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. A nucleic acid molecule encoding the heavy chain variable (VH) region amino acid sequence and the light chain variable (VL) region amino acid sequence of an anti-PD1 antibody or an antigen-binding portion thereof, 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 nucleic acid molecule 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 nucleic acid molecule of claim 1 , wherein the antibody or antigen-binding portion is humanized or chimeric.
4. The nucleic acid molecule 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 nucleic acid molecule 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 nucleic acid molecule 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 nucleic acid molecule 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 nucleic acid molecule of claim 1 , wherein the nucleic acid molecule further encodes an immunoglobulin constant region.
9. The nucleic acid molecule of claim 8 , wherein the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY.
10. The nucleic acid molecule of claim 9 , wherein the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2.
11. The nucleic acid molecule of claim 8 , wherein the immunoglobulin constant region is immunologically inert.
12. The nucleic acid molecule 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.
13. The nucleic acid molecule of claim 8 , wherein the immunoglobulin constant region comprises any one of SEQ ID NOS:13-19.
14. The nucleic acid molecule 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 a diabody, a triabody, a tetrabody, or a bis-scFv.
15. An expression vector comprising the nucleic acid molecule of claim 1 .
16. A recombinant host cell comprising the expression vector of claim 15 .
17. A recombinant host cell comprising the nucleic acid molecule of claim 1 .