US 2020/0399385 A1 · ANTIBODIES AGAINST OX-40 AND USES THEREOF

Antibodies against ox-40 and uses thereof

AssigneeBristol-Myers Squibb Company

InventorsZhehong CAI, Indrani CHAKRABORTY, Marie-Michelle Navarro GARCIA, Thomas D. KEMPE, Alan J. KORMAN, Alexander T. KOZHICH, Hadia LEMAR, Mark MAURER, Christina Maria MILBURN, Michael QUIGLEY, Xiang SHAO, Mohan SRINIVASAN, Kent THUDIUM, Susan Chien-Szu WONG, Jochem GOKEMEIJER, Xi-Tao WANG, Han CHANG, Patrick GUIRNALDA

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Abstract

Provided herein are antibodies, or antigen binding portions thereof, that bind to OX40. Also provided are uses of these proteins in therapeutic applications, such as in the treatment of cancer. Further provided are cells that produce the antibodies, polynucleotides encoding the heavy and/or light chain variable region of the antibodies, and vectors comprising the polynucleotides encoding the heavy and/or light chain variable region of the antibodies.

Claims22

Dependent claims

1-20. (canceled)

A method of stimulating an antigen-specific T cell response comprising contacting an antigen-specific T cell with an isolated antibody that binds to human OX40 (“anti-OX40 antibody”), such that an antigen-specific T cell response is stimulated, and wherein the anti-OX40 antibody comprises:

(a) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
317, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92;
(b) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
11, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
12, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
13, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
14, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
15, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
16;
(c) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
22, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
23, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
24;
(d) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
25, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
26, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
27;
(e) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
31, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
32, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
33, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
34, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
35, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
36;
(f) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
42, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
43, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
44;
(g) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
45, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
46, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
47;
(h) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
51, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
52, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
53, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
54, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
55, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
56;
(i) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
59, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
60, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
61, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
62, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
63, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
64;
(j) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
67, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
68, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
69, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
70, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
71, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
72;
(k) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
78, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
79, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
80, wherein, optionally, the Asp-Gly sequence in SEQ ID NO:
76 is replaced with an amino acid sequence that does not under isomerization;
(l) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
81, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
82, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
83;
or
(m) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
88, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92.

90 more elements

A method of reducing or depleting the number of T regulatory cells in a tumor of a subject in need thereof comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to human OX40 (“anti-OX40 antibody”), such that the number of T regulatory cells is reduced or depleted, and wherein the anti-OX40 antibody comprises:

(a) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
317, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92;
(b) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
11, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
12, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
13, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
14, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
15, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
16;
(c) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
22, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
23, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
24;
(d) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
25, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
26, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
27;
(e) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
31, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
32, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
33, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
34, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
35, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
36;
(f) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
42, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
43, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
44;
(g) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
45, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
46, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
47;
(h) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
51, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
52, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
53, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
54, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
55, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
56;
(i) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
59, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
60, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
61, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
62, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
63, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
64;
(j) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
67, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
68, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
69, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
70, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
71, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
72;
(k) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
78, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
79, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
80, wherein, optionally, the Asp-Gly sequence in SEQ ID NO:
76 is replaced with an amino acid sequence that does not under isomerization;
(l) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
81, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
82, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
83;
or
(m) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
88, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92.

90 more elements

A method of inhibiting the growth of tumor cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to human OX40 (“anti-OX40 antibody”), such that the growth of tumor cells is inhibited, and wherein the anti-OX40 antibody comprises:

(a) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
317, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92;
(b) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
11, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
12, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
13, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
14, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
15, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
16;
(c) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
22, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
23, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
24;
(d) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
19, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
20, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
21, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
25, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
26, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
27;
(e) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
31, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
32, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
33, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
34, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
35, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
36;
(f) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
42, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
43, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
44;
(g) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
39, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
40, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
41, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
45, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
46, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
47;
(h) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
51, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
52, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
53, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
54, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
55, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
56;
(i) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
59, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
60, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
61, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
62, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
63, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
64;
(j) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
67, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
68, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
69, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
70, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
71, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
72;
(k) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
78, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
79, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
80, wherein, optionally, the Asp-Gly sequence in SEQ ID NO:
76 is replaced with an amino acid sequence that does not under isomerization;
(l) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
75, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
76, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
77, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
81, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
82, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
83;
or
(m) a heavy chain variable region CDR1 comprising the sequence of SEQ ID NO:
87, a heavy chain variable region CDR2 comprising the sequence of SEQ ID NO:
88, and a heavy chain variable region CDR3 comprising the sequence of SEQ ID NO:
89, and a light chain variable region CDR1 comprising the sequence of SEQ ID NO:
90, a light chain variable region CDR2 comprising the sequence of SEQ ID NO:
91, and a light chain variable region CDR3 comprising the sequence of SEQ ID NO:
92.

90 more elements

Dependencies are inferred from the claim text.