH CDR1 (SEQ ID NO:) VH CDR2 (SEQ ID NO:) VH CDR3 (SEQ ID NO:) 231-32-15DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)Hum231#1DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)Hum231#2DYAMY (13)VIRTYSGDVTYNQKFKD (14)SGTVRGFAY (15)pab1964GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab1965GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)pab1966GYAMY (19)VIKTYSGGVTYNQKFRG (26)SGTVRGFAY (34)pab1967GYAMH (20)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)pab1968DYAMY (21)VIRTFSGDLTYNQKFQD (28)SGTVRGFAY (34)pab1969EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1970DYAMY (21)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab1971DYAMY (21)VIRTYSGDVSYNQKFRG (177)SGTVRGFAY (34)pab1972EYAMY (23)LIRTYSGGVSYNQKFRD (31)SGTVRGFAY (34)pab1973GYAMY (19)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)pab1975EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1976EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1977EYAMH (22)LIRTYSGGVSYNQKFQG (29)SGTVRGFAY (34)pab1979EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1980EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1981EYAMH (22)VIRTYSGGVSYNQKFQE (33)SGTVRGFAY (34)pab1983GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)pab2159GYAMY (19)LIRTYSGEVSYNQKFRG (144)SGTVRGFAY (34)pab2160GYVMH (119)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)pab2161EYAMH (22)LIQTYSGDVSYNQKFRG (121)SGTVRGFAY (34)1EYAMY (23)VIRTYSGGVTYNQKFQG (187)SGTVRGFAY (34)2EYAMH (22)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)4EYAMY (23)LIRTFSGDVSYNQKFQD (124)SGTVRGFAY (34)5EYAMH (22)LIRTYSGGVTYNQKFRG (151)SGTVRGFAY (34)6EYAMY (23)LIRTFSGGVSYNQKFKG (135)SGTVRGFAY (34)9GYAMY (19)LIRTYSGEVSYNQKFRG (144)SGTVRGFAY (34)10EYAMY (23)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)11DYAMH (117)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)15DYAMY (21)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)16GYAMY (19)LIRTFSGGVTYNQKFRE (140)SGTVRGFAY (34)18GYAMY (19)LIRTFSGEVTYNQKFRG (130)SGTVRGFAY (34)20DYAMY (21)VIRTFSGDLSYNQKFRG (114)SGTVRGFAY (34)21GYVMH (119)VIRTFSGDVSYNQKFRE (162)SGTVRGFAY (34)25EYAMY (23)LIRTFSGGVSYNQKFRG (138)SGTVRGFAY (34)29DYAMY (21)VIRTFSGGVTYNQKFKG (172)SGTVRGFAY (34)31EYAMY (23)LIRTFSGGLTYNQKFKD (133)SGTVRGFAY (34)33GYAMY (19)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)34DYAMY (21)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)35GYAMY (19)VIRTFSGDVTYNQKFRG (25)SGTVRGFAY (34)36DYAMY (21)VIRTFSGGVSYNQKFRD (168)SGTVRGFAY (34)37EYAMY (23)LIRTFSGEVTYNQKFKD (129)SGTVRGFAY (34)38GYAMY (19)VIKTYSGGVTYNQKFRG (26)SGTVRGFAY (34)39GYAMH (20)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)42DYAMY (21)VIRTFSGDLTYNQKFQD (28)SGTVRGFAY (34)43EYAMY (23)LIRTFSGDVSYNQKFKG (123)SGTVRGFAY (34)45EYAMY (23)LIRTYSGGVSYNQKFQG (147)SGTVRGFAY (34)46EYAMY (23)LIRTFSGDLSYNQKFRG (122)SGTVRGFAY (34)47DYAMY (21)VIRTYSGGVTYNQKFRD (188)SGTVRGFAD (189)49GYAMY (19)VIRTYSGDVTYNQKFRE (179)SGTVRGFAY (34)50DYAMY (21)LIRTFSGGVSYNQKFKE (134)SGTVRGFAY (34)52DYAMY (21)LIRTYSGGVSYNQKFRE (27)SGTVRGFAY (34)54EYAMH (22)LIRTYSGGVSYNQKFQG (147)SGTVRGFAY (34)55DYAMY (21)LIRTYSGGVTYNQKFQG (24)SGTVRGFAY (34)58DYAMY (21)VIRTYSGGVTYNQKFKG (186)SGTVRGFAY (34)59EYAMY (23)LIRTYSGGVSYNQKFRD (31)SGTVRGFAY (34)61EYAMH (22)LIRTYSGGVSYNQKFQE (115)SGTVRGFAY (34)68GYAMY (19)LIRTYSGGVTYNQKFRG (151)SGTVRGFAY (34)70GYAMY (19)VIRTYSGDVTYNQKFKD (178)SGTVRGFAY (34)71GYAMY (19)VIRTFSGGVTYNQKFRG (32)SGTVRGFAY (34)75GYAMY (19)VIRTYSGGVTYNQKFQG (187)SGTVRGFAY (34)76DYAMH (117)LIRTFSGDVSYNQKFRE (125)SGTVRGFAY (34)78DYAMY (21)VIKTYSGGVTYNQKFRD (155)SGTVRGFAY (34)79EYAMH (22)LIRTYSGGVTYNQKFRE (150)SGTVRGFAY (34)80EYAMH (22)LIRTFSGDVSYNQKFRG (126)SGTVRGFAY (34)85EYAMY (23)VIRTYSGGVTYNQKFKD (185)SGTVRGFAY (34)86EYAMY (23)VIRTYSGGVTYNQKFRD (188)SGTVRGFAY (34)91EYAMH (22)LIRTYSGGVSYNQKFQE (115)SGTVRGFAY (34)92EYAMY (23)LIRTFSGGVTYNQKFQG (139)SGTVRGFAY (34)94GYAMY (19)VIRTFSGGVTYNQKFRD (173)SGTVRGFAY (34)95DYAMY (21)LIRTYSGGVSYNQKFRG (148)SGTVRGFAY (34)96EYAMY (23)VIRTYSGGLTYNQKFRD (184)SGTVRGFAY (34)97EYAMH (22)LIRTFSGGLSYNQKFRD (131)SGTVRGFAY (34)101DYAMH (117)LIRTFSGGVSYNQKFQD (136)SGTVRGFAY (34)102GYAMY (19)VIRTYSGGVSYNQKFRD (194)SGTVRGFAY (34)105EYAMY (23)LIRTFSGGVSYNQKFKG (135)SGTVRGFAY (34)107GYAMY (19)VIRTYSGDVSYNQKFRD (176)SGTVRGFAY (34) 2< The VH CDRs in Table 6 were determined according to Kabat. Table 7. VL FR Amino Acid Sequences 3< Antibody VL FR1 (SEQ ID NO:) VL FR2 (SEQ ID NO:) VL FR3 (SEQ ID NO:) VL FR4 (SEQ ID NO:) 231-32-15FGGGTKLEIK (641)Hum231 #1FGQGTKLEIK (643)Hum231 #2FGQGTKLEIK (643)pab1964FGQGTKLEIK (643)pab1965FGQGTKLEIK (643)pab1966FGQGTKLEIK (643)pab1967FGQGTKLEIK (643)pab1968FGQGTKLEIK (643)pab1969FGQGTKLEIK (643)pab1970FGQGTKLEIK (643)pab1971FGQGTKLEIK (643)pab1972FGQGTKLEIK (643)pab1973FGQGTKLEIK (643)pab1975FGQGTKLEIK (643)pab1976FGQGTKLEIK (643)pab1977FGQGTKLEIK (643)pab1979FGQGTKLEIK (643)pab1980FGQGTKLEIK (643)pab1981FGQGTKLEIK (643)pab1983FGQGTKLEIK (643)pab2159FGQGTKLEIK (643)pab2160FGQGTKLEIK (643)pab2161FGQGTKLEIK (643)1FGQGTKLEIK (643)2FGQGTKLEIK (643)4FGQGTKLEIK (643)5FGQGTKLEIK (643)6FGQGTKLEIK (643)9FGQGTKLEIK (643)10FGQGTKLEIK (643)11FGQGTKLEIK (643)15FGQGTKLEIK (643)16FGQGTKLEIK (643)18FGQGTKLEIK (643)20FGQGTKLEIK (643)21FGQGTKLEIK (643)25FGQGTKLEIK (643)29FGQGTKLEIK (643)31FGQGTKLEIK (643)33FGQGTKLEIK (643)34FGQGTKLEIK (643)35FGQGTKLEIK (643)36FGQGTKLEIK (643)37FGQGTKLEIK (643)38FGQGTKLEIK (643)39FGQGTKLEIK (643)42FGQGTKLEIK (643)43FGQGTKLEIK (643)45FGQGTKLEIK (643)46FGQGTKLEIK (643)47FGQGTKLEIK (643)49FGQGTKLEIK (643)50FGQGTKLEIK (643)52FGQGTKLEIK (643)54FGQGTKLEIK (643)55FGQGTKLEIK (643)58FGQGTKLEIK (643)59FGQGTKLEIK (643)61FGQGTKLEIK (643)68FGQGTKLEIK (643)70FGQGTKLEIK (643)71FGQGTKLEIK (643)75FGQGTKLEIK (643)76FGQGTKLEIK (643)78FGQGTKLEIK (643)79FGQGTKLEIK (643)80FGQGTKLEIK (643)85FGQGTKLEIK (643)86FGQGTKLEIK (643)91FGQGTKLEIK (643)92FGQGTKLEIK (643)94FGQGTKLEIK (643)95FGQGTKLEIK (643)96FGQGTKLEIK (643)97FGQGTKLEIK (643)101FGQGTKLEIK (643)102FGQGTKLEIK (643)105FGQGTKLEIK (643)107FGQGTKLEIK (643) 3< The VL framework regions described in Table 7 are determined based upon the boundaries of the Kabat numbering system for CDRs. In other words, the VL CDRs are determined by Kabat and the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Table 8. VH FR Amino Acid Sequences 4< Antibody VHFR1 (SEQ ID NO:) VH FR2 (SEQ ID NO:) VH FR3 (SEQ ID NO:) VH FR4 (SEQ ID NO:) 231-32-15WGQGTLVTVSS (668)Hum231#1WGQGTLVTVSS (668)Hum231#2WGQGTLVTVSS (668)pab1964WGQGTLVTVSS (668)pab1965WGQGTLVTVSS (668)pab1966WGQGTLVTVSS (668)pab1967WGQGTLITVSS (667)pab1968WGQGTLVTVSS (668)pab1969WGQGTLVTVSS (668)pab1970WGQGTLVTVSS (668)pab1971WGQGTLVTVSS (668)pab1972WGQGTLVTVSS (668)pab1973WGQGTLVTVSS (668)pab1975WGQGTLVTVSS (668)pab1976WGQGTLVTVSS (668)pab1977WGQGTLVTVSS (668)pab1979WGQGTLVTVSS (668)pab1980WGQGTLVTVSS (668)pab1981WGQGTLVTVSS (668)pab1983WGQGTLVTVSS (668)pab2159WGQGTLVTVSS (668)pab2160WGQGTLVTVSS (668)pab2161WGQGTLVTVSS (668)1WGQGTLVTVSS (668)2WGQGTLVTVSS (668)4WGQGTLVTVSS (668)5WGQGTLVTVSS (668)6WGQGTLVTVSS (668)9WGQGTLVTVSS (668)10WGQGTLVTVSS (668)11WGQGTLVTVSS (668)15WGQGTLVTVSS (668)16WGQGTLVTVSS (668)18WGQGTLVTVSS (668)20WGQGTLVTVSS (668)21WGQGTLVTVSS (668)25WGQGTLVTVSS (668)29WGQGTLVTVSS (668)31WGQGIPVTVSS (664)33WGQGTLVTVSS (668)34WGQGTLVTVSS (668)35WGQGTLVTVSS (668)36WGQGTLVTVSS (668)37WGQGTLVTVSS (668)38WGQGTLVTVSS (668)39WGQGTLITVSS (667)42WGQGTLVTVSS (668)43WGQGTLVTVSS (668)45WGQGTFVTVSS (665)46WGQGTLVTVSS (668)47WGQGTLVTVSS (668)49WGQGTLVTVSS (668)50WGQGTLVTVSS (668)52WGQGTLVTVSS (668)54WGQGTLVTVSS (668)55WGQGTLVTVSS (668)58WGQGTLVTVSS (668)59WGQGTLVTVSS (668)61WGQGTLVTVSS (668)68WGQGTLVTVSS (668)70WGQGTLVTVSS (668)71WGQGTLVTVSS (668)75WGQGTLVTVSS (668)76WGQGTLVTVSS (668)78WGRGTLVTVSS (669)79WGQGTLVTVSS (668)80WGQGTLVTVSS (668)85WGQGTLVTVSS (668)86WGQGTLVTVSS (668)91WGQGTLVTVSS (668)92WGQGTLVTVSS (668)94WGQGTFVTVSS (666)95WGQGTFVTVSS (666)96WGQGTLVTVSS (668)97WGQGTLVTVSS (668)101WGQGTLVTVSS (668)102WGQGTLVTVSS (668)105WGQGTLVTVSS (668)107WGQGTLVTVSS (668) The VH framework regions described in Table 8 are determined based upon the boundaries of the Kabat numbering system for CDRs. In other words, the VH CDRs are determined by Kabat and the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0098] In another aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, ForM X 2 is L, A, V, I, P, F, M or S X 3 is N, G, Q, S, T, C, W, Y or A X 4 is S, G, N, Q, T, C, W, Y or A X 5 is G, N, Q, S, T, C, W, Y or A X 6 is N, G, Q, S, T, C, W, Y or A X 7 is Q, G, N, S, T, C, W, Y or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is T, G, N, Q, S, C, W, Y, V, I or A; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A X 2 is E, D or A X 3 is S, G, N, Q, T, C, W, Y or A; and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y X 2 is D, E or Y X 3 is S, G, N, Q, T, C, W, Y or A X 4 is Y, G, N, Q, S, T, C, W, F, H, L, or A; and / or (d) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A X 2 is A, V, L, I, P, F, M or Y X 3 is Y, G, N, Q, S, T, C, W, F or H; and / or (e) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T X 2 is R, K, H, Q or A X 3 is T, G, N, Q, S, C, W, Y, V, I or P X 4 is Y, G, N, Q, S, T, C, W, F, H, or A X 5 is D, E, G or A X 6 is V, A, L, I, P, F, M or T X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is K, R, H, Q or A X 10 is D, E, G or A; and / or (f) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S X 2 is A, or D X 3 is Y, G, N, Q, S, T, C, W, F, H or V. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, three, four, five or all six of the CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row of Table 2, for example, all of the VH CDRs are from the antibody 231-32-15). In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row of Table 1, for example, all of the VLCDRs are from the antibody 231-32-15).

[0099] In another aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein (i) the VL comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein: X 1 is L, A, V, I, P, F or M X 2 is L, A, V, I, P, F, M or S X 3 is N, G, Q, S, T, C, W, Y or A X 4 is S, G, N, Q, T, C, W, Y or A X 5 is G, N, Q, S, T, C, W, Y or A X 6 is N, G, Q, S, T, C, W, Y or A X 7 is Q, G, N, S, T, C, W, Y or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is T, G, N, Q, S, C, W, Y, V, I or A; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 ASTRX 2 X 3 (SEQ ID NO: 5), wherein: X 1 is W, G, N, Q, S, T, C, Y, F, H or A X 2 is E, D or A X 3 is S, G, N, Q, T, C, W, Y or A; and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein: X 1 is N, G, Q, S, T, C, W or Y X 2 is D, E or Y X 3 is S, G, N, Q, T, C, W, Y or A X 4 is Y, G, N, Q, S, T, C, W, F, H, L, or A; and (ii) the VH comprises: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 1), wherein X 1 is D, E, G or A X 2 is A, V, L, I, P, F, M or Y X 3 is Y, G, N, Q, S, T, C, W, F or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 X 10 (SEQ ID NO: 2), wherein X 1 is V, A, L, I, P, F, M or T X 2 is R, K, H, Q or A X 3 is T, G, N, Q, S, C, W, Y, V, I or P X 4 is Y, G, N, Q, S, T, C, W, F, H, or A X 5 is D, E, G or A X 6 is V, A, L, I, P, F, M or T X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A X 8 is N, G, Q, S, T, C, W, Y or A X 9 is K, R, H, Q or A X 10 is D, E, G or A; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S X 2 is A, or D X 3 is Y, G, N, Q, S, T, C, W, F, H or V. In specific aspects, the VL comprises two or all three of the VL CDRs above and / or the VH comprises two or all three of the VH CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain embodiments, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row of Table 2). In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row in Table 1).

[0100] In another aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) comprising: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S X 2 is T or S; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence WASTRES (SEQ ID NO: 11); and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E X 2 is Y, F or S. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, or all three of the VL CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row of Table 1). In some aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions (FRs) of an antibody set forth in Table 3 (e.g., one, two, three, or four of the framework regions in one row of Table 3).

[0101] In another aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region (VH) comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G X 2 is A or V X 3 is Y or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L X 2 is R, K or Q X 3 is Y or F X 4 is D, E or G X 5 is V or L X 6 is T or S X 7 is K, R or Q X 8 is D, E or G; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGFAY (SEQ ID NO: 9). In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row in Table 2). In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH frameworks described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises the VH framework regions of an antibody set forth in Tables 4 (e.g., one, two, three or four of the framework regions in one row of Table 4).

[0102] In a particular aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S X 2 is T or S; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence WASTRES (SEQ ID NO: 11); and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E X 2 is Y, F or S. (d) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G X 2 is A or V X 3 is Y or H; and / or (e) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L X 2 is R, K or Q X 3 is Y or F X 4 is D, E or G X 5 is V or L X 6 is T or S X 7 is K, R or Q X 8 is D, E or G; and / or (f) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGFAY (SEQ ID NO: 9). In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, three, four, five or all six of the CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row in Table 2). In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row in Table 1).

[0103] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein (i) the VL comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S X 2 is T or S; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence WASTRES (SEQ ID NO: 11); and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E X 2 is Y, F or S; and (ii) the VH comprises: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G X 2 is A or V X 3 is Y or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L X 2 is R, K or Q X 3 is Y or F X 4 is D, E or G X 5 is V or L X 6 is T or S X 7 is K, R or Q X 8 is D, E or G; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGFAY (SEQ ID NO: 9). In specific aspects, the VL comprises two or all three of the VL CDRs above and / or the VH comprises two or all three of the VH CDRs above. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain aspects, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row in Table 2). In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g., the VL CDRs in one row in Table 1).

[0104] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein (i) the VL comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein X 1 is G or S X 2 is T or S; and / or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence WASTRES (SEQ ID NO: 11); and / or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein X 1 is D or E X 2 is Y, F, or S; and (ii) the VH comprises: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein X 1 is D, E or G X 2 is A or V X 3 is Y or H; and / or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein X 1 is V or L X 2 is R, K or Q X 3 is Y or F X 4 is D, E or G X 5 is V or L X 6 is T or S X 7 is K, R or Q X 8 is D, E or G; and / or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGX 1 X 2 X 3 (SEQ ID NO: 3), wherein X 1 is F, A, V, L, I, P, M, Y, W, H or S X 2 is A or D X 3 is Y, G, N, Q, S, T, C, W, F, H or V.

[0105] In certain aspects, provided herein is an antibody or fragment thereof which specifically binds to GITR (e.g., human GITR) and comprises one, two or three of the light chain variable region (VL) complementarity determining regions (CDRs) of an antibody in Table 1 (e.g., the VL CDRs in one row of Table 1). In some aspects, provided herein is an antibody or fragment thereof which specifically binds to GITR (e.g., human GITR) and comprises one, two or three of the heavy chain variable region (VH) CDRs of any one of any one of antibodies in Table 2 (e.g., the VH CDRs in one row of Table 2).

[0106] In certain aspects, provided herein is an antibody or fragment thereof which specifically binds to GITR (e.g., human GITR) and comprises a light chain variable region (VL) comprising one, two or all three of the VL CDRs of an antibody in Table 1 (e.g., the VL CDRs in one row of Table 1). In some aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or all four of the VL framework regions described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or all four of the VL framework regions (FRs) set forth in Table 3 (e.g., one, two, three or four of the framework regions in one row in Table 3).

[0107] In certain aspects, provided herein is an antibody or fragment thereof which specifically binds to GITR (e.g., human GITR) and comprises a heavy chain variable region (VH) comprising one, two or all three of the VH CDRs of an antibody in Table 2 (e.g., the VH CDRs in one row of Table 2). In some aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or all four of the VH framework regions described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or all four of the VH framework regions (FRs) set forth in Table 4 (e.g., one, two, three, or four of the framework regions in one row in Table 4).

[0108] In certain aspects, provided herein is an antibody or fragment thereof which specifically binds to GITR (e.g., human GITR) and comprises light chain variable region (VL) CDRs and heavy chain variable region (VH) CDRs of any one of antibodies Hum231#2, pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, Hum231#1, 231-32-15 or antibodies 1-107, or antibodies pab2159, pab2160, or pab2161, for example as set forth in Tables 1 and 2 (e.g., the VH CDRs and VL CDRs in the same row are all from the same antibody as designated by the name of the antibody in the first column of Tables 1 and 2, for example, the VL CDRs and VH CDRs in the first row of Tables land 2 respectively are all from antibody 231-32-15). In some aspects, the antibody or antigen-binding fragment thereof comprises the VL framework regions and VH frameworks described herein. In specific aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions (FRs) and VH framework regions set forth in Tables 3 and 4 (e.g., the VL FRs and VH FRs are all from the same antibody).

[0109] In a particular aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 as set forth in Table 1, for example, VL CDR1, VL CDR2, and VL CDR3 of any one of antibodies Hum231#2, pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, Hum231#1, 231-32-15 or antibodies 1-107, or antibodies pab2159, pab2160, or pab2161, (e.g., the VL CDRs are in one row of Table 1). In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., one, two, three, or four of the framework regions in one row in Table 3). In certain aspects, the antibody or antigen-binding fragment thereof comprises a light chain variable region sequence comprising one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 204 or SEQ ID NO: 205. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or four of the framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of a light chain variable region sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208, and SEQ ID NOs: 400-518. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or four of the framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 519. In certain aspects, an antibody or antigen-binding fragment thereof comprises a light chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGKV4-1 ∗< 01 (SEQ ID NO: 607) and IGKV3-7 ∗< 02 (SEQ ID NO: 608). In specific aspects, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human light chain variable framework region. In some aspects, an antibody or antigen-binding fragment thereof comprises a light chain variable framework region that is derived from amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608, wherein at least one amino acid in amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 is substituted with an amino acid in an analogous position in a corresponding non-human light chain variable framework region. In a specific aspect, the amino acid substitution is at amino acid position 87, wherein the amino acid position is indicated according to the Kabat numbering. In particular aspects, the amino acid substitution is 87H, wherein the amino acid position is indicated according to the Kabat numbering.

[0110] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of Hum231#1, for example, the VL CDR1, VL CDR2, and VL CDR3 of Hum231#1 as set forth in Table 1 (SEQ ID NOS: 16, 17, and 18, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of Hum231#1).

[0111] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of Hum231#2, for example, the VL CDR1, VL CDR2, and VL CDR3 of Hum231#2 as set forth in Table 1 (SEQ ID NOS: 16, 17, and 18, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of Hum231#2).

[0112] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl964, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl964 as set forth in Table 1 (SEQ ID NOS: 101, 105, and 106, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1964).

[0113] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of A pab1965, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1965 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1965).

[0114] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1966, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1966 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1966).

[0115] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl967, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl967 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 108, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1967).

[0116] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl968, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl968 as set forth in Table 1 (SEQ ID NOS: 101, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1968).

[0117] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl969, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl969 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 109, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1969).

[0118] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1970, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1970 as set forth in Table 1 (SEQ ID NOS: 101, 105, and 109, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1970).

[0119] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1971, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl971 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab 1971).

[0120] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1972, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1972 as set forth in Table 1 (SEQ ID NOS: 104, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1972).

[0121] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1973, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1973 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1973).

[0122] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl975, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl975 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1975).

[0123] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl976, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl976 as set forth in Table 1 (SEQ ID NOS: 101, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1976).

[0124] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl977, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl977 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1977).

[0125] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl979, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl979 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pabl979).

[0126] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl980, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl980 as set forth in Table 1 (SEQ ID NOS: 101, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1980).

[0127] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pabl981, for example, the VL CDR1, VL CDR2, and VL CDR3 of pabl981 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1981).

[0128] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab1983, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab1983 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab1983).

[0129] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab2159, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab2159 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 109, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab2159).In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab2160, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab2160 as set forth in Table 1 (SEQ ID NOS: 102, 105, and 107, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab2160).

[0130] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, and VL CDR3 of pab2161, for example, the VL CDR1, VL CDR2, and VL CDR3 of pab2161 as set forth in Table 1 (SEQ ID NOS: 103, 105, and 109, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from a human light chain variable kappa subfamily. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions of an antibody set forth in Table 3 (e.g., the framework regions of pab2161).

[0131] In a particular aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 as set forth in Table 2, for example, VH CDR1, VH CDR2, and VH CDR3 of any one of antibodies Hum231#1, Hum231#2, pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, 231-32-15, or antibodies 1-107, or antibodies pab2159, pab2160, or pab2161, (e.g., the VH CDRs in one row in Table 2). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., one, two, three, or four of the framework regions in one row in Table 4). In certain aspects, the antibody or antigen-binding fragment thereof comprises one, two, three or all four of the framework regions of the heavy chain variable region sequence of SEQ ID NO: 203. In some aspects, the antibody or antigen-binding fragment thereof comprises one, two, three, or four of the framework regions of a heavy chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95% or 100% identical to one, two, three or four of the framework regions of a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 201, SEQ ID NO: 206, and SEQ ID NOS: 215 to 389. In certain aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGHV1-2 ∗< 02 (SEQ ID NO: 601), IGHV1-3 ∗< 01 (SEQ ID NO: 602), IGHV1-46 ∗< 01 (SEQ ID NO: 603), IGHV1-18 ∗< 01 (SEQ ID NO: 604), IGHV1-69 ∗< 01 (SEQ ID NO: 605), and IGHV7-4-1 ∗< 02 (SEQ ID NO: 606). In specific aspects, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region. In specific aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain variable framework region that is derived from amino acid sequence SEQ ID NO: 601, wherein at least one amino acid of amino acid sequence SEQ ID NO: 601 is substituted with an amino acid in an analogous position in a corresponding non-human heavy chain variable framework region. In certain aspects, the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71, 73, and 94, wherein the amino acid position of each group member is indicated according to the Kabat numbering. In specific aspects, the amino acid substitution selected from the group consisting of 24G, 48I, 67A, 71V, 73K, and 94K, wherein the amino acid position of each group member is indicated according to the Kabat numbering.

[0132] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of Hum231#1, for example, the VH CDR1, VH CDR2, and VH CDR3 of Hum231#1 as set forth in Table 2 (SEQ ID NOS: 13, 14, and 15, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of Hum231#1).

[0133] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of Hum231#2, for example, the VH CDR1, VH CDR2, and VH CDR3 of Hum231#2 as set forth in Table 2 (SEQ ID NOS: 13, 14, and 15, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of Hum231#2).

[0134] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1964, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1964 as set forth in Table 2 (SEQ ID NOS: 19, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1964).

[0135] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1965, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1965 as set forth in Table 2 (SEQ ID NOS: 19, 25, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some embodiments, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1965).

[0136] In a particular embodiment, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1966, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1966 as set forth in Table 2 (SEQ ID NOS: 19, 26, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1966).

[0137] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1967, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1967 as set forth in Table 2 (SEQ ID NOS: 20, 27, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1967).

[0138] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1968, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1968 as set forth in Table 2 (SEQ ID NOS: 21, 28, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some embodiments, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1968).

[0139] In a particular embodiment, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1969, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1969 as set forth in Table 2 (SEQ ID NOS: 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1969).

[0140] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1970, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1970 as set forth in Table 2 (SEQ ID NOS: 21, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1970).

[0141] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1971, for example, the VH CDR1, VH CDR2, and VH CDR3 of pabl971 as set forth in Table 2 (SEQ ID NOS: 21, 177, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some embodiments, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1971).

[0142] In a particular embodiment, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1972, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1972 as set forth in Table 2 (SEQ ID NOS: 23, 31, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1972).

[0143] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1973, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1973 as set forth in Table 2 (SEQ ID NOS: 19, 32, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab 1973).

[0144] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1975, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1975 as set forth in Table 2 (SEQ ID NOS: 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1975).

[0145] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1976, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1976 as set forth in Table 2 (SEQ ID NOS: 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1976).

[0146] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1977, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1977 as set forth in Table 2 (SEQ ID NOS: 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1977).

[0147] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1979, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1979 as set forth in Table 2 (SEQ ID NOS: 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1979).

[0148] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pabl980, for example, the VH CDR1, VH CDR2, and VH CDR3 of pabl980 as set forth in Table 2 (SEQ ID NOS: 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1980).

[0149] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1981, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1981 as set forth in Table 2 (SEQ ID NOS: 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some embodiments, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1981).

[0150] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab1983, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab1983 as set forth in Table 2 (SEQ ID NOS: 19, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab1983).

[0151] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab2159, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab2159 as set forth in Table 2 (SEQ ID NOS: 19, 144, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab2159).

[0152] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab2160, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab2160 as set forth in Table 2 (SEQ ID NOS: 119, 162, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some embodiments, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab2160).

[0153] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VH CDR1, VH CDR2, and VH CDR3 of pab2161, for example, the VH CDR1, VH CDR2, and VH CDR3 of pab2161 as set forth in Table 2 (SEQ ID NOS: 22, 121, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In specific aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VH framework regions derived from a human heavy chain variable subfamily (e.g., one of subfamilies 1 to 7). In some aspects, the antibody or antigen-binding fragment thereof comprises VH framework regions of an antibody set forth in Table 4 (e.g., the framework regions of pab2161).

[0154] In a particular aspect, an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR (e.g., human GITR), comprises (i) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 as set forth in Table 2, for example, VH CDR1, VH CDR2, and VH CDR3 of any one of antibodies Hum231#1, Hum231#2, pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, 231-32-15 or antibodies 1-107, or antibodies pab2159, pab2160, or pab2161, (e.g. the VH CDRs in one row in Table 2), and (ii) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 as set forth in Table 1, for example, VL CDR1, VL CDR2, and VL CDR3 of any one of antibodies Hum231#1, Hum231#2, pab1964, pab1965, pab1966, pab1967, pab1968, pab1969, pab1970, pab1971, pab1972, pab1973, pab1975, pab1976, pab1977, pab1979, pab1980, pab1981, pab1983, 231-32-15 or antibodies 1-107, or antibodies pab2159, pab2160, or pab2161, (e.g., the VL CDRs in one row in Table 1). In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of a single antibody as designated by its name, for example, all of the FRs are from Hum231#1 or Hum231#2).

[0155] In some aspects, the antibody or antigen-binding fragment thereof described herein comprises one, two, three or four framework regions of a heavy chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95% or 100% identical to one, two, three or four of the framework regions of a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 201, SEQ ID NO: 206, and SEQ ID NOS: 215 to 389. In certain aspects, the antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGHV1-2 ∗< 02 (SEQ ID NO: 601), IGHV1-3 ∗< 01 (SEQ ID NO: 602), IGHV1-46 ∗< 01 (SEQ ID NO: 603), IGHV1-18 ∗< 01 (SEQ ID NO: 604), IGHV1-69 ∗< 01 (SEQ ID NO: 605), and IGHV7-4-1 ∗< 02 (SEQ ID NO: 606). In specific aspects, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region. In specific aspects, the antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable framework region that is derived from amino acid sequence SEQ ID NO: 601, wherein at least one amino acid in amino acid sequence SEQ ID NO: 601 is substituted with an amino acid in an analogous position in a corresponding non-human light chain variable framework region. In certain aspects, the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71, 73, and 94, wherein the amino acid position of each group member is indicated according to the Kabat numbering. In specific aspects, the amino acid substitution is selected from the group consisting of 24G, 48I, 67A, 71V, 73K, and 94K, wherein the amino acid position of each group member is indicated according to the Kabat numbering.

[0156] In some aspects, the antibody or antigen-binding fragment thereof described herein comprises VL framework regions of an antibody set forth in Table 3. In certain aspects, the antibody or antigen-binding fragment thereof described herein comprises a light chain variable region sequence comprising one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 204 or SEQ ID NO: 205. In some aspects, the antibody or antigen-binding fragment thereof described herein comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of a light chain variable region sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208, and SEQ ID NOs: 400-518. In some aspects, the antibody or antigen-binding fragment thereof described herein comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 519. In certain aspects, an antibody or antigen-binding fragment thereof described herein comprises a light chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGKV4-1 ∗< 01 (SEQ ID NO: 607) and IGKV3-7 ∗< 02 (SEQ ID NO: 608). In specific aspects, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. In a particular aspect, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human light chain variable framework region. In some aspects, an antibody or antigen-binding fragment thereof described herein comprises a light chain variable framework region that is derived from amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608, wherein at least one amino acid of amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 with an amino acid in an analogous position in a corresponding non-human light chain variable framework region. In a specific aspect, the amino acid substitution is at amino acid position 87, wherein the amino acid position is indicated according to the Kabat numbering. In particular aspects, the amino acid substitution is 87H, wherein the amino acid position is indicated according to the Kabat numbering.

[0157] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of Hum231#1, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of Hum231#1 as set forth in Tables 1 and 2 (SEQ ID NOS: 16, 17, 18, 13, 14, and 15, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VH of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of Hum231#1).

[0158] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of Hum231#2, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of Hum231#2 as set forth in Tables 1 and 2 (SEQ ID NOS: 16, 17, 18, 13, 14, and 15, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the frameworks of a single antibody as designated by its name, for example, the framework regions of Hum231#1 or Hum231#2).

[0159] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1964, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1964 as set forth in Tables 1 and 2 (SEQ ID NOS: 101, 105, 106, 19, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1964).

[0160] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1965, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1965 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 19, 25, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1965).

[0161] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1966, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1966 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 19, 26, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1966).

[0162] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1967, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1967 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 108, 20, 27, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1967).

[0163] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1968, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1968 as set forth in Tables 1 and 2 (SEQ ID NOS: 101, 105, 107, 21, 28, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1968).

[0164] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1969, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1969 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 109, 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1969).

[0165] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1970, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1970 as set forth in Tables 1 and 2 (SEQ ID NOS: 101, 105, 109, 21, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1970).

[0166] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1971, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1971 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 107, 21, 177, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1971).

[0167] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1972, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1972 as set forth in Tables 1 and 2 (SEQ ID NOS: 104, 105, 107, 23, 31, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1972).

[0168] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pabl973, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1973 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 107, 19, 32, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1973).

[0169] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1975, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1975 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1975).

[0170] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pabl976, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1976 as set forth in Tables 1 and 2 (SEQ ID NOS: 101, 105, 107, 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1976).

[0171] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1977, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1977 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 107, 22, 29, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1977).

[0172] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pabl979, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1979 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1979).

[0173] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1980, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1980 as set forth in Tables 1 and 2 (SEQ ID NOS: 101, 105, 107, 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1980).

[0174] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1981, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1981 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 107, 22, 33, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1981).

[0175] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1983, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab1983 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 19, 24, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab1983).

[0176] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2159, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2159 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 109, 19, 144, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab2159).

[0177] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2160, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2160 as set forth in Tables 1 and 2 (SEQ ID NOS: 102, 105, 107, 119, 162, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab2160).

[0178] In a particular aspect, an antibody or fragment thereof described herein, which specifically binds to GITR (e.g., human GITR), comprises the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2161, for example, the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of pab2161 as set forth in Tables 1 and 2 (SEQ ID NOS: 103, 105, 109, 22, 121, and 34, respectively). In certain aspects, the antibody or antigen-binding fragment further comprises one, two, three or all four VL framework regions derived from the VL of a human or primate antibody and one, two, three or all four VH framework regions derived from the VH of a human or primate antibody. In some aspects, the antibody or antigen-binding fragment thereof comprises VL framework regions and VH framework regions of an antibody set forth in Tables 3 and 4, respectively (e.g., the framework regions of pab2161).

[0179] In certain aspects, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising the amino acid sequence of a VL domain of an antibody listed in Figure 23 or any one of Figures 24A-24C (e.g., the VL domain in one row of Figure 23 or any one of Figures 24A-24C). In certain aspects, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising the amino acid sequence of a VL domain of an antibody listed in Table 17 (e.g., the VL domain in one row of Table 17). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 207 (e.g., antibody Hum231#1). The antibody that specifically binds to GITR (e.g., human GITR) of the invention comprises a VL domain comprising SEQ ID NO: 208 (e.g., antibody Hum231#2). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 435 (e.g., antibody pab1964). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 437 (e.g., antibody pab1965). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 440 (e.g., antibody pab1966). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 441 (e.g., antibody pab1967). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 444 (e.g., antibody pab1968). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 458 (e.g., antibody pab1969). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 459 (e.g., antibody pab1970). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 453 (e.g., antibody pab1971). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 463 (e.g., antibody pab1972). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 519 (e.g., antibody pab1973). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 440 (e.g., antibody pab1975). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 444 (e.g., antibody pab1976). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 453 (e.g., antibody pab1977). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 440 (e.g., antibody pab1979). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 444 (e.g., antibody pab1980). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 453 (e.g., antibody pab1981). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 440 (e.g., antibody pab1983). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 408 (e.g., antibody pab2159). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 423 (e.g., antibody pab2160). In a specific aspect, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain comprising SEQ ID NO: 486 (e.g., antibody pab2161).

[0180] In some aspects, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL domain consisting of or consisting essentially of the amino acid sequence of a VL domain of an antibody listed in Figure 23 or any one of Figures 24A-24C (e.g., the VL domain in one row of Figure 23 or any one of Figures 24A-24C). In some aspects, an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprises a VL dom...

Claims

1. An isolated agonistic antibody that specifically binds to human glucocorticoid-induced TNFR-related protein (GITR) comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 206 and comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 208, wherein the antibody further comprises a heavy chain constant region.

2. The antibody of claim 1, wherein the heavy chain constant region is human immunoglobulin IgG1.

3. The antibody of claim 1, wherein the heavy chain constant region is human immunoglobulin IgG4.

4. The antibody of any one of claims 1 or 2, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 567, and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 576.

5. The antibody of any one of claims 1 or 3, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 554, and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 576.

6. The antibody of any one of claims 1-5, wherein the antibody induces, activates or enhances an activity of human GITR, optionally in a cell independent of TCR triggering.

7. An isolated nucleic acid molecule encoding the VH and / or the VL, or the light chain and / or the heavy chain, of the antibody of any one of claims 1-68. The isolated nucleic acid molecule of claim 7, encoding the VH of the antibody of any one of claims 1-6 or encoding the heavy chain of the antibody of any one of claims 1-69. The isolated nucleic acid molecule of claim 7, encoding the VL of the antibody of any one of claims 1-6 or encoding the light chain of the antibody of any one of claims 1-610. The isolated nucleic acid molecule of claim 7, encoding the VH and the VL of the antibody of any one of claims 1-6 or encoding the light chain and the heavy chain of the antibody of any one of claims 1-611. A pharmaceutical composition comprising the antibody of any one of claims 1-6 or the nucleic acid molecule of any one of claims 7-10, and a pharmaceutically acceptable carrier or excipient.

12. The antibody of any one of claims 1-6 the pharmaceutical composition of claim 11 for use in the treatment of cancer.

13. The antibody or the pharmaceutical composition for use of claim 12, wherein the cancer is endometrial cancer, gastric cancer, stomach cancer, esophageal cancer, gastroesophageal junction carcinoma, head and neck squamous cell carcinoma, melanoma, non-small cell lung cancer, or renal cell carcinoma.

14. The antibody of any one of claims 1-6 or the pharmaceutical composition of claim 11 for use in the treatment of a viral infection.

15. The antibody of any one of claims 1-6, wherein the antibody is bispecific.

16. An isolated vector comprising the nucleic acid molecule of any one of claims 7-10.

17. The isolated vector of claim 16, comprising the nucleic acid molecule of claim 8.

18. The isolated vector of claim 16, comprising the nucleic acid molecule of claim 9.

19. The isolated vector of claim 16, comprising the nucleic acid molecule of claim 10.

20. A population of vectors comprising a first vector comprising a nucleic acid encoding the light chain or the VL of the antibody of any one of claims 1-6, and a second vector comprising a nucleic acid encoding the heavy chain or the VH of the antibody of any one of claims 1-6.

21. A host cell comprising the isolated nucleic acid molecule of any one of claims 7-10, or the isolated vector of any one of claims 16-19, or the population of vectors of claim 20.

22. The host cell of claim 21, comprising: (i) the isolated nucleic acid of claim 8, wherein the isolated nucleic acid encodes the VH of the antibody of claim 4 or encodes the heavy chain of the antibody of claim 4, and the isolated nucleic acid of claim 9, wherein the isolated nucleic acid encodes the VL of the antibody of claim 4 or encodes the light chain of the antibody claim 4, or (ii) the isolated nucleic acid of claim 10, wherein the isolated nucleic acid encodes the VH and the VL of the antibody of claim 4, or encodes the light chain and the heavy chain of the antibody of claim 4, or (iii) the isolated vector of claim 17, wherein the isolated vector comprises the nucleic acid molecule encoding the VH of the antibody of claim 4 or encoding the heavy chain of the antibody of claim 4, and the isolated vector of claim 18, wherein the isolated vector comprises the nucleic acid molecule encoding the VL of the antibody of claim 4 or encoding the light chain of the antibody of claim 4, or (iv) the isolated vector of claim 19, wherein the isolated vector comprises the nucleic acid molecule encoding the VH of the antibody of claim 4 and the VL of the antibody of claim 4, or wherein the isolated vector comprises the nucleic acid molecule encoding the light chain of the antibody of claim 4 and the heavy chain of the antibody of claim 4, or (v) the population of vectors of claim 20, wherein the population of vectors comprises a first vector comprising a nucleic acid encoding the light chain or the VL of the antibody of claim 4, and a second vector comprising a nucleic acid encoding the heavy chain or the VH of the antibody of claim 4.

23. The host cell of claim 21, wherein a) the host cell contains a vector comprising a nucleic acid molecule encoding the heavy chain and light chain of an antibody of any one of claims 1-6, or b) the host cell contains two different vectors, a first vector comprising a nucleic acid molecule encoding a heavy chain or heavy chain variable region of an antibody of any one of claims 1-6, and a second vector comprising a nucleic acid molecule encoding a light chain or light chain variable region of an antibody of any one of claims 1-6.

24. The host cell of claim 21, wherein the nucleic acid molecule encodes a light chain and / or a heavy chain of the antibody of claim 4, or wherein the vector(s) comprise(s) a nucleic acid molecule encoding a light chain and / or a heavy chain of the antibody of claim 4.

25. The host cell of claim 21, wherein the nucleic acid molecule encodes a light chain and / or a heavy chain of the antibody of claim 5, or wherein the isolated vector(s) comprise(s) a nucleic acid molecule encoding a light chain and / or a heavy chain of the antibody of claim 5.

26. The host cell of any of claims 21-25, which is a CHO cell.

27. A method of producing an agonistic antibody that binds to human GITR comprising culturing the host cell of any of claims 21-26, so that the nucleic acid molecule(s) is / are expressed and the antibody is produced.

28. The method of producing an agonistic antibody that binds to human GITR of claim 27, comprising culturing the host cell of claim 22 or 24, wherein the host cell is a CHO cell.

29. The method of producing an antibody that binds to human GITR of claim 27, comprising culturing the host cell of claim 25, wherein the host cell is a CHO cell.

30. The method of producing an agonistic antibody that binds to human GITR of claim 27, wherein a first host cell comprises a first vector comprising a nucleic acid molecule encoding a heavy chain or heavy chain variable region of an antibody of any one of claims 1-6, and a second host cell comprises a second vector comprising a nucleic acid molecule encoding a light chain or light chain variable region of an antibody of any one of claims 1-6, and wherein the heavy chain or heavy chain variable region expressed by the first cell associates with the light chain or light chain variable region of the second cell, to form the antibody.