Anti-GITR Antibodies and Methods of Use Thereof

• US 20150368349A1
• Filed: 05/28/2015
• Published: 12/24/2015
• 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: 4-Antibody AG
• Inventors: Underwood, Dennis J., Ritter, Gerd, GONZALEZ, Ana M., Wilson, Nicholas S., Seibert, Volker, Lger, Olivier, van Dijk, Marc, Zappasodi, Roberta, Merghoub, Taha, Wolchok, Jedd David, Schaer, David, Tsuji, Takemasa
• Granted Patent: US 10,155,818 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/464417 Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
• 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
• 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. (canceled)

2. An isolated antibody that specifically binds to human GITR, comprising:

(a) a heavy chain variable region (VH) CDR1 comprising 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) a VH CDR2 comprising 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) a VH CDR3 comprising the amino acid sequence of SGTVRGFAY (SEQ ID NO;

     9);

(d) a light chain variable region (VL) CDR1 comprising the amino acid sequence of KSSQSLLNSX₁NQKNYLX₂ (SEQ ID NO;

     10), wherein

X₁ is G or S; and

X₂ is T or S;

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

     11); and

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

     12), wherein

X₁ is D or E; and

X₂ is Y, F or S.

15. The antibody of claim 2, comprising:

(a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of DYAMY (SEQ ID NO;

     13),

a VH CDR2 comprising the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO;

     14), and

a VH CDR3 comprising the amino acid sequence of SGTVRGFAY (SEQ ID NO;

     15); and

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

     16),

a VL CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO;

     17), and

a VL CDR3 comprising the amino acid sequence of QNDYSYPYT (SEQ ID NO;

     18).

22. The antibody of claim 2, wherein the antibody specifically binds to human GITR and partially inhibits human GITR ligand (GITRL) from binding to human GITR.

56. The antibody of claim 2, 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.

57. The antibody of claim 2, 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;

208.

60. The antibody of claim 2, 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.

61. The antibody of claim 2, 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 400-519.

68. The antibody of claim 2, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL amino acid sequences comprise the amino acid sequence listed in a single row of FIG. 23 or any one of FIGS. 24A-24C.

69. The antibody of claim 2, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL amino acid sequences comprise the amino acid sequence listed in a single row of Table 17.

89. The antibody of claim 2, 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.

90. The antibody of claim 2, wherein the antibody 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.

94. An isolated antibody that binds to the same epitope of human GITR as the antibody of claim 2.

112. An isolated antibody that competes with the antibody of claim 2 for binding to human GITR to the extent that the antibody of claim 2 self-competes for binding to human GITR.

128. An isolated 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 the antibody of claim 2.

131. An isolated vector comprising the nucleic acid molecule of claim 128.

135. An isolated antibody that specifically binds to human GITR and is encoded by the isolated nucleic acid molecule of claim 128.

136. A pharmaceutical composition comprising the antibody of claim 2 and a pharmaceutically acceptable carrier or excipient.

138. A method of modulating an immune response in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 2.

140. A method for enhancing the expansion of T cells and T cell effector function in a subject, comprising administering to the subject an effective amount of the antibody of claim 2.

142. 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 of claim 136.

143. A method for inducing, activating or enhancing an activity of NF-κ

B independent of TCR triggering in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 136.

144. 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 of claim 136.

145. A method for increasing surface expression of OX40, PD-1, or a combination thereof, in activated T cells in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 136.

146. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 2.

149. The method of claim 146, further comprising administering to the subject an inhibitor of indoleamine-2,3-dioxygenase (IDO).

150. The method of claim 149, wherein the inhibitor is selected from the group consisting of epacadostat, F001287, indoximod, and NLG919.

155. A method of treating a viral infection in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 2.

174. A method of treating cancer or a viral infection in a first subject, the method comprising the steps of:

(a) incubating T cells ex vivo with the antibody of claim 2; and

(b) infusing the T cells into the first subject.

182. An ex vivo method for enhancing the expansion of T cells and T cell effector function, comprising incubating ex vivo T cells with the antibody of claim 2.

186. A method for enhancing the stimulation of T cells, comprising incubating ex vivo T cells, which have been stimulated with a TCR complex stimulating agent, with the antibody of claim 2.

187. A method for activating T cells, comprising incubating ex vivo T cells with a TCR complex stimulating agent and the antibody of claim 2.

193. A method for preferential expansion of effector T-cells over the expansion of T-regulatory cells in a subject, comprising administering to the subject an effective amount of the antibody of claim 2.

203. The antibody of claim 2, wherein said antibody is capable of inducing, activating, or enhancing an activity of GITR in a cell in the absence of TCR triggering.

204. The antibody of claim 2, wherein said antibody is capable of inducing, activating, or enhancing an activity of NF-κ

B in a cell in the absence of TCR triggering.

3-14. -14. (canceled)

16. An isolated antibody that specifically binds to human GITR, comprising the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 of antibody 22 as set forth in Table 1 and Table 2.

17-21. -21. (canceled)

23-55. -55. (canceled)

58. (canceled)

59. (canceled)

62-67. -67. (canceled)

70-88. -88. (canceled)

91-93. -93. (canceled)

95-104. -104. (canceled)

105. 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.

108. The antibody of claim 105, wherein the antibody binds at least one of residues 60 or 63 of SEQ ID NO:

701.

106. (canceled)

107. (canceled)

109. 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, the variant 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.

110. 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.

111. (canceled)

113-127. -127. (canceled)

129. (canceled)

130. (canceled)

132. A host cell comprising the isolated nucleic acid molecule of 128.

134. A method of producing an antibody that binds to human GITR comprising culturing the host cell of claim 132.

133. (canceled)

137. (canceled)

139. (canceled)

141. (canceled)

147. (canceled)

148. (canceled)

151-154. -154. (canceled)

156-168. -168. (canceled)

169. A method of treating cancer in a subject, the method comprising administering an anti-PD-1 antibody or an anti-OX40 antibody to a subject who has received an anti-GITR antibody, 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.

170-173. -173. (canceled)

175-181. -181. (canceled)

183-185. -185. (canceled)

188-192. -192. (canceled)

194. (canceled)

195. 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.

196-202. -202. (canceled)

205. (canceled)