Anti-PD1 antibodies and their use as therapeutics and diagnostics
Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) and inhibit PD1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD1-mediated functions.
1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody which binds human PD-1, wherein the IgG Fc region of the antibody is a human IgG4 Fc region containing at least three mutations, at positions 228, 234, and 235; wherein the antibody has reduced binding to an Fcγ receptor relative to Fc binding of a reference IgG4 antibody having a mutation at position 228 and no other Fc region mutation, wherein the antibody exhibits anti-tumor activity, and wherein the numbering of the residues in the IgG4 Fc region is that of the EU numbering system.
2. The method of claim 1 , wherein the antibody exhibits reduced effector function relative to the reference IgG4 antibody.
3. The method of claim 2 , wherein the reduced effector function is antibody-dependent cell-mediated cytotoxicity (ADCC).
4. The method of claim 1 , wherein the Fcγ receptor is selected from FcγRI, FcγRIIA, FcγRIIB, and FcγRIIIA.
5. The method of claim 1 , wherein the binding of the IgG4 Fc region of the antibody containing the at least three amino acid mutations to one or more Fcγ receptors is reduced to null.
6. The method of claim 1 , wherein the IgG4 Fc region comprises at least one additional mutation at a position selected from the group consisting of 233, 265, 309, and 409, or a combination thereof.
7. The method of claim 6 , wherein the IgG4 Fc region comprises amino acid mutations selected from the group consisting of S228P, E233P, F234V, L235A, D265A, L309V, and R409K, or a combination thereof.
8. The method of claim 1 , wherein the IgG4 Fc region containing the amino acid mutation comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, or SEQ ID NO: 88.
9. The method of claim 1 , wherein the cancer is selected from lung cancer, liver cancer, stomach cancer, breast cancer, ovarian cancer, pancreatic cancer, esophageal cancer, and melanoma.
10. The method of claim 1 , wherein the administration of the antibody inhibits tumor progression in the subject.
11. The method of claim 1 , wherein the administration of the antibody suppresses PD-1 mediated signal transduction.