ANTI-CD3 MULTISPECIFIC ANTIBODIES AND METHODS OF USE
The present disclosure provides for antibodies and antigen-binding fragments thereof that bind to human CD3, a pharmaceutical composition comprising said antibody or antigen-binding fragments thereof, and use of the antibody or antigen-binding fragments thereof or the composition for treating a disease, such as cancer.
1 . An antibody or antigen-binding fragment thereof, comprising an antigen binding domain that specifically binds to human cluster of differentiation 3 (CD3).
2 . The antibody or antigen-binding fragment of claim 1 , wherein the antigen binding domain that specifically binds to human CD3 comprises:
(a) a heavy chain variable region that comprises (i) a heavy chain complementarity determining region (HCDR)1 having an amino acid sequence of SEQ ID NO: 48, (ii) a HCDR2 having an amino acid sequence of SEQ ID NO: 71, (iii) a HCDR3 having an amino acid sequence of SEQ ID NO: 75, and a light chain variable region that comprises: (iv) a light chain complementarity-determining region (LCDR)1 having an amino acid sequence of SEQ ID NO: 51, (v) a LCDR2 having an amino acid sequence of SEQ ID NO: 52, and (vi) a LCDR3 having an amino acid sequence of SEQ ID NO: 53; or
(b) a heavy chain variable region that comprises (i) a HCDR1 having an amino acid sequence of SEQ ID NO: 48, (ii) a HCDR2 having an amino acid sequence of SEQ ID NO: 71, (iii) a HCDR3 having an amino acid sequence of SEQ ID NO: 50, and a light chain variable region that comprises: (iv) a LCDR1 having an amino acid sequence of SEQ ID NO: 51, (v) a LCDR2 having an amino acid sequence of SEQ ID NO: 52, and (vi) a LCDR3 having an amino acid sequence of SEQ ID NO: 53.
3 . The antibody or antigen-binding fragment of claim 1 , wherein the antigen binding domain comprises:
(i) a heavy chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 76, and a light chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 68;
(ii) a heavy chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 58, and a light chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 59;
(iii) a heavy chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 62, and a light chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 63;
(iv) a heavy chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 62, and a light chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 68; or
(v) a heavy chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 72, and a light chain variable region having an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 68.
4 . The antibody or antigen-binding fragment of claim 3 , wherein one, two, three, four, five, six, seven, eight, nine, or ten amino acids of SEQ ID NOS: 62, 63, 68, 72 or 76 have been inserted, deleted or substituted.
5 . The antibody or antigen-binding fragment of claim 1 , wherein the antigen binding domain comprises:
(i) a heavy chain variable region having an amino acid sequence that comprises SEQ ID NO: 76, and a light chain variable region having an amino acid sequence that comprises SEQ ID NO: 68;
(ii) a heavy chain variable region having an amino acid sequence that comprises SEQ ID NO: 58, and a light chain variable region having an amino acid sequence that comprises SEQ ID NO: 59;
(iii) a heavy chain variable region having an amino acid sequence that comprises SEQ ID NO: 62, and a light chain variable region having an amino acid sequence that comprises SEQ ID NO: 63;
(iv) a heavy chain variable region having an amino acid sequence that comprises SEQ ID NO: 62, and a light chain variable region having an amino acid sequence that comprises SEQ ID NO: 68; or
(v) a heavy chain variable region having an amino acid sequence that comprises SEQ ID NO: 72, and a light chain variable region (VL) that comprises SEQ ID NO: 68.
6 . The antibody or antigen-binding fragment of claim 1 , the antigen binding domain comprises:
(i) a single chain variable fragment (scFv) having an amino acid sequence that comprises SEQ ID NO: 77;
(ii) a single chain variable fragment (scFv) having an amino acid sequence that comprises SEQ ID NO: 66;
(iii) a single chain variable fragment (scFv) having an amino acid sequence that comprises SEQ ID NO: 69; or
(iv) a single chain variable fragment (scFv) having an amino acid sequence that comprises SEQ ID NO: 73.
7 . The antibody or antigen-binding fragment of claim 1 , which is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, or a multi-specific antibody.
8 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is a bispecific antibody.
9 . (canceled)
10 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof has antibody dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).
11 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof has reduced glycosylation or no glycosylation or is hypofucosylated.
12 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises increased bisecting GlcNac structures.
13 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises a Fc domain that is an IgG1 with reduced effector function.
14 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises a Fc domain that is an IgG4.
15 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.
16 . The pharmaceutical composition of claim 15 , further comprising a histidine/histidine HCl, a trehalose dihydrate, and/or a polysorbate 20.
17 . A method of treating cancer comprising administering to a patient in need an effective amount of the antibody or antigen-binding fragment of claim 1 .
18 - 24 . (canceled)
25 . An isolated nucleic acid that encodes the antibody or antigen-binding fragment of claim 1 .
26 . A vector comprising the nucleic acid of claim 25 .
27 . A host cell comprising the vector of claim 26 .
28 . A process for producing an antibody or antigen-binding fragment thereof comprising cultivating the host cell of claim 27 in culture and recovering the antibody or antigen-binding fragment from the culture.
29 - 31 . (canceled)