Claims for Patent: 9,464,139

Summary for Patent: 9,464,139

Title:	GITR antigen binding proteins and methods of use thereof
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.
Inventor(s):	Beers; Courtney (Seattle, WA), O\'Neill; Jason C. (Brier, WA), Foltz; Ian (Burnaby, CA), Ketchem; Randal R. (Snohomish, WA), Piasecki; Julia C. (Seattle, WA)
Assignee:	AMGEN INC. (Thousand Oaks, CA)
Application Number:	14/472,116
Patent Claims:	1. An antigen binding protein, wherein said 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.sub.1YGMX.sub.2 (SEQ ID NO:436), wherein X1 is S or N; and X2 is H or Y; CDRH2 comprises the sequence VIWYX.sub.1GSNKYYADSVX.sub.2G (SEQ ID NO:437), wherein X1 is E, V, A, P; and X2 is K or R; CDRH3 comprises the sequence GGX.sub.1LX.sub.2X.sub.3X.sub.4YYX.sub.5GMDV (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.sub.1IRNDLG (SEQ ID NO:439), wherein X1 is G or V; CDRL2 comprises the sequence X.sub.1X.sub.2SX.sub.3LQS (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.sub.1QX.sub.2X.sub.3X.sub.4YPX.sub.5T (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. 2. The antigen binding protein of claim 1, 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. 3. The antigen binding protein of claim 1, 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. 4. The antigen binding protein of claim 1, 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. 5. The antigen binding protein of claim 4, 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. 6. The antigen binding protein of claim 1, 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%, 9'7% 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. 7. The antigen binding protein of claim 6, 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. 8. The antigen binding protein of claim 1, 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. 9. The antigen binding protein of claim 8 that is a fully human antibody. 10. The antigen binding protein of claim 1, that 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. 11. The antigen binding protein of claim 1 that is a fully human IgG1 antibody. 12. The antigen binding protein of claim 1 that is capable of binding Fcgamma receptor (Fc.gamma.R). 13. The antigen binding protein of claim 12 that is capable of binding Fcgamma receptor (Fc.gamma.R) such that a cluster of antigen binding proteins is formed. 14. The antigen binding protein of claim 1, 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.sub.D of less than .ltoreq.10 nM; b) binds to cyno GITR polypeptide of SEQ ID NO:2, with a K.sub.D of less than .ltoreq.500 nM. 15. The antigen binding protein of claim 1, wherein the antigen binding protein is a fully human monoclonal antibody of the IgG1 type that agonizes human GITR. 16. The antigen binding protein of claim 1 that binds human GITR of SEQ ID NO:1 with K.sub.D.ltoreq.10 nM and binds cyno GITR of SEQ ID NO:2 with K.sub.D.ltoreq.500 nM. 17. A method for inducing or enhancing an immune response in a subject, the method comprising administering the antigen binding protein of claim 1 to a subject in an amount effective to induce or enhance the immune response. 18. The method of claim 17, wherein the immune response is generated against a tumor antigen. 19. The method of claim 17, wherein the immune response is generated against an infectious agent. 20. The method of claim 17, wherein the antigen binding protein is administered in an amount sufficient to achieve one or more of the following in the subject: a) reduce regulatory T cells suppression of activity of effector T cells; b) decrease levels of circulating regulatory T cells; c) activation of effector T cells; d) induce or enhance effector T cell proliferation; e) inhibit tumor growth; and f) induce tumor regression. 21. A method for treating cancer in a subject with cancer, the method comprising administering an effective amount of an antigen binding protein of claim 1 to the subject. 22. The method of claim 21, wherein the cancer is a solid cancer. 23. The method of claim 21, wherein the cancer is a hematological cancer. 24. A method for inhibiting metastasis in a subject with cancer, the method comprising administering an effective amount of an antigen binding protein of claim 1 to the subject. 25. The method of claim 21, wherein the method further comprises one or more of the following a) administering chemotherapy; b) administering radiation therapy; or c) administering one or more additional therapeutic agents. 26. The method of claim 25, wherein the additional therapeutic agent is an immunostimulatory agent. 27. The method of claim 26, wherein the immunostimulatory agent is selected from the group consisting of talimogene laherparepvec (T-VEC), a PD1 antagonist, a PDL1 antagonist, a CTLA-4 antagonist and a Bispecific T-cell Engager (BiTE). 28. A method for treating a subject with an infection, the method comprising administering an antigen binding protein of claim 1 in an amount effective to treat the infection.

Details for Patent 9,464,139

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	IMLYGIC	talimogene laherparepvec	For Injection	125518	10/27/2015		2033-08-30