ANTI-CD137 ANTIBODIES AND METHODS OF USE
Provided are antigen-binding fragments thereof that bind to human CD137, multispecific antibodies that recognize CD137 as one antigen and at least one other antigen, a pharmaceutical composition comprising CD137 antibodies, and use of the antibody, multispecific antibody or the composition for treating a disease, such as cancer.
1 . An antibody or antigen-binding fragment thereof that specifically binds human CD137, the antibody or antigen-binding fragment thereof comprising:
(i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 14, (b) a HCDR2 of SEQ ID NO: 29, and (c) a HCDR3 of SEQ ID NO: 30;
(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 14, (b) a HCDR2 of SEQ ID NO: 22, and (c) a HCDR3 of SEQ ID NO: 16;
(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:14, (b) a HCDR2 of SEQ ID NO: 15, and (c) a HCDR3 of SEQ ID NO: 16; or
(iv) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 4, (b) a HCDR2 of SEQ ID NO: 5, and (c) a HCDR3 of SEQ ID NO: 6.
2 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
(i) a heavy chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33;
(ii) a heavy chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24;
(iii) a heavy chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19;
(iv) a heavy chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 9; or
(v) a heavy chain variable region comprising an amino acid sequence at least 90 99% identical to SEQ ID NO: 103.
3 . The antibody or antigen-binding fragment thereof of claim 2 , wherein one, two, three, four, five, six, seven, eight, nine, or ten amino acids within SEQ ID NO:33, 24, 19, 9, or 103 have been inserted, deleted or substituted.
4 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
(i) a heavy chain variable region comprising SEQ ID NO: 33;
(ii) a heavy chain variable region comprising SEQ ID NO: 24;
(iii) a heavy chain variable region comprising SEQ ID NO: 19;
(iv) a heavy chain variable region comprising SEQ ID NO: 9; or
(v) a heavy chain variable region comprising SEQ ID NO: 103.
5 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is a heavy chain (scFv), a heavy chain Fab fragment, a heavy chain Fab′ fragment, or a heavy chain F(ab′) 2 fragment.
6 . A multispecific antibody comprising at least a first antigen binding domain that specifically binds human CD137, wherein the first antigen binding domain comprises:
(i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 14, (b) a HCDR2 of SEQ ID NO: 29, and (c) a HCDR3 of SEQ ID NO: 30;
(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 14, (b) a HCDR2 of SEQ ID NO: 22, and (c) a HCDR3 of SEQ ID NO: 16;
(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:14, (b) a HCDR2 of SEQ ID NO: 15, and (c) a HCDR3 of SEQ ID NO: 16; or
(vi) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:4, (b) a HCDR2 of SEQ ID NO: 5, and (c) a HCDR3 of SEQ ID NO: 6,
and at least a second antigen binding domain that specifically binds a human tumor-associated antigen (TAA).
7 . The multispecific antibody of claim 6 , wherein the first antigen binding domain comprises:
(i) a heavy chain variable region comprising SEQ ID NO: 33;
(ii) a heavy chain variable region comprising SEQ ID NO: 24;
(iii) a heavy chain variable region comprising SEQ ID NO: 19;
(iv) a heavy chain variable region comprising SEQ ID NO: 9; or
(iv) a heavy chain variable region comprising SEQ ID NO: 103.
8 . The multispecific antibody of claim 7 , wherein the multispecific antibody is a bispecific antibody.
9 . The multispecific antibody of claim 8 , wherein the bispecific antibody is in the 1+1 format, 1+2 format, or 2+2 format.
10 .- 12 . (canceled)
13 . The multispecific antibody of claim 8 , further comprising a linker, wherein the linker is any sequence of SEQ ID NO:239 to SEQ ID NO:280.
14 . The multispecific antibody of claim 13 , wherein the linker is SEQ ID NO: 246 or SEQ ID NO: 251.
15 . (canceled)
16 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof has one or more of the following: antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), reduced glycosylation, no glycosylation, hypofucosylation, or increased bisecting GlcNac structures.
17 .- 18 . (canceled)
19 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the Fc domain is an IgG1.
20 . The antibody or antigen-binding fragment thereof of claim 19 , wherein the IgG1 has reduced ADCC.
21 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
22 . A method of treating cancer comprising administering to a patient in need an effective amount of the antibody or antigen-binding fragment thereof of claim 1 .
23 .- 26 . (canceled)
27 . An isolated nucleic acid that encodes the antibody or antigen-binding fragment thereof of claim 1 .
28 . A vector comprising the nucleic acid of claim 27 .
29 . A host cell comprising the nucleic acid of claim 27 .
30 . A process for producing an antibody or antigen-binding fragment thereof comprising cultivating the host cell of claim 29 and recovering the antibody or antigen-binding fragment thereof from the culture.