PD1 binding agents
Provided herein are antibody molecules that bind specifically to Programmed cell death 1 (PD1) and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.
1. An anti-PD1 antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein
(a) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGSEKYYVDSVKG (SEQ ID NO: 39) and HCDR3 of QLYGFDY (SEQ ID NO: 40); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQS (SEQ ID NO: 42) and LCDR3 of QQSYSTPWT (SEQ ID NO: 43);
(b) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGSEKYYVDSVKG (SEQ ID NO: 39) and HCDR3 of QVYYFDY (SEQ ID NO: 44); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQS (SEQ ID NO: 42) and LCDR3 of QQSYSTPWT (SEQ ID NO: 43);
(c) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGSEKYYVDSVKG (SEQ ID NO: 39) and HCDR3 of QLYFFDY (SEQ ID NO: 45); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQS (SEQ ID NO: 42) and LCDR3 of QQSYSTPWT (SEQ ID NO: 43);
(d) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGSEKYYVDSVKG (SEQ ID NO: 39) and HCDR3 of QLYAFDY (SEQ ID NO: 46); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQS (SEQ ID NO: 42) and LCDR3 of QQSYSTPWT (SEQ ID NO: 43);
(e) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGSETYYVDSVKG (SEQ ID NO: 48) and HCDR3 of QLYGFDY (SEQ ID NO: 40); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQS (SEQ ID NO: 42) and LCDR3 of QQSYSIPWT (SEQ ID NO: 47); or
(f) the VH region amino acid sequence comprises HCDR1 of GFTFSSYLMS (SEQ ID NO: 38), HCDR2 of VATISGGGAEKYYVDSVKG (SEQ ID NO: 49) and HCDR3 of QLYGFDY (SEQ ID NO: 40); and the VL region amino acid sequence comprises LCDR1 of RASQSISSWLN (SEQ ID NO: 41), LCDR2 of AASSLQD (SEQ ID NO: 50) and LCDR3 of QQSYSTPWT (SEQ ID NO: 43).
2. The antibody or antigen-binding portion of claim 1 , wherein
(a) the VH region amino acid sequence comprises SEQ ID NO:1 and the VL region amino acid sequence comprises SEQ ID NO:2;
(b) the VH region amino acid sequence comprises SEQ ID NO:3 and the VL region amino acid sequence comprises SEQ ID NO:4;
(c) the VH region amino acid sequence comprises SEQ ID NO:5 and the VL region amino acid sequence comprises SEQ ID NO:6;
(d) the VH region amino acid sequence comprises SEQ ID NO:7 and the VL region amino acid sequence comprises SEQ ID NO:8;
(e) the VH region amino acid sequence comprises SEQ ID NO:9 and the VL region amino acid sequence comprises SEQ ID NO:10; or
(f) the VH region amino acid sequence comprises SEQ ID NO:11 and the VL region amino acid sequence comprises SEQ ID NO:12.
3. The antibody or antigen-binding portion of claim 1 , wherein the antibody is humanized or chimeric.
4. The antibody or antigen-binding portion of claim 1 , wherein the VH region, the VL region, or both the VH and the VL region comprise one or more human framework region amino acid sequences.
5. The antibody or antigen-binding portion of claim 1 , wherein the VH region, the VL region, or both the VH and the VL region comprise a human variable region framework scaffold amino acid sequence into which the CDRs have been inserted.
6. The antibody or antigen-binding portion of claim 1 , wherein the VH region comprises an IGHV3-7 human germline scaffold amino acid sequence into which the HCDR1, HCDR2 and HCDR3 amino acid sequences have been inserted.
7. The antibody or antigen-binding portion of claim 1 , wherein the VL region comprises an IGKV1-39 human germline scaffold amino acid sequence into which the LCDR1, LCDR2 and LCDR3 amino acid sequences have been inserted.
8. The antibody or antigen-binding portion of claim 1 , wherein the antibody comprises an immunoglobulin constant region.
9. The antibody or antigen-binding portion of claim 8 , wherein the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY.
10. The antibody or antigen-binding portion of claim 9 , wherein the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2.
11. The antibody or antigen-binding portion of claim 8 , wherein the immunoglobulin constant region is immunologically inert.
12. The antibody or antigen-binding portion of claim 11 , wherein the immunoglobulin constant region comprises any one of SEQ ID NOS: 13-19.
13. The antibody or antigen-binding portion of claim 8 , wherein the immunoglobulin constant region is a wild-type human IgG4 constant region, a human IgG4 constant region comprising the amino acid substitution S228P, a wild-type human IgG1 constant region, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A and G237A or a wild-type human IgG2 constant region wherein numbering is according to the EU index as in Kabat.
14. The antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is an Fab, an Fab′, an F(ab′) 2 , an Fv, an scFv, a maxibody, a minibody, an intrabody, a diabody, a triabody, a tetrabody, or a bis-scFv.
15. The antibody or antigen-binding portion of claim 1 , wherein the antibody is monoclonal.
16. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion binds specifically to (a) human PD1 or (b) human PD1 and cynomolgus PD1.
17. An immunoconjugate comprising the antibody or antigen-binding portion of claim 1 linked to a therapeutic agent.
18. The immunoconjugate of claim 17 , wherein the therapeutic agent is a cytotoxin, a radioisotope, a chemotherapeutic agent, an immunomodulatory agent, an anti-angiogenic agent, an antiproliferative agent, a pro-apoptotic agent, a cytostatic enzyme, a cytolytic enzymes, a therapeutic nucleic acid, an anti-angiogenic agent, an anti-proliferative agent, or a pro-apoptotic agent.
19. A pharmaceutical composition comprising the immunoconjugate of claim 17 and a pharmaceutically acceptable carrier, diluent or excipient.
20. A pharmaceutical composition comprising the antibody or antigen-binding portion of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.