Gitr antigen binding proteins

Abstract

Antigen binding proteins that activate GITR are provided. Nucleic acids encoding the antigen binding proteins and vectors and cells containing such nucleic acids are also provided. The antigen binding proteins have value in therapeutic methods in which it is useful to stimulate GITR signaling, thereby inducing or enhancing an immune response in a subject. Accordingly, the antigen binding proteins have utility in a variety of immunotherapy treatments, including treatment of various cancers and infections.

1 .- 20 . (canceled) 
     
     
         21 . A nucleic acid that encodes
 a) a VL, a VH or both of an antigen binding protein; or   b) a LC, an HC or both of an antigen binding protein wherein the antigen binding protein is an antibody or a functional fragment thereof that agonizes human glucocorticoid-induced TNFR-related protein (“GITR”), said antigen binding protein comprising:   a) a variant VH comprising a CDRH1, a CDRH2 and a CDRH3, wherein one or more of CDRH1, CDRH2 and CDRH3 differ in sequence relative to the corresponding CDRH1, CDRH2 and CDRH3 of the VH of any single antigen binding protein selected from the group of Ab1 to Ab59 inclusive, provided however that the sequence differences in the CDRH1, CDRH2 and CDRH3 of the variant VH relative to the corresponding CDRs of the VH sequence collectively total no more than 1, 2, 3, 4 or 5 amino acids; and
 a variant VL comprising a CDRL1, a CDRL2 and a CDRL3, wherein one or more of CDRL1, CDRL2 and CDRL3 differ in sequence relative to the corresponding CDRL1, CDRL2 and CDRL3 of the VL of any single antigen binding protein selected from the group of Ab1 to Ab59 inclusive, provided however that the sequence differences in the CDRL1, CDRL2 and CDRL3 of the variant VL relative to the corresponding CDRs of the VL sequence collectively total no more than 1, 2, 3, 4 or 5 amino acids, provided that the variant VH and the variant VL are, respectively, variants of the VH and VL of the same antigen binding protein as specified in Table 1; 
   b) a VH comprising a CDRH1, a CDRH2 and a CDRH3, wherein CDRH1 comprises the sequence X 1 YGMX 2  (SEQ ID NO:436), wherein X1 is S or N; and X2 is H or Y;
 CDRH2 comprises the sequence VIWYX 1 GSNKYYADSVX 2 G (SEQ ID NO:437), wherein X1 is E, V, A, P; and X2 is K or R; 
 CDRH3 comprises the sequence GGX 1 LX 2 X 3 X 4 YYX 5 GMDV (SEQ ID NO:438), wherein X1 is Q, L, E, or R; X2 is G, R, or S; X3 is K, Y, L, F, or R; and X4 is Y or D; and X5 is Y or S; and 
 a VL comprising a CDRL1, a CDRL2 and a CDRL3, wherein 
 CDRL1 comprises the sequence RASQX 1 IRNDLG (SEQ ID NO:439), wherein X1 is G or V; 
 CDRL2 comprises the sequence X 1 X 2 SX 3 LQS (SEQ ID NO:440), wherein X1 is A or D; X2 is A or T; and X3 is S or T; 
 CDRL3 comprises the sequence X 1 QX 2 X 3 X 4 YPX 5 T (SEQ ID NO:441), wherein X1 is L or Q; X2 is H or L; X3 is N or H; X4 is S, N or T, and X5 is W, L or I; 
   c) a CDRH1, a CDRH2 and a CDRH3, each from the same VH of an antigen binding protein of Ab1 to Ab59 inclusive as specified in Table 1; and
 the CDRL1, a CDRL2, and a CDRL3, each from the same VL of an antigen binding protein of Ab1 to Ab59 inclusive as specified in Table 1, wherein the VH and the VL are from the same antigen binding protein; 
   d) a VH that is at least 80%, 85%, 90%, 95%, 97% or 99% identical in amino acid sequence to the VH sequence of any one of antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1; and
 a VL that is at least 80%, 85%, 90%, 95%, 97% or 99% identical in amino acid sequence to the VL sequence of any one of antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1, wherein the VH and the VL are from the same antigen binding protein as specified in Table 1; 
   e) a VH comprising the amino acid sequence of the VH of any one of antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1; and
 a VL comprising the amino acid sequence of the VL of any one of antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1, wherein the VH and the VL are from the same antigen binding protein as specified in Table 1; 
   f) a full length heavy chain (HC) that is at least 90%, 95%, 97% or 99% identical in amino acid sequence to the full length heavy chain sequence of any one of antigen binding proteins Ab1 to AB59 inclusive as specified in Table 1; and
 a full length light chain (LC) that is at least 90%, 95%, 97% or 99% identical in amino acid sequence to the full length light chain sequence of any one of antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1, wherein the full length heavy chain and the full length light chain are from the same antigen binding protein as specified in Table 1; or 
   g) a full length heavy chain comprising the amino acid sequence of the full length heavy chain of any one of the antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1; and
 a full length light chain comprising the amino acid sequence of the full length light chain of any one of the antigen binding proteins Ab1 to Ab59 inclusive as specified in Table 1, wherein the full length heavy chain and the full length light chain are from the same antigen binding protein as specified in Table 1. 
   
     
     
         22 . The nucleic acid of  claim 21 , wherein:
 a) the VL nucleic acid and the VH nucleic acid respectively comprise the VL nucleotide sequence and the VH nucleotide sequence as set forth for any single antibody selected from the group of Ab1 to Ab59 inclusive as specified in TABLE 4; or   b) the LC nucleic acid or the HC nucleic acid respectively comprise the LC nucleotide sequence and the HC nucleotide sequence as set forth for any single antibody selected from the group of Ab1 to Ab59 inclusive as specified in TABLE 4.   
     
     
         23 .- 34 . (canceled) 
     
     
         35 . The nucleic acid of  claim 21 , wherein the antigen binding protein comprises a CDRL1, a CDRL2, a CDRL3, a CDRH1, a CDRH2 and a CDRH3, and wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3 differ in sequence relative to the corresponding CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3 of any single antibody selected from the group of Ab1 to Ab59 inclusive, provided however that the sequence differences in the CDRs collectively total no more than 1, 2, 3, 4, or 5 amino acids. 
     
     
         36 . The nucleic acid of  claim 21 , wherein the antigen binding protein comprises a CDRL1, a CDRL2, a CDRL3, a CDRH1, a CDRH2 and a CDRH3, and wherein:
 a) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:11, CDRL3 comprises SEQ ID NO:19, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:36 and CDRH3 comprises SEQ ID NO:47;   b) CDRL1 comprises SEQ ID NO:5 CDRL2 comprises SEQ ID NO:12, CDRL3 comprises SEQ ID NO:18, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:40 and CDRH3 comprises SEQ ID NO:52;   c) CDRL1 comprises SEQ ID NO:10, CDRL2 comprises SEQ ID NO:17, CDRL3 comprises SEQ ID NO:28, CDRH1 comprises SEQ ID NO:35, CDRH2 comprises SEQ ID NO:45 and CDRH3 comprises SEQ ID NO:62;   d) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:12, CDRL3 comprises SEQ ID NO:29, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:37 and CDRH3 comprises SEQ ID NO:58;   e) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:14, CDRL3 comprises SEQ ID NO:30, CDRH1 comprises SEQ ID NO:3, CDRH2 comprises SEQ ID NO:36 and CDRH3 comprises SEQ ID NO:63;   f) CDRL1 comprises SEQ ID NO:10, CDRL2 comprises SEQ ID NO:17, CDRL3 comprises SEQ ID NO:28, CDRH1 comprises SEQ ID NO:35, CDRH2 comprises SEQ ID NO:45 and CDRH3 comprises SEQ ID NO:76;   g) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:12, CDRL3 comprises SEQ ID NO:29, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:37 and CDRH3 comprises SEQ ID NO:58;   h) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:14, CDRL3 comprises SEQ ID NO:30, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:71 and CDRH3 comprises SEQ ID NO:63; or   i) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:11, CDRL3 comprises SEQ ID NO:19, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:71 and CDRH3 comprises SEQ ID NO:47;   j) CDRL1 comprises SEQ ID NO:5, CDRL2 comprises SEQ ID NO:12, CDRL3 comprises SEQ ID NO:18, CDRH1 comprises SEQ ID NO:31, CDRH2 comprises SEQ ID NO:73 and CDRH3 comprises SEQ ID NO:52.   
     
     
         37 . The nucleic acid of  claim 21 , wherein the antigen binding protein comprises a VL and a VH, and wherein:
 a) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:119 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:138;   b) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:124 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:143;   c) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:134 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:153;   d) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:135 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:154;   e) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:136 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:155;   f) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:242 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:282;   g) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:255 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:295;   h) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:262 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:302;   i) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:267 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:307;   j) the amino acid sequence of the VL is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:272 and the amino acid sequence of VH is at least 80%, 85%, 90%, 95%, 97% or 99% identical to SEQ ID NO:312.   
     
     
         38 . The nucleic acid of  claim 37 , wherein the antigen binding protein comprises a VL and a VH, and wherein:
 a) the VL comprises SEQ ID NO:119 and the VH comprises SEQ ID NO:138;   b) the VL comprises SEQ ID NO:124 and the VH comprises SEQ ID NO:143;   c) the VL comprises SEQ ID NO:134 and the VH comprises SEQ ID NO:153;   d) the VL comprises SEQ ID NO:135 and the VH comprises SEQ ID NO:154;   e) the VL comprises SEQ ID NO:136 and the VH comprises SEQ ID NO:155;   f) the VL comprises SEQ ID NO:242 and the VH comprises SEQ ID NO:282;   g) the VL comprises SEQ ID NO:255 and the VH comprises SEQ ID NO:295;   h) the VL comprises SEQ ID NO:262 and the VH comprises SEQ ID NO:302;   i) the VL comprises SEQ ID NO:267 and the VH comprises SEQ ID NO:307; or   j) the VL comprises SEQ ID NO:272 and the VH comprises SEQ ID NO:312.   
     
     
         39 . The nucleic acid of  claim 21 , wherein the antigen binding protein comprises a LC and HC, and wherein:
 a) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:317 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:336;   b) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:322 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:341;   c) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:332 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:351;   d) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:333 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:352;   e) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:334 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:353;   f) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:360 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:400;   g) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:373 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:413;   h) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:380 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:420;   i) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:385 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:425;   j) the LC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:390 and the HC is at least 90%, 95%, 97% or 99% identical in amino acid sequence to SEQ ID NO:430.   
     
     
         40 . The nucleic acid of  claim 39 , wherein the antigen binding protein comprises a LC and HC, and wherein:
 a) the LC comprises SEQ ID NO:317 and the HC comprises SEQ ID NO:336;   b) the LC comprises SEQ ID NO:322 and the HC comprises SEQ ID NO:341;   c) the LC comprises SEQ ID NO:332 and the HC comprises SEQ ID NO:351;   d) the LC comprises SEQ ID NO:333 and the HC comprises SEQ ID NO:352;   e) the LC comprises SEQ ID NO:334 and the HC comprises SEQ ID NO:353;   f) the LC comprises SEQ ID NO:360 and the HC comprises SEQ ID NO:400;   g) the LC comprises SEQ ID NO:373 and the HC comprises SEQ ID NO:413;   h) the LC comprises SEQ ID NO:380 and the HC comprises SEQ ID NO:420;   i) the LC comprises SEQ ID NO:385 and the HC comprises SEQ ID NO:425; or   j) the LC comprises SEQ ID NO:390 and the HC comprises SEQ ID NO:430.   
     
     
         41 . The nucleic acid of  claim 21 , wherein the antigen binding protein has one or more of the following characteristics:
 a) is a monoclonal antibody;   b) is a human antibody, a humanized antibody, or a chimeric antibody;   c) is a multispecific antibody;   d) is of the IgG1, IgG2, IgG3, or the IgG4 type;   e) is an antigen-binding antibody fragment;   f) is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, or an Fv fragment;   g) is a diabody, a single chain antibody, a domain antibody, or a nanobody;   h) is labeled.   
     
     
         42 . The nucleic acid of  claim 41 , wherein the antigen binding protein is a fully human antibody. 
     
     
         43 . The nucleic acid of  claim 21 , wherein the antigen binding protein has one or more of the following activities:
 a) cross-competes with GITRL for binding to GITR;   b) can be internalized into human CD4 cells;   c) reduces suppression of regulatory T cells;   d) decreases circulating regulatory T cells;   e) activates effector T cells;   f) has a half life of at least 6, 7, 9 or 12 days in human serum.   
     
     
         44 . The nucleic acid of  claim 21 , wherein the antigen binding protein is a fully human IgG1 antibody. 
     
     
         45 . The nucleic acid of  claim 21 , wherein the antigen binding protein is capable of binding Fcgamma receptor (FcγR). 
     
     
         46 . The nucleic acid of  claim 21 , wherein the antigen binding protein is capable of binding Fcgamma receptor (FcγR) such that a cluster of antigen binding proteins is formed. 
     
     
         47 . The nucleic acid of  claim 21 , wherein the antigen binding protein has one or more of the following characteristics:
 a) binds to human GITR polypeptide of SEQ ID NO:1 with a K D  of less than ≦10 nM;   b) binds to cyno GITR polypeptide of SEQ ID NO:2, with a K D  of less than ≦500 nM.   
     
     
         48 . The nucleic acid of  claim 21 , wherein the antigen binding protein is a fully human monoclonal antibody of the IgG1 type that agonizes human GITR. 
     
     
         49 . The nucleic acid of  claim 21 , wherein the antigen binding protein binds human GITR of SEQ ID NO:1 with K D ≦10 nM and binds cyno GITR of SEQ ID NO:2 with K D ≦500 nM.