Anti-GITR Antibodies and Methods of Use Thereof

• US 20180355051A1
• Filed: 04/25/2018
• Published: 12/13/2018
• Est. Priority Date: 05/28/2014
• Status: Active Grant

• Current Assignee: Agenus Inc., Ludwig Institute for Cancer Research, Ltd., Memorial Sloan-Kettering Cancer Center
• Original Assignee: Agenus Inc., Ludwig Institute for Cancer Research, Ltd., Memorial Sloan-Kettering Cancer Center
• Inventors: GONZALEZ, Ana M., WILSON, Nicholas S., UNDERWOOD, Dennis J., SEIBERT, Volker, LEGER, Olivier, VAN DIJK, Marc, ZAPPASODI, Roberta, MERGHOUB, Taha, WOLCHOK, Jedd David, SCHAER, David, RITTER, Gerd, TSUJI, Takemasa
• Granted Patent: US 10,800,849 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/70578 : NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95 NGF-receptor G01N2333/71, TNF-receptor G01N2333/7151
• CPC Class Codes: G01N 33/502 : for testing non-proliferative effects
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

1-205. -205. (canceled)

206. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an 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.

207. The method of claim 206, wherein the antibody binds to at least one of, or at least both of residues 62 and 63 of SEQ ID NO:

701.

208. The method of claim 206, wherein the antibody binds to at least residue 62 of SEQ ID NO:

701.

209. The method of claim 206, wherein the antibody binds to at least residue 63 of SEQ ID NO:

701.

210. The method of claim 206, 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 the amino acid substitution G63A.

211. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human GITR, wherein the antibody comprises:

(a) a heavy chain variable region (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence of X₁YX₂MX₃ (SEQ ID NO;

     1), wherein

X₁ is D, E, G or A;

X₂ is A, V, L, I, P, F, M or Y; and

X₃ is Y, G, N, Q, S, T, C, W, F or H;

(b) a VH CDR2 comprising the amino acid sequence of X₁IX₂X₃X₄SGX₅X₆X₇YX₈QKFX₉X₁₀ (SEQ ID NO;

     2), wherein

X₁ is V, A, L, I, P, F, M or T;

X₂ is R, K, H, Q or A;

X₃ is T, G, N, Q, S, C, W, Y, V, I or P;

X₄ is Y, G, N, Q, S, T, C, W, F, H, or A;

X₅ is D, E, G or A;

X₆ is V, A, L, I, P, F, M or T;

X₇ is T, G, N, Q, S, C, W, Y, V, I, P or A;

X₈ is N, G, Q, S, T, C, W, Y or A;

X₉ is K, R, H, Q or A; and

X₁₀ is D, E, G or A;

(c) a VH CDR3 comprising the amino acid sequence of SGTVRGX₁X₂X₃ (SEQ ID NO;

     3), wherein

X₁ is F, A, V, L, I, P, M, Y, W, H or S;

X₂ is A, or D; and

X₃ is Y, G, N, Q, S, T, C, W, F, H or V;

(d) a light chain variable region (VL) CDR1 comprising the amino acid sequence of KSSQSX₁X₂X₃X₄X₅X₆X₇KX₈YLX₉ (SEQ ID NO;

     4), wherein;

X₁ is L, A, V, I, P, F or M;

X₂ is L, A, V, I, P, F, M or 5;

X₃ is N, G, Q, S, T, C, W, Y or A;

X₄ is S, G, N, Q, T, C, W, Y or A;

X₅ is G, N, Q, S, T, C, W, Y or A;

X₆ is N, G, Q, S, T, C, W, Y or A;

X₇ is Q, G, N, S, T, C, W, Y or A;

X₈ is N, G, Q, S, T, C, W, Y or A; and

X₉ is T, G, N, Q, S, C, W, Y, V, I or A;

(e) a VL CDR2 comprising the amino acid sequence of X₁ASTRX₂X₃ (SEQ ID NO;

     5), wherein;

X₁ is W, G, N, Q, S, T, C, Y, F, H or A;

X₂ is E, D or A; and

X₃ is S, G, N, Q, T, C, W, Y or A; and

(f) a VL CDR3 comprising the amino acid sequence of QX₁X₂YX₃X₄PYT (SEQ ID NO;

     6), wherein;

X₁ is N, G, Q, S, T, C, W or Y;

X₂ is D, E or Y; and

X₃ 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.

212. The method of claim 211, wherein:

(a) the VH CDR1 comprises the amino acid sequence of X₁YX₂MX₃ (SEQ ID NO;

     7), wherein

X₁ is D, E or G;

X₂ is A or V; and

X₃ is Y or H;

(b) the VH CDR2 comprises the amino acid sequence of X₁IX₂TX₃SGX₄X₅X₆YNQKFX₇X₈ (SEQ ID NO;

     8), wherein

X₁ is V or L;

X₂ is R, K or Q;

X₃ is Y or F;

X₄ is D, E or G;

X₅ is V or L;

X₆ is T or S;

X₇ is K, R or Q; and

X₈ is D, E or G;

(c) the VH CDR3 comprises the amino acid sequence of SGTVRGFAY (SEQ ID NO;

     9);

(d) the VL CDR1 comprises the amino acid sequence of KSSQSLLNSX₁NQKNYLX₂ (SEQ ID NO;

     10), wherein

X₁ is G or S; and

X₂ is T or 5;

(e) the VL CDR2 comprises the amino acid sequence of WASTRES (SEQ ID NO;

     11); and

(f) the VL CDR3 comprises the amino acid sequence of QNX₁YSX₂PYT (SEQ ID NO;

     12), wherein

X₁ is D or E; and

X₂ is Y, F or S.

213. The method of claim 211, wherein

(a) the VH CDR1 comprises the amino acid sequence of DYAMY (SEQ ID NO:

13),

(b) the VH CDR2 comprises the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO;

     14), and

(c) the VH CDR3 comprises the amino acid sequence of SGTVRGFAY (SEQ ID NO;

     15);

(d) the VL CDR1 comprises the amino acid sequence of KSSQSLLNSGNQKNYLT (SEQ ID NO;

     16),

(e) the VL CDR2 comprises the amino acid sequence of WASTRES (SEQ ID NO;

     17), and

(f) the VL CDR3 comprises the amino acid sequence of QNDYSYPYT (SEQ ID NO;

     18).

214. The method of claim 213, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:

206.

215. The method of claim 213, wherein the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:

208.

216. The method of claim 213, wherein the antibody comprises:

(a) a VH comprising the amino acid sequence of SEQ ID NO;

206; and

(b) a VL comprising the amino acid sequence of SEQ ID NO;

208.

217. The method of claim 213, wherein the antibody comprises:

(a) a VH consisting of the amino acid sequence of SEQ ID NO;

206; and

(b) a VL consisting of the amino acid sequence of SEQ ID NO;

208.

218. The method of claim 213, wherein the antibody 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.

219. The method of claim 213, wherein the antibody comprises:

(a) a heavy chain consisting of the amino acid sequence of SEQ ID NO;

567; and

(b) a light chain consisting of the amino acid sequence of SEQ ID NO;

576.

224. The method of claim 216, wherein the antibody further comprises a human immunoglobulin IgG₁ heavy chain constant region.

225. The method of claim 216, wherein the antibody further comprises a human immunoglobulin IgG kappa light chain constant region.

226. The method of claim 216, wherein the antibody further comprises a human immunoglobulin IgG₁ heavy chain constant region and a human immunoglobulin IgG kappa light chain constant region.

227. The method of claim 216, wherein the antibody binds to the same epitope of human GITR as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:

206 and a VL comprising the amino acid sequence of SEQ ID NO;

208.

228. The method of claim 213, wherein the antibody is produced by culturing a host cell comprising a nucleic acid molecule encoding the amino acid sequence of SEQ ID NO:

206 so that the nucleic acid molecule is expressed and the antibody is produced.

229. The method of claim 228, wherein the host cell further comprises a nucleic acid molecule encoding the amino acid sequence of SEQ ID NO:

576.

230. The method of claim 213, wherein the antibody is produced by culturing a host cell comprising a nucleic acid molecule encoding the amino acid sequence of SEQ ID NO:

576 so that the nucleic acid molecule is expressed and the antibody is produced.

231. The method of claim 213, wherein the antibody is produced by culturing a host cell comprising a first nucleic acid molecule encoding the amino acid sequence of SEQ ID NO:

206 and a second nucleic acid molecule encoding the amino acid sequence of SEQ ID NO;

208 so that the first nucleic acid molecule and the second nucleic acid molecule are expressed and the antibody is produced.

232. The method of claim 231, wherein the host cell is a CHO cell.

233. The method of claim 211, further comprising administering to the subject an inhibitor of indoleamine-2,3-dioxygenase (IDO).

234. The method of claim 233, wherein the inhibitor is selected from the group consisting of epacadostat, F001287, indoximod, and NLG919.

235. The method of claim 211, further comprising administering an anti-PD-1 antibody or an anti-OX40 antibody to the subject who has received the antibody that specifically binds to human GITR;

wherein the anti-PD-1 antibody or the anti-OX40 antibody is administered at a time at which the anti-GITR antibody has increased expression of PD-1 or OX40 in the subject relative to expression of PD-1 or OX40 in the subject at the time of the administering.

236. A method of treating cancer in a subject, the method comprising the steps of:

(a) incubating T cells ex vivo with an antibody of claim 211; and

(b) infusing the T cells into the subject.

220. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human GITR, wherein the antibody comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:

206.

221. The method of claim 220, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:

576.

222. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human GITR, wherein the antibody comprises a VH and a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO:

208.

223. The method of claim 222, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

567.