IMMUNOMODULATORY AGENTS
The invention provides antibodies that specifically bind to PD-1, nucleic acid molecules encoding the same, and therapeutic compositions thereof. The agents inhibit PD-1-mediated immunosuppression and enhance cell and cytokine mediated immunity for the treatment of neoplastic and infectious diseases.
1 . An antibody or fragment thereof that binds to PD-1, which comprises a heavy chain variable domain with a CDR-1H, a CDR-2H, and a CDR-3H as set forth in Table 1.
2 . An antibody or fragment thereof that binds to PD-1, which comprises a light chain variable domain with a CDR-1L, a CDR-2L, and a CDR-3L as set forth in Table 1.
3 . The antibody or fragment of claim 1 , which comprises a light chain variable domain with a CDR-1L, a CDR-2L, and a CDR-3L as set forth in Table 1.
4 . An antibody or fragment thereof that binds to PD-1, which comprises a heavy chain variable domain sequence set forth in Table 1, or a heavy chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 80% identical to the heavy chain variable domain sequence set forth in Table 1.
5 . The antibody or fragment thereof of claim 4 , which comprises a heavy chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 85% identical to the heavy chain variable domain sequence set forth in Table 1.
6 . The antibody or fragment thereof of claim 4 , which comprises a heavy chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 90% identical to the heavy chain variable domain sequence set forth in Table 1.
7 . The antibody or fragment thereof of claim 4 , which comprises a heavy chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 95% identical to the heavy chain variable domain sequence set forth in Table 1.
8 . An antibody or fragment thereof that binds to PD-1, which comprises a light chain variable domain sequence set forth in Table 1, or a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that is at least 80% identical to the light chain variable domain sequence set forth in Table 1.
9 . The antibody or fragment thereof of claim 8 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 85% identical to the light chain variable domain sequence set forth in Table 1.
10 . The antibody or fragment thereof of claim 8 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 90% identical to the light chain variable domain sequence set forth in Table 1.
11 . The antibody or fragment thereof of claim 8 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 95% identical to the light chain variable domain sequence set forth in Table 1.
12 . The antibody or fragment of claim 4 , which comprises a light chain variable domain sequence set forth in Table 1, or a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that is at least 80% identical to the light chain variable domain sequence set forth in Table 1.
13 . The antibody or fragment thereof of claim 12 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 85% identical to the light chain variable domain sequence set forth in Table 1.
14 . The antibody or fragment thereof of claim 12 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 90% identical to the light chain variable domain sequence set forth in Table 1.
15 . The antibody or fragment thereof of claim 12 , which comprises a light chain variable domain sequence set forth in Table 1 with conservative substitutions such that it is at least 95% identical to the light chain variable domain sequence set forth in Table 1.
16 . A conjugate of the antibody or fragment of any one of claims 1 to 15 , further comprising an imaging agent, a therapeutic agent, or a cytotoxic agent.
17 . An isolated nucleic acid sequence that encodes an antibody variable domain or fragment of any one of claims 1 to 15 .
18 . A nucleic acid vector comprising the nucleic acid of claim 17 .
19 . A prokaryotic or eukaryotic host cell comprising the nucleic acid of claim 17 .
20 . A composition comprising an antibody or fragment of any one of claims 1 to 15 and a pharmaceutically acceptable carrier.
21 . A method of inhibiting the interaction of PD-1 with PD-L1 in a subject, which comprises administering an effective amount of an antibody or fragment of any one of claims 1 to 15 .
22 . A method of inhibiting immunosuppression mediated by PD-1 in a subject, which comprises administering an effective amount of the antibody or fragment of any one of claims 1 to 15 .
23 . A method of stimulating an immune response against a cell that expresses PD-1, which comprises administering to a subject an effective amount of the antibody or fragment of any one of claims 1 to 15 .
24 . The method of claim 23 , wherein the cell that expresses PD-1 is a tumor cell.
25 . The method of claim 23 , wherein the cell that expresses PD-1 is infected with a virus.